The Pharmaceutical Regulatory Process

The Pharmaceutical Regulatory Process
Copyright 2005 by Marcel Dekker
DRUGS AND THE PHARMACEUTICAL SCIENCES

Executive Editor
James Swarbrick
PharmaceuTech, Inc. Pinehurst, North Carolina
Advisory Board
Larry L. Augsburger
University of Maryland Baltimore, Maryland
Harry G. Brittain
Center for Pharmaceutical Physics Milford, New Jersey
Jennifer B. Dressman
Johann Wolfgang Goethe University Frankfurt, Germany
Anthony J. Hickey
University of North Carolina School of Pharmacy Chapel Hill, North Carolina
Jeffrey A. Hughes
University of Florida College of Pharmacy Gainesville, Florida
Ajaz Hussain
U.S. Food and Drug Administration Frederick, Maryland
Trevor M. Jones
The Association of the British Pharmaceutical Industry London, United Kingdom
Hans E. Junginger
Leiden/Amsterdam Center for Drug Research Leiden, The Netherlands
Vincent H. L. Lee
University of Southern California Los Angeles, California
Stephen G. Schulman
University of Florida Gainesville, Florida
Jerome P. Skelly
Alexandria, Virginia
Elizabeth M. Topp
University of Kansas School of Pharmacy Lawrence, Kansas
Geoffrey T. Tucker
University of Sheffield Royal Hallamshire Hospital Sheffield, United Kingdom
Peter York
University of Bradford School of Pharmacy Bradford, United Kingdom
DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs
1. Pharmacokinetics, Milo Gibaldi and Donald Perrier 2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV 3. Microencapsulation, edited by J. R. Nixon 4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and Peter Jenner 5. New Drugs: Discovery and Development, edited by Alan A. Rubin 6. Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson 7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T. Rhodes 8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz 9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney 10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and Bernard Testa 11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by James W. Munson 12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky 13. Orphan Drugs, edited by Fred E. Karch 14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts, Biomedical Assessments, Yie W. Chien 15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi and Donald Perrier 16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Second Edition, Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV 17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger 18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry 19. The Clinical Research Process in the Pharmaceutical Industry, edited by Gary M. Matoren 20. Microencapsulation and Related Drug Processes, Patrick B. Deasy 21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe and T. Colin Campbell 22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and Robert A. Nash 24. Anticancer and Interferon Agents: Synthesis and Properties, edited by Raphael M. Ottenbrite and George B. Butler 25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford Bolton 26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzinowicz 27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos 28. Solubility and Related Properties, Kenneth C. James 29. Controlled Drug Delivery: Fundamentals and Applications, Second Edition, Revised and Expanded, edited by Joseph R. Robinson and Vincent H. Lee 30. New Drug Approval Process: Clinical and Regulatory Management, edited by Richard A. Guarino 31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien 32. Drug Delivery Devices: Fundamentals and Applications, edited by Praveen Tyle 33. Pharmacokinetics: Regulatory Industrial Academic Perspectives, edited by Peter G. Welling and Francis L. S. Tse 34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato 35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives, edited by Jonathan Hadgraft and Richard H. Guy 36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by James W. McGinity 37. Pharmaceutical Pelletization Technology, edited by Isaac GhebreSellassie 38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch 39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang 40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 41. Specialized Drug Delivery Systems: Manufacturing and Production Technology, edited by Praveen Tyle 42. Topical Drug Delivery Formulations, edited by David W. Osborne and Anton H. Amann 43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications, Second Edition, Revised and Expanded, Sanford Bolton 45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark Chasin and Robert Langer 46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S. Tse and James J. Jaffe 47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong and Stanley K. Lam 48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L. S. Tse, and Shrikant V. Dinghe 49. Pharmaceutical Dissolution Testing, Umesh V. Banakar 50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded, Yie W. Chien 51. Managing the Clinical Drug Development Process, David M. Cocchetto and Ronald V. Nardi 52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Third Edition, edited by Sidney H. Willig and James R. Stoker 53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan 54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J. Hickey 55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian D. Nunn 56. New Drug Approval Process: Second Edition, Revised and Expanded, edited by Richard A. Guarino 57. Pharmaceutical Process Validation: Second Edition, Revised and Expanded, edited by Ira R. Berry and Robert A. Nash 58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra 59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A. Walters and Jonathan Hadgraft 60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck 61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited by Alain Rolland 62. Drug Permeation Enhancement: Theory and Applications, edited by Dean S. Hsieh 63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan 64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls 65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie 66. Colloidal Drug Delivery Systems, edited by Jrg Kreuter
67. Pharmacokinetics: Regulatory Industrial Academic Perspectives, Second Edition, edited by Peter G. Welling and Francis L. S. Tse 68. Drug Stability: Principles and Practices, Second Edition, Revised and Expanded, Jens T. Carstensen 69. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg 70. Physical Characterization of Pharmaceutical Solids, edited by Harry G. Brittain 71. Pharmaceutical Powder Compaction Technology, edited by Gran Alderborn and Christer Nystrm 72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 73. Microencapsulation: Methods and Industrial Applications, edited by Simon Benita 74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone 75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt and Michael Montagne 76. The Drug Development Process: Increasing Efficiency and Cost Effectiveness, edited by Peter G. Welling, Louis Lasagna, and Umesh V. Banakar 77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen and Howard Bernstein 78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sidney H. Willig and James R. Stoker 79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: Second Edition, Revised and Expanded, edited by James W. McGinity 80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition, Sanford Bolton 81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M. Parikh 82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded, edited by William R. Strohl 83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and Richard H. Guy 84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharp 85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by John A. Bontempo 86. Pharmaceutical Project Management, edited by Tony Kennedy
87. Drug Products for Clinical Trials: An International Guide to Formulation Production Quality Control, edited by Donald C. Monkhouse and Christopher T. Rhodes 88. Development and Formulation of Veterinary Dosage Forms: Second Edition, Revised and Expanded, edited by Gregory E. Hardee and J. Desmond Baggot 89. Receptor-Based Drug Design, edited by Paul Leff 90. Automation and Validation of Information in Pharmaceutical Processing, edited by Joseph F. deSpautz 91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts and Kenneth A. Walters 92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and Roger Phan-Tan-Luu 93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III 94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spectroscopy, David E. Bugay and W. Paul Findlay 95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain 96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products, edited by Louis Rey and Joan C. May 97. Percutaneous Absorption: DrugsCosmeticsMechanismsMethodology, Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and Howard I. Maibach 98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development, edited by Edith Mathiowitz, Donald E. Chickering III, and Claus-Michael Lehr 99. Protein Formulation and Delivery, edited by Eugene J. McNally 100. New Drug Approval Process: Third Edition, The Global Challenge, edited by Richard A. Guarino 101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid 102. Transport Processes in Pharmaceutical Systems, edited by Gordon L. Amidon, Ping I. Lee, and Elizabeth M. Topp 103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A. Kotkoskie 104. The Clinical Audit in Pharmaceutical Development, edited by Michael R. Hamrell 105. Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud and Gilberte Marti-Mestres 106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B. Dressman and Hans Lennerns
107. Drug Stability: Principles and Practices, Third Edition, Revised and Expanded, edited by Jens T. Carstensen and C. T. Rhodes 108. Containment in the Pharmaceutical Industry, edited by James P. Wood 109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control from Manufacturer to Consumer, Fifth Edition, Revised and Expanded, Sidney H. Willig 110. Advanced Pharmaceutical Solids, Jens T. Carstensen 111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition, Revised and Expanded, Kevin L. Williams 112. Pharmaceutical Process Engineering, Anthony J. Hickey and David Ganderton 113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer, and Rachel F. Tyndale 114. Handbook of Drug Screening, edited by Ramakrishna Seethala and Prabhavathi B. Fernandes 115. Drug Targeting Technology: Physical Chemical Biological Methods, edited by Hans Schreier 116. DrugDrug Interactions, edited by A. David Rodrigues 117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian and Anthony J. Streeter 118. Pharmaceutical Process Scale-Up, edited by Michael Levin 119. Dermatological and Transdermal Formulations, edited by Kenneth A. Walters 120. Clinical Drug Trials and Tribulations: Second Edition, Revised and Expanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III 121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 122. Surfactants and Polymers in Drug Delivery, Martin Malmsten 123. Transdermal Drug Delivery: Second Edition, Revised and Expanded, edited by Richard H. Guy and Jonathan Hadgraft 124. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg 125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity Testing: Third Edition, Revised and Expanded, Michael J. Akers, Daniel S. Larrimore, and Dana Morton Guazzo 126. Modified-Release Drug Delivery Technology, edited by Michael J. Rathbone, Jonathan Hadgraft, and Michael S. Roberts 127. Simulation for Designing Clinical Trials: A Pharmacokinetic-Pharmacodynamic Modeling Perspective, edited by Hui C. Kimko and Stephen B. Duffull
128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics, edited by Reinhard H. H. Neubert and Hans-Hermann Rttinger 129. Pharmaceutical Process Validation: An International Third Edition, Revised and Expanded, edited by Robert A. Nash and Alfred H. Wachter 130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and Expanded, edited by Ashim K. Mitra 131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and Sean M. Sullivan 132. Biomarkers in Clinical Drug Development, edited by John C. Bloom and Robert A. Dean 133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie and Charles Martin 134. Pharmaceutical Inhalation Aerosol Technology: Second Edition, Revised and Expanded, edited by Anthony J. Hickey 135. Pharmaceutical Statistics: Practical and Clinical Applications, Fourth Edition, Sanford Bolton and Charles Bon 136. Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics, edited by Carmen Medina 137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products: Second Edition, Revised and Expanded, edited by Louis Rey and Joan C. May 138. Supercritical Fluid Technology for Drug Product Development, edited by Peter York, Uday B. Kompella, and Boris Y. Shekunov 139. New Drug Approval Process: Fourth Edition, Accelerating Global Registrations, edited by Richard A. Guarino 140. Microbial Contamination Control in Parenteral Manufacturing, edited by Kevin L. Williams 141. New Drug Development: Regulatory Paradigms for Clinical Pharmacology and Biopharmaceutics, edited by Chandrahas G. Sahajwalla 142. Microbial Contamination Control in the Pharmaceutical Industry, edited by Luis Jimenez 143. Generic Drug Development: Solid Oral Dosage Forms, edited by Leon Shargel and Izzy Kanfer 144. The Pharmaceutical Regulatory Process, edited by Ira R. Berry
ADDITIONAL VOLUMES IN PREPARATION

Drug Delivery to the Oral Cavity: Molecules to Market, edited by Tapash Ghosh and William R. Pfister
The Pharmaceutical Regulatory Process

Ira R. Berry
International Regulatory Business Consultants, L.L.C., Maplewood, New Jersy, U.S.A.
Marcel Dekker
New York
Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-5464-6 This book is printed on acid-free paper. Headquarters Marcel Dekker, 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright 2005 by Marcel Dekker. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA
Preface
Welcome to the world of regulations and controls over the pharmaceutical industry. This is not necessarily a negative concept but is rather a necessary framework under which pharmaceutical products can be assured to provide safe and efficacious use. This book will trace the development and history of pharmaceutical regulations from their early beginnings to the present time. The process is never ending in that regulatory agencies such as the U.S. Food and Drug Administration (FDA), and industry, are constantly striving to improve the regulatory process through the enactment of legislation and revised regulations and guidances. The book is divided into two sections the legal basis for regulation and FDA requirements for product approvals and after. In the pharmaceutical regulatory process, there are a legal basis, government regulatory requirements, academia influence and industry perspective. The needs and bases for these groups must be directed toward the same common goal to provide safe and effective medicines. It is in this framework that the book aims to provide the reader with a basic understanding of the process by which pharmaceutical products are approved by the Food and Drug Administration for commercial sale and marketing in the United States. The book is intended to be an introduction to the regulatory requirements and procedures utilized by pharmaceutical companies to comply with these requirements. In addition, the book is intended to be a tool and source of information for the pharmaceutical industry professional who wishes more advanced training in pharmaceutical regulations.
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Preface
The first section of the book deals with chapters that discuss the legal background and history of the product approval process. A chapter on Pharmaceutical Regulation Before and After the Food, Drug, and Cosmetic Act describes the creation of FDA and the reasons for its existence to protect the consumer in sustaining a high level of public health by monitoring pharmaceutical product safety and efficacy. The next chapters deal with pharmaceutical company, or sponsor, requirements for preparing product submissions in compliance with regulatory requirements. The chapter, New Drug Approval Process: Before and After 1962 follows. The year 1962 was very significant as a turning point for regulations pertaining to the pharmaceutical industry and this chapter traces the changes in the regulatory requirements of the approval process for new drugs, or new chemical entities. Following this chapter, is the FDA Regulation of Biological Products that describes the requirements for biological products as compared to pharmaceutical chemical products. Following these are the chapters Generic Drug Approval Process: Pre-1984 History Concerning Generic Drugs and Generic Drug Approval Process: Post 1984: Hatch-Waxman Reform that describe the corresponding requirements to obtain regulatory approval of generic drugs. The chapter, Food and Drug Administration Modernization Act, addresses the efforts that have been underway to streamline the regulatory process, as expressed by Congress with a specific example applicable to antibiotic products. Product approval requirements for antibiotics followed a different pathway in earlier years and are described in the chapter FDAs Antibiotic Regulatory Scheme: Then and Now. Patent issues influence the approval process for all pharmaceutical products and are described in the next chapter, Pioneer and Generic Drugs: Balance Between Product Life Cycle Extension and Anti-Competitive Behavior. With the approval timelines associated with pharmaceutical products being as long as they are, and with efforts to shorten the approval times by providing FDA with additional resources, the next chapter focuses on The Influence of the Prescription Drug User Fee Act on the Approval Process. Pharmaceutical products are not approved by FDA without demonstration of bioavailability or bioequivalence, perhaps as part of a clinical research program, and the next chapter addresses Clinical Research Requirements for New Drug Applications.
Preface
The second section of the book addresses the FDA Requirements for Product Approvals and After. The section begins with a chapter on Active Pharmaceutical Ingredients. There are specific requirements for manufacturers of active pharmaceutical ingredients (or bulk pharmaceutical chemicals), mostly contained in Drug Master Files and expressed by Good Manufacturing Practice for APIs, in order that a drug product license application may be approved. The next chapter deals with the process for Obtaining Approval of New Drug Applications and Abbreviated New Drug Applications from a Chemistry, Manufacturing, and Controls Perspective, i.e., the requirements for a new drug product sponsor in preparing a product submission for approval. Following is a chapter describing the process of a generic drug sponsor in Obtaining Approval of a Generic Drug. A drug product license application will not be approved without consideration being given to the compliance profile and manufacturing practices followed by the listed manufacturers in the application and Current Good Manufacturing Practice and the Drug Approval Process is the chapter that follows. In preparation of a product application for approval, attention is given to anticipating any changes that may be required to the manufacturing and control process after the product application is approved. This matter is discussed in the chapter CMC Post-Approval Regulatory Affairs: Constantly Managing Change. The next chapter deals with The Influence of the USP on the Drug Approval Process. In keeping with all these requirements for product approval, it is appropriate to next consider Ways and Means to U.S. Registration of Foreign Drugs. In todays world, it is imperative to address the issues of registration of pharmaceutical products in the global marketplace and the next chapter deals with the Common Technical Document Quality (M4-Q): One Regulatory Participants Perspective. In addition, computerization is becoming more prominent in todays standards and we consider 21 CFR Part 11 Compliance and Beyond. We must consider also the methods used in promoting pharmaceutical products, which are very different today as compared to past years, and the following chapter does this, Marketing and Advertising/Promotion: The Impact of Government Regulations. The major emphasis in this book is on the process and issues relating to the approval process for registration of prescription drugs; however, we have a very important sector of the health care market devoted to over-the-counter drugs so the next
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chapter focuses on Approval and Marketing of Nonprescription or OTC Human Drugs. The totality of the book has presented a comprehensive review of the history and background for the current pharmaceutical regulatory process in the U.S., in a global environment. With the background in place, the book further describes the steps and current requirements to obtain regulatory approval. It can be used as a training tool for individuals beginning to work in regulatory affairs, compliance and quality as well as to provide a general understanding of the regulatory process to all pharmaceutical industry and regulatory agency personnel. I want to extend my personal gratitude to the contributing authors who have given their personal time to write this book and provide an education that is not attainable otherwise. Ira R. Berry
Contributors
Ann Begley U.S.A.
Kirkpatrick and Lockhart LLP, Washington, D.C.,
Barbara A. Binzak Buchanan Ingersoll Professional Corporation, Washington, D.C., U.S.A. Nicholas Buhay Maryland, U.S.A. Food and Drug Administration, Rockville, BPI Technologies, Arlington, Texas, U.S.A.
Richard L. Burcham
Edward M. Cohen Consultant in Pharmaceutical Sciences, Newtown, Connecticut, U.S.A. James N. Czaban Heller Ehrman White & McAuliff LLP, Washington, D.C., U.S.A. Loren Gelber Andrx Corporation, Davie, Florida, U.S.A. Bradley Pharmaceuticals Inc., Fairfield, New Bradley Pharmaceuticals Inc., Fairfield, New
Daniel Glassman Jersey, U.S.A. Gene Goldberg Jersey, U.S.A.
Alberto Grignolo PAREXEL International Corporation, Waltham, Massachusetts, U.S.A. Marc S. Gross Darby & Darby, P.C., New York, New York, U.S.A.
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Contributors
Jill E. Kompa PAREXEL International Corporation, Waltham, Massachusetts, U.S.A. Kristin Behrendt Kosinski New York, U.S.A. Darby & Darby, P.C., New York,
Max S. Lazar FDA Regulatory Compliance Consulting, Surprise, Arizona, U.S.A. Natasha Leskovsek Heller Ehrman White & McAuliff LLP, Washington, D.C., U.S.A. Leo J. Lucisano GlaxoSmithKline, Research Triangle Park, North Carolina, U.S.A. S. Peter Ludwig Darby & Darby, P.C., New York, New York, U.S.A. Bradley Pharmaceuticals Inc., Fairfield,
Philip W. McGinn, Jr. New Jersey, U.S.A. William J. Mead Kevin A. Miller Carolina, U.S.A.
Consultant, Rowayton, Connecticut, U.S.A. GlaxoSmithKline, Research Triangle Park, North
Patricia E. Pahl Olsson, Frank & Weeda, P.C., Washington, D.C., U.S.A. Michael P. Peskoe U.S.A. Palmer & Dodge, Boston, Massachusetts,
Robert G. Pinco Buchanan Ingersoll Professional Corporation, Washington, D.C., U.S.A. David L. Rosen Gray Washington, D.C., U.S.A. Marc J. Scheineson U.S.A. Cary Ware & Freidenrich, LLP,
Alston & Bird LLP, Washington, D.C., International Corporation,
Richard J. Schwen PAREXEL Waltham, Massachusetts, U.S.A. Dhiren N. Shah U.S.A. Atul R. Singh
Aventis Pharmaceuticals, Kansas City, Missouri,
Darby & Darby, P.C., New York, New York, U.S.A.
Contributors
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David Skarinsky PAREXEL Waltham, Massachusetts, U.S.A. John P. Swann Maryland, U.S.A. Arthur Y. Tsien U.S.A.
International
Corporation,
Food and Drug Administration, Rockville, Olsson, Frank & Weeda, P.C., Washington, D.C., Food and Drug Administration,
Ubrani V. Venkataram Rockville, Maryland, U.S.A.
Irving L. Wiesen Law Offices of Irving L. Wiesen, Esq., Stamford, Connecticut, U.S.A. Gary Yingling U.S.A. Kirkpatrick and Lockhart LLP, Washington, D.C.,
Contents
Preface Contributors 1. Pharmaceutical Regulation Before and After the Food, Drug, and Cosmetic Act John P. Swann The New Drug-Approval ProcessBefore and After 1962 Michael P. Peskoe FDA Regulation of Biological Products James N. Czaban and Natasha Leskovsek Generic Drug Approval Process: Pre-1984 History Concerning Generic Drugs David L. Rosen Generic Drug Approval Process, Post-1984: Hatch-Waxman Reform Marc S. Gross, S. Peter Ludwig Kristin Behrendt Kosinski and Atul R. Singh Food and Drug Administration Modernization Act Arthur Y. Tsien and Patricia E. Pahl FDA Antibiotic Regulatory Scheme: Then and Now Irving L. Wiesen
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47 73
3. 4.
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5.
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6. 7.
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Contents
8.
Pioneer and Generic Drugs: Balance Between Product Life Cycle Extension and Anticompetitive Behavior Robert G. Pinco and Barbara A. Binzak The Influence of the Prescription Drug User Fee Act on the Approval Process Marc J. Scheineson Clinical Research Requirements for New Drug Applications Gary Yingling and Ann Begley Active Pharmaceutical Ingredients Max S. Lazar Obtaining Approval of New Drug Applications and Abbreviated New Drug Applications from a Chemistry, Manufacturing, and Controls Perspective Dhiren N. Shah Obtaining Approval of a Generic Drug Loren Gelber Current Good Manufacturing Practice and the Drug Approval Process Nicholas Buhay CMC Post-approval Regulatory Affairs: Constantly Managing Change Leo J. Lucisano and Kevin A. Miller The Influence of the USP on the Drug Approval Process Edward M. Cohen Ways and Means to U.S. Registration of Foreign Drugs Alberto Grignolo, Jill E. Kompa, Richard J. Schwen and David Skarinsky Common Technical DocumentQuality (M4-Q): One Regulatory Participants Perspective Ubrani V. Venkataram
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10.
349 377
11. 12.
393 415
13. 14.
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15.
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18.
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Contents
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19. 20.
21 CFR Part 11 Compliance and Beyond Richard L. Burcham Marketing and Advertising/Promotion: The Impact of Government Regulations Daniel Glassman, Philip W. McGinn, Jr., and Gene Goldberg Approval and Marketing of Nonprescription or OTC Human Drugs William J. Mead
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1
Pharmaceutical Regulation Before and After the Food, Drug, and Cosmetic Act
JOHN P. SWANN Food and Drug Administration Rockville, Maryland, U.S.A.
1. INTRODUCTION: NINETEENTH-CENTURY BACKGROUND TO DRUG REGULATION IN THE UNITED STATES Federal drug regulation in nineteenth-century America was a fleeting phenomenon, limited in part by a lack of both scientific capacity and sustained political exigency. Citizens stood a better chance of being safeguarded by their own states, though the legislation and enforcement varied widely in this period. But by the turn of the twentieth century, Connecticut,
1
Swann
Georgia, Illinois, Iowa, the Oklahoma territory, California, and most other states had outlawed drug adulteration and/or failure to label a medicine that had morphine, cocaine, digitalis, nux vomica, chloroform, cantharides, strychnine, ergot, or a host of other substances (1,2). Typically, violations were considered misdemeanors and penalized accordingly. But absent a federal proscription, it was all the protection a citizen might hope for. Still, there were some notable though short-lived developments at the national level. Baltimore physician James Smith, inspired by the marketing of spurious smallpox vaccine, convinced Congress to pass a law in 1813 to ensure the provision of reliable vaccine. Under this law, the president appointed a socalled vaccine agent (Smith) to preserve the genuine vaccine matter, and to furnish the same to any citizen of the United States, whenever it may be applied for, through the medium of the post office. The blame for a smallpox outbreak in North Carolina in 1822 was assigned to vaccine supplied by the vaccine agent, though this was never proven. But the impact of the event led to repeal of the vaccine act and restoration to states of the responsibility for pure and effective smallpox vaccine (3). The publication of the United States Pharmacopoeia (USP) in 1820 was a milestone in the history of drug regulation because it established a national compendium of drug standards to help respond to what medical and pharmaceutical professionals observed to be an increasingly corrupt drug supply. Ultimately it would prove to be unique among most legally recognized publications of this kind in the world because it was, and still is, a private venture. There had been occasional local compilations of standard drugs and their preparation, the first of which was the Lititz Pharmacopoeia of 1778. But the convention that assumed responsibility for a national collection of drug standards and their preparation had something broader in mind. Led by New Hampshire native Lyman Spalding, 11 physician-delegates from medical societies and schools across the country, representing four districts, met in Washington in January 1820 to discuss drafts and recommendations from district proceedings and what would and would not be included
History of Pharmaceutical Regulation
in the USP. The first USP aimed to select from among substances which possess medical power, those, the utility of which is most fully established and best understood; and to form from them preparations and compositions, in which their powers may be exerted to the greatest advantage (4). The USP thus endeavored to elevate the pharmaceutical armamentarium in a way that would make both the practice of medicine and the practice of pharmacy more reliable (58). The first federal law that addressed pharmaceuticals in general invoked the USP as well as other pharmacopoeias. Lewis Caleb Becks 1846 publication, Adulteration of Various Substances Used in Medicine and the Arts, with the Means of Detecting Them: Intended as a Manual for the Physician, the Apothecary, and the Artisan, revealed an American marketplace rife with adulterated medicines. Opium, one of the most valued medicines, was most frequently subjected to fraud, mixed with all manner of deceptive ingredients, such as gum arabic, sand, and lead. Beck identified many other drugs commonly adulterated, including tartar emetic, quinine, and rhubarb. It was a state of affairs perhaps best captured by British statesman and pharmacist Jacob Bell, who related the widespread belief abroad that drugs rendered unsuitable by decay or fraud were still good enough for America (9). If Becks book provided the scientific evidence why the United States needed a law to protect the drug supply, then the Mexican-American War (18461848) provided the political impetus. Many in Congress blamed adulterated drugs for the massive wartime deaths. In truth, considering the drugs then available, it would have made little difference whether or not the drugs were pure. Squalid camps, inadequate nutrition, and an understaffed medical corps were largely responsible for deaths due to diseaseabout 10% of the total fighting force each year, a rate seven times the mortality rate due to combat (10). The continuing prevalence of drug adulteration in the 1840s, particularly evident in the ports, produced, as James Harvey Young showed, a sense of outrage. Senator John Davis of Massachusetts believed that, If we can stop the importation of the spurious drug from abroad, we shall
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know how to deal with those who may choose to go into their adulteration in the United States (11). Such sentiments, combined with Congresss conception of pharmaceutical fraud in the Mexican conflict and the documentation supplied by Beck, helped shape a law that attempted to bring some order to the chaos. The Drug Import Law, signed by President James K. Polk on June 26, 1848, required the examination of all drugs that came into the ports of New York, Boston, Philadelphia, Baltimore, Charleston, and New Orleans for quality, purity, and fitness for medical purposes. The law identified the USP as well as the pharmacopoeias and dispensatories of Edinburgh, London, France, and Germany as the source of standards used by the port examiners in their appraisals. Drugs had to be labeled with the name of the manufacturer and the place of preparation. The Secretary of the Treasury was authorized to appoint suitably qualified personnel at each of these ports. Any drug so adulterated or deteriorated to fall short of the standard of purity or strength as established by these compendia would not pass the customhouse. The owner or consignee could request a reexamination by an analytical chemist endorsed by the medical profession and the local school of medicine or pharmacy. But if that analysis upheld the port examiner, the violative drug would be either removed by the owner or destroyed by the port (12). Initially, the law was enforced vigorously by those appointed by Secretary of the Treasury Robert J. Walker. In the first few months, the New York port was reported to have turned away over 90,000 pounds of drugs. Some even hoped, like Senator Davis, that it might be possible to address the problem of domestic traffic in problematical drugs. However, the impact of the law soon diminished. In part, this was due to inadequately developed methods of analysis, a problem that pharmacists in particular tried to rectify. But the problem also rested in the appointment of unqualified individuals to special examiner positions, appointments which began to be awarded more on the basis of political debts than the suitable qualifications as stated in the law. By 1860 Edward Squibb announced that the law was barely
enforced any more, and that remained the case despite the efforts of some physicians and pharmacists for the remainder of the century (1315).
2. EARLY REGULATION OF BIOLOGICAL THERAPIES The next significant milestone in the history of regulating therapeutic products in the United State followed a major advancement in biological therapeutics. In 1890 Emil von Behring and Shibasaburo Kitasato, working at the Robert Koch Institute in Berlin, announced that they had successfully treated diphtheria by injecting patients with blood serum of animals immunized against the pathogen. The last two decades of the nineteenth century witnessed the identification of nearly two dozen microorganisms responsible for disease, and the work of von Behring, Kitasato, Louis Pasteur, Emile Roux, and others applied these discoveries to develop and refine biological treatments for these diseases (16,17). State and local public health laboratories and a few commercial concerns soon began producing their own diphtheria antitoxin once European scientists perfected the production methodology. On the eve of this milieu, Joseph Kinyoun, head of the Hygienic Laboratory of the U.S. Marine Hospital Service (later renamed the Public Health Service), warned the Surgeon General in November 1894 of . . . what will evidently ensue in our country. Many persons will, during the ensuing year, commence to prepare the [antidiphtheria] serum as a business enterprise, and there will, without a doubt, be many worthless articles called antitoxin thrown upon the market. All the serum intended for sale should be made or tested by competent persons. The testing, in fact, should be done by disinterested parties. The danger with us is perhaps greater than could exist here [in Germany] under any circumstances (18). Early in 1895, the Hygienic Laboratory developed a standard diphtheria antitoxin for distribution (1921). Businesses, as Kinyoun suspected, indeed took up production, but it was the antitoxin manufactured by a municipal public health
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Figure 1 This cartoon from Puck, 1880, deftly captures the fear of vaccination with unreliable vaccine matter. (Courtesy of William Helfand.)
laboratory that launched a movement for regulatory intervention (see Fig. 1). In October 1901 the St. Louis Health Department produced a batch of antitoxin that killed 13 children being treated
for diphtheria; the cause of death in each case was tetanus. An investigation led by the city council and the health department revealed that the consulting bacteriologist who had produced the antitoxin had used a horse that contracted and later died of tetanus. The bacteriologist allegedly was aware of the horses condition but failed to destroy the product or otherwise prevent its distribution. Though he was unaware of the tainted source of the antitoxin, the janitor in the laboratory had responsibility for bottling the product; he complicated recovery of the antitoxin by initially claiming the antitoxin had been destroyed. The incident in St. Louis was not isolated. There were other accidents involving biological medicines, such as about 100 cases of postvaccination tetanus that occurred in Camden, New Jersey, also in the Fall of 1901, where nine children died. But it was the St. Louis disaster that was specifically invoked (22) in the hearings on a bill that proposed bringing production of biologics under federal control. Introduced on April 5, 1902, President Theodore Roosevelt signed the Biologics Control Act on July 1, 1902, virtual light speed compared to the quarter-century it took for the admittedly more comprehensive and much more hotly contested Food and Drugs Act of 1906 (23). The Hygienic Laboratory was responsible for enforcement of the 1902 legislation. Drawing upon extant legislation in Europe, this law required manufacturers of any biological medicine or analogous product to be licensed annually by the government, and licensure was predicated on a satisfactory and unannounced inspection of the establishment. All aspects of production could be examined, including records. Samples of licensed products were obtained on the open market and tested at the Hygienic Laboratory for purity and potency. Licenses could be suspended pending correction of a manufacturing or product defect, and violation of the law was subject to a fine of up to $500 and/or imprisonment for up to one year. While there certainly were cases of license suspensions, there appears to be little evidence that the Hygienic Laboratory pursued fines or imprisonment under the law until the early 1960s (2426). The number of licenses issued by the Hygienic Laboratory grew quickly, from 13 concerns licensed to produce mostly
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diphtheria antitoxin and smallpox vaccine in 1904, to two dozen operations producing about 20 different medicines in 1908, to 41 establishments licensed for over 100 biologics in 1921 (2730). 3. FEDERAL AND PRIVATE REGULATION OF DRUGS IN THE EARLY TWENTIETH CENTURY Other federal agencies offered limited regulation over pharmaceuticals beginning in the early twentieth century. The Post Office Department, for example, was able to prosecute some products that were otherwise beyond the reach of the government under the postal fraud laws of 1872 and 1895 (31,32). These laws prohibited the use of mail to collect money under fraudulent pretenses. Violations resulted in a fraud order, wherein the offending mail was intercepted and returned to the sender. Thus in 1928 the Post Office secured a fraud order, upheld on appeal, against Tuberclecide, a worthless treatment for tuberculosis, and years earlier against Habitina, an alleged drug addiction cure that contained both morphine and heroin (33,34). The Federal Trade Commission (FTC) exercised its jurisdiction over drug advertising from time to time following its establishment in 1914. For example, it attempted to regulate Marmola, a hazardous thyroid preparation intended for weight reduction, on two occasions in the 1920s and 1930s (35). The Wheeler-Lea Amendment of 1938 clarified FTCs unique authority over all drug advertising, though jurisdiction over prescription drug advertising was transferred to the U.S. Food and Drug Administration (FDA) in 1962 (3638). Ironically, probably the most significant effort to regulate prescription drugs prior to 1938 was a private venture that was voluntary, under the American Medical Association (AMA). Shortly after the turn of the century the AMA and the American Pharmaceutical Association (APA) combined resources to press for the establishment of a federal authority that would certify drugsand thus help rid the landscape of
patent medicines. These not only posed a threat to the public health, they represented some competition for physicians. Nostrums certainly played an important role in the retail business of many pharmacists, but others in the profession excoriated their sale. The AMA abandoned the idea of federal certification and instead formed its own Council on Pharmacy and Chemistry in 1905, a 15-member group that included physicians, pharmacists, pharmacologists, chemists, and government representatives. The AMA Board of Trustees charged the council to publish an annual volume of proprietary pharmaceuticals approved by the council that were not, according to pharmacopoeial rules, permitted in the USP (3941). Manufacturers submitted to the council evidence to support any claims made for the drug and a proposed name, and the council relied heavily on the advice of outside consultants to evaluate these data. An accepted drug would be included in its compendium, New and Nonofficial Remedies (NNR), which entitled the firm to label its drug with the councils accepted seal. But under the councils rules, no pharmaceutical would be admitted to NNR if it had unwarranted, exaggerated or misleading statements as to therapeutic value. Moreover, a drug would not be accepted if its firm derived substantial earnings from products not listed in NNR. But rejection by the council meant more than just failure to appear in NNR or enhance its label. Unaccepted drugs were denied the right to advertise in the family of AMA journals (4245). The council terminated its acceptance program in 1955, due largely to the AMAs depletion of cash reserves and a growing apathy for the program within the association, according to one informed observer (46). However, the council continued to publish its compendium of drugs for reference use of the profession. With the proscriptive element of the program inactivated, the possibility existed in which a drug might be advertised in the Journal of the American Medical Association (JAMA) for an indication not supported in NNR (47). Moreover, firms were less compelled to submit the sort of evidence to the council that they had in the past, such that the councils consultants had to search for supplemental data on NNR candidates elsewhere. Still, NNR included comparative
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assessments of a drugs efficacy, something FDA did not do when the efficacy statutes were passed (4850). 4. THE DRUG MARKETPLACE AT THE TURN OF THE CENTURY Federal regulation over the bulk of the drug supply was still nonexistent at the turn of the twentieth century. It was a menacing marketplace. Despite the existence of several comprehensive drug compendiaincluding the USPthere were no legally required standards of identity for drugs, whether the pharmaceutical were prescribed by a physician and dispensed by a pharmacist (so-called ethical drugs) or purchased directly by the consumer for self-medication. Some of the manufacturers of the former by this time had quality-control procedures in place and produced standardized drugs of predictable therapeutic response. Parke-Davis was the first firm to subscribe to this approach, introducing 20 chemically assayed fluidextracts of botanicals by 1883 (51,52). Parke-Davis and Mulford were the early leaders in the production of biologicals, a venture that by definition and by law required the institutionalization of science. Incorporating science was, as Jonathan Liebenau points out, good business for drug manufacturers even at this early stage. And they made sure their clientele knew it (53). But science was still very much in its infancy for most of the American pharmaceutical industry at the turn of the century. It was an expensive proposition, and many company chiefs remained to be convinced that more (or any) science and research necessarily meant more business (54). To be sure, even the ethical industry had its share of scientifically questionable products. One of Eli Lilly and Companys best sellers at this time was Succus Alterans, a blood purifier and treatment for rheumatism, syphilis, and a variety of skin diseases that Lilly supposedly derived from a Creek Indian remedy (55). In 1889 Smith Kline & French purchased the D. B. Hand Company and then manufactured and distributed the Hand line of products, still under the Hand brand. This inventory consisted of teething lotions, colic cures, croup and cough
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medicine, worm elixir, and other preparations advertised for infants and children. Like so many other pediatric products of other firms at this time, these Hand medicines typically contained alcohol, opium, and chloral hydrate (5658). But regardless of the extent to which the ethical industry marketed nostrums, it paled next to the patent medicine industry, those who vended William Radams Microbe Killer, Mrs. Winslows Soothing Syrup, Swaims Panacea, Benjamin Byes Soothing Balmy Oils to cure cancer, Dr. Hollicks Aphrodisiac Remedy, and on and on (59). Nostrums were omnipresent in late nineteenth-century America, their rise, not coincidentally, paralleling that of advertising. Products appealed to exotica, the medical knowledge of Native Americans, death, religion, patriotism, mythology, and eventually new developments in science. Nothing but the size of the bottle prevented patent medicines makers from claiming anything and putting anything in their products (see Fig. 2). At the same time, the biomedical sciences awaited elaboration, leaving medicine illequipped to deal with most diseases. If there were a demand for cancer and arthritis cures, baldness remedies, bust developers, manhood restorers, a cure could be supplied. And if there were not a demand, that too could be manufactured. The nostrum industry undoubtedly knew how to market its wares, but companies also promoted their interests in more surreptitious ways. For example, they subdued any curiosity in the press with their economic strength. By the 1890s, patent medicine manufacturers used so-called red clauses in their advertising contracts to muzzle newspapers and magazines. The contracts would be voided if a state law regulating nostrums were passed. Thus, not only were many editorials silent on the need for such laws, they actively campaigned against them. 5. THE FEDERAL FOOD AND DRUGS ACT OF 1906 Such was the pharmaceutical landscape in America as the twentieth century began. A few muckraking journalists
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Figure 2 Hunts Remedy, manufactured since 1850, illustrates the unrestricted claims and eye-catching advertising imagery that characterized many patent medicines at the turn of the twentieth century. This particular advertisement was used for the design of a 1998 U.S. postage stamp to commemorate the 1906 Food and Drugs Act.
helped reveal the red clauses, the false testimonials, the nostrums laden with harmful ingredients, the unfounded cures for cancer, tuberculosis, syphilis, narcotic addiction, and other serious as well as self-limited diseases. The most influential patent medicine expose was a 10-part series entitled The Great American Fraud, by Samuel Hopkins Adams, which began in Colliers on October 7, 1905, and ended the following February. A subsequent series by Adams examined doctors who advertised fake clinics. That same month saw the publication of another work that, more than any other single event,
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spurred on passage of a comprehensive federal law. Socialist writer Upton Sinclair published The Jungle, a fact-based novel about immigrant life in the meatpacking industry of Chicago. Sinclairs shocking and revolting story was verified by government undercover investigators. The search for a federal law to correct abuses in the food and drug marketplace began long before Adams and Sinclair initiated their investigations. Congress received the first bill to address these concerns in January 1879, though that version addressed only foods; some months later another bill, this time encompassing drugs as well as foods, was introduced in the House. Every session of Congress for the next 25 years considered at least one sweeping food and drug control bill (60). Those who believed they would be adversely affected by an omnibus law managed to thwart passage of the dozens of bills that were introduced during this span. But their opponents obviously were equal to the taskor at least persistent. Many championed a food and drug law, but one person more than any other was responsible for keeping the need for such a law squarely in front of both Congress and the people. Harvey Washington Wiley was a chemist on the faculty of Purdue University when he came to Washington in 1883 to become the fourth chief chemist in the Department of Agriculture. From the time of his arrival in the capital, Wiley was an enthusiastic, infectious, and effective champion for remedial legislation. When he was not stumping for a law, he was publishing extensively on the proliferation of food adulteration (61). His forceful personality and commitment to reform brought together important but disparate groups to help lobby Capitol Hill, including state food and drug officials, the General Federation of Womens Clubs, the American Pharmaceutical Association, and the American Medical Association (6264). On June 30, 1906, President Roosevelt signed the Food and Drugs Act into law (65), nearly 4 years to the day after he signed the Biologics Control Act. The law prohibited interstate commerce in adulterated or misbranded foods and drugs. It was unlawful to add an ingredient to a food that would represent a health hazard, result in a filthy or decomposed
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product, conceal damage, or substitute for the food itself. If the manufacturer chose to label the weight or measure of the food, that had to be done accurately. A food or drug label could not be false or misleading in any particular. A drug under the act was any substance intended for the cure, mitigation, or prevention of disease in humans or animals. It could not be sold in any condition of purity, strength, or quality other than that stated in the USP or the National Formulary, unless the specific variation from that standard were stated on the label. The presence and amount of 11 dangerous ingredients, including heroin, morphine, cocaine, and alcohol, had to be labeled on all drugs (and foods). Violative goods were subject to seizure and, if upheld by the court, destruction. Infractions were considered misdemeanors, and those behind the offense could be fined up to $500 and imprisoned for up to one year. The Bureau of Chemistry of the Department of Agriculture, the home of more chemists than anywhere else in the U.S. government (66), was assigned to enforce the law and promulgate regulations (67). 6. APPLYING THE NEW LAW TO DRUGS One immediate impact of the law was to persuade many patent medicine manufacturers to remove ingredients from their preparations that were subject to labeling. Therapeutic claims, however, were another story. The Bureau of Chemistry quickly applied the law to products that bore false therapeutic claims, based on a charge of misbranding. About 100 such cases were made in 5 years (68). However, when the bureau tried to move against Dr. Johnsons Mild Combination Treatment for Cancer, the firm prevailed over the bureau in court. The case reached the Supreme Court in 1911, which ruled in a 6-3 decision against the government. The majority believed that the 1906 act pertained only to ingredients of a product, its identity. Moreover, the Court believed that the Bureau of Chemistry was capable of making an informed judgment about a drugs contents, but hardly so as to medical effects. Finally, based on an earlier case involving the Post Office, the court argued
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that ideas about therapeutics were still too far ranging to come to definitive conclusions (69). President William Howard Taft asked Congress to develop a legislative solution for the 150 pending drug misbranding cases, as well as those yet to come. Among these cases, according to the president, were some of the rankest frauds by which the American people were ever deceived (70). Congress responded in 1912 with the Sherley Amendment, couched as severely as members believed possible without infringing on expressions of opinion. The new law prohibited statements about a products ingredients or its curative or therapeutic effect that were false and fraudulent (71,72). However, to establish fraud meant that the bureau of chemistry had to show that the manufacturer knew the product was worthlessthat there was intent to defraud the consumer. This proved to be difficult in many cases. For example, Lee Barlett, a former shirt salesman from Pittsburgh, promoted a medicine called Banbar, an extract of the horsetail weed, as an effective treatment for diabetes. Barlett sold Banbar for $12 a pint, a hefty price in the 1920s, but it allowed diabetics to take their medicine orally rather than administering injections of insulin, which Frederick Banting and his colleagues at the University of Toronto had introduced in 1923. The government took Barlett to court for selling a misbranded drug. Elliott P. Joslin, the internationally recognized authority on diabetes, was the plaintiffs principal witness. On the basis of the 12,000 diabetic patients he saw every year, Joslin testified that insulincombined with diet and exercise was the only effective treatment for this disease. The defense offered hundreds of testimonial letters on behalf of Banbar. The jury found in favor of the defense, despite the fact that the government presented death certificatesattributed to diabetesfor individuals who had submitted these testimonials (73). Under Wiley, enforcement of the Food and Drugs Act weighed heavily toward foods. Of the first 1000 actions taken by the bureau up to 1911, fewer than one quarter dealt with drugs. And those drug actions typically addressed patent medicines; as seen above, false therapeutic claims were a driving
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force for action. Official drugs such as belladonna and asafetida were the subject of fewer than 100 of these actions. Most defendants did not challenge the bureau, but rather paid their fines, adjusted their labeling, and continued to advertise as before, since the latter was beyond the reach of the 1906 law (74). Carl Alsberg followed Wiley as chief chemist in 1912, and he continued to favor foods. But he also focused more attention on ethical drugs. To address these, the bureau developed new analyses for crude drugs, and by the 1920s bureau scientists pioneered biological assays for ergot, digitalis, and other drugs, which were adopted by the USP (75) (see Fig. 3). The bureau also monitored drugs dispensed by pharmacists in the District of Columbia (believing state pharmacy boards were the more appropriate monitor elsewhere) beginning in the 1910s and found substantial deviations from official standards.
Figure 3 Pharmacologists in the Bureau of Chemistry employed biological assays to develop the first reference standards issued to industry to promote compliance with the testing requirements for select pharmaceuticals in USP X (1926).
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By the early 1930s FDA and the American Pharmaceutical Association reached an agreement as to what would be considered reasonable tolerances for dispensed drugs (76). When Walter Campbell succeeded Alsberg in 1921, he revitalized the drug regulatory effort, beginning with the appointment of George Hoover, a physician and chemist, to head drug regulation. The bureau consequently expanded its interests from crude drugs to tablets, discovering fairly wide variations from official standards. But by this time, when the Republicans came to power and the policy was made to be more cooperative with business, court action began to be superceded by negotiation. Hoover met with the pharmaceutical industrys trade associations, the American Drug Manufacturers Association and the American Pharmaceutical Manufacturers Association, which in turn formed so-called contact committees to investigate the tablet problems in cooperation with the bureau. The committees helped improve tableting technologies and negotiated with the bureau over allowable deviations from the labeled amount of active ingredient. But in the New Deal era, drug regulation took a less collaborative tone with industry (77). 7. TOWARD THE 1938 FOOD, DRUG, AND COSMETIC ACT The 1906 act was arguably the pinnacle of Progressive Era legislation, but the difficulty of prosecuting medicines with false therapeutic claims was just one of many shortcomings of the 1906 act. Foods did not have standards, cosmetics and medical devices were unregulated, the penalties imposed by the law were paltry relative to the crime, with the exception of the 11 ingredients there was no required listing of drug ingredients, factory inspectionsthough interpreted and executed by the bureau as warranted under the lawwere not explicitly authorized, and though the law prohibited a food that was made to be unsafe, there was no similar protection for drugs. By the 1920s, and increasing considerably after Franklin Roosevelt became president in 1932, FDA began to publicize
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rather creatively the more egregious examples of deceptive and hazardous products that were on the market and perfectly within the law, an argument for a new comprehensive law (78). Indeed, shortly after FDRs inauguration, Congress began considering bills that would replace the Food and Drugs Act and plug the holes left in consumer protection legislation (79). The publics vulnerability became dramatically clear in October 1937. Months after the introduction of the wonder drug sulfanilamide, the S. E. Massengill Company of Bristol, Tennessee, began investigating a liquid dosage form for the drug. Their investigation consisted of finding a solvent in which the drug would dissolve (sulfanilamide was known to be stubbornly insoluble) and flavoring and coloring the preparation so as to be especially useful for children and others not inclined toward tablets. Quality control amounted to little more than an organoleptic appraisal. Harold Watkins, the company chemist, selected diethylene glycol as the vehicle for the sulfa without testing the solvent or even examining the medical literature. Had he at least bothered to look, the latter certainly attested to the glycols poisonous nature. He didnt bother testing it himself, he claimed, because glycols were related to glycerine, which had long been used in medicines. The company thus began shipping its Elixir Sulfanilamide from Tennessee and its Kansas City office in early September. On October 11, a representative from the Tulsa County Medical Society contacted the AMA to inform them that several deaths in the Oklahoma county appeared to be associated with the Massengill product. The physician wanted to know what the AMAs Council on Pharmacy and Chemistry could tell them about the preparation. Neither Elixir Sulfanilamide nor any Massengill product had ever been accepted by the Council. The Food and Drug Administration heard about the suspicious deaths 3 days after the AMA, from a New York physician with ties to Massengill. FDA learned the Elixir was involved in all the Tulsa fatalities, at which point the agency dispatched its chief medical officer and one of its finest field investigators to Bristol to investigate. They learned that
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proprietor Samuel E. Massengill issued an inadequate recall notice and that 240 gallons remained unaccounted for. FDA dedicated virtually its entire field force to tracking down the remaining productthough forced to rely on a technical error for legal cause. Nothing in the 1906 act prohibited unsafe drugs. Rather, FDA was allowed to seize Elixir Sulfanilamide because it was misbranded; an elixir, by definition, had to employ alcohol, and the Massengill medicine of course had none. Most physicians and pharmacists encountered by FDA investigators during the frantic recovery effort were helpful, but some were uncooperative and even obstructive, no doubt to deflect personal responsibility and liability. Much was recovered from warehouses, pharmacy shelves, and medicine cabinets But overall, Elixir Sulfanilamide killed at least 107, mostly in the South. Many were children, such as the 6-year-old girl from Tulsa who perished in this ordeal (see Fig. 4). Her mother, Marie Nidiffer, wrote to President Roosevelt on November 9th: Tonight Mr. Roosevelt that little voice is stilled. The first time I ever had occasion to call in a doctor for her and she was given the Elixir of Sulfanilamide. Tonight our little home is bleak and full of despair. . . . Even the memory of her is mixed with sorrow for we can see her little body turning to and fro and hear that little voice screaming with pain and it seems as tho it drives me insane. . . . Tonight President Roosevelt as you enjoy your little grandchildren of whom we read about, it is my plea that you will take steps to prevent such sales of drugs that will take little lives and leave such suffering behind. . . . (8082). The bills to correct the gaps in the 1906 act had been delayed and diluted over the previous 5 years. However, the impact of the Elixir Sulfanilamide tragedy was to strengthen the drug provisions of the latest bills and in fact propel passage of the law itself. Roosevelt signed the bill on June 25, 1938 (83). The Food, Drug, and Cosmetic Act brought medical devices and cosmetics under regulation, provided for standards of identity for foods, prohibited once and for all false therapeutic claims on drug labeling, required that drugs be labeled with adequate directions for use, authorized factory inspections (which had been executed anyway under the bureaus interpretation of
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Figure 4 The face of a drug disaster. This excerpt from a moving letter to President Roosevelt from Mrs. J. Nidiffer of Tulsa describes her anguish and helplessness over the loss of her six-year-old daughter, Joan Marlar. Ironically, sulfanilamide saved the life of FDRs son just one year earlier, not long after American clinicians got their hands on the drug.
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the old law), instituted court injunctions for violative products, corrected abuses in the quality and packaging of foods, instituted adequate drug manufacturing controls (84), and, most important from the standpoint of the history of drug regulation, mandated that all new drugs had to be shown by the manufacturer to be safe before they could be marketedthe birth of the new drug application. The premarket provision, inspired by the fear of another Elixir Sulfanilamide disaster, had an immediate impact, with over 6000 thousand new drug applications (NDAs) filed in the first 9 years, and 13,000 by 1962 (85). 8. DRUG REGULATION AND THE POSTWAR CHEMOTHERAPEUTIC REVOLUTION One early development under the drug provisions of the 1938 act concerned self-medication. The law called for adequate directions for use by the patient, and by 1940 FDA issued nearly 30 detailed warning statements to be labeled on a variety of drugs. For example, bromides were labeled with the following: Warning: Frequent or continued use may lead to mental derangement, skin eruptions or other serious effects. Do not take more than the dosage recommended. Not to be taken by those suffering from kidney disease (86). However, it was FDAs opinion within weeks of the law that some drugs simply could not be labeled with adequate directions. For example, the use of a sulfa drug in a venereal disease was hardly routine, complicated as it was by both the adverse reactions that many of the early sulfas produced and the identification and progress of the disease. In other words, FDA ruled that in some cases medical expertise had to be involved in the medication process for the drug to be safe. The agency identified an increasing number of drugs that had to be labeled for dispensing only on the order of a physician or dentistthe birth of another standard of modern medicine, the prescription drug (8790). This created confusion about how a drug would be categorizedprescription or nonprescriptionand who would have primary responsibility for
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that designation. The absence of statutory direction was resolved in 1951 when the Durham-Humphrey Amendment was passed. That law established broad parameters for deciding which drugs merited designation as prescription legend status and which could be available over the counter (91). The illegal sale of two groups of prescription drugs, amphetamines and barbiturates, took up more of FDAs drug enforcement time in the 1940s, 1950s, and 1960s than all other drug violations under the 1938 act combined. At first the agency focused on pharmacies, some of which were either selling these drugs over the counter without a prescription or incessantly refilling old prescriptions that did not authorize any refills. By the mid-1950s, FDAs attention turned to the trucking industry, a major source of traffic in these pharmaceuticals, where some spectacular and highly publicized highway crashes were directly connected to the use of amphetamines and barbiturates (92). Eventually many other drugs prone to abuse, such as hallucinogens, were consolidated for special interdiction by FDA under the Drug Abuse Control Amendments of 1965 (93,94). However, 3 years later that function was transferred to what would become the Drug Enforcement Administration (DEA). The introduction of the sulfa drugs, beginning with sulfanilamide in 1935, launched a revolution in chemotherapy. Statutes and regulations did their best to keep track of new therapies. For example, literally hours before expiration of the patent on insulin (and the University of Torontos oversight of quality control in the production of the hormone) in 1941, Congress passed the Insulin Amendment to require FDA to test every batch of insulin produced for strength, quality, and purity to ensure its safety and effectiveness (95). A similar law in 1945 provided for FDA certification of batches of penicillin a continuation of service provided by FDA beginning in 1943 to the War Production Board for penicillin headed for troops. As additional antibiotics were discovered, laws were passed to accommodate them (9698). As mentioned above, companies flooded FDA with drug applications at the outset. The agency received an average of over 100 NDAs monthly from 1938 to 1941 because sponsors
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were apparently unsure of what constituted a new drug. NDA 1596, received on August 30, 1939, and approved on September 20, 1939, was for 4-H Household Cough Syrup, consisting of horehound, molasses, and vinegar. The Aiellos Ped-Vale Company submitted NDA 407 on January 12, 1939, for Aiellos Foot Remedy Powder, made up solely of boric acid; FDA approved the application on April 1 of that year. During this period seven firms and one physician submitted NDAs for aspirin that were approved by FDA. Interestingly, in January 1945 the agency ruled that the indications for aspirin were so well known to consumers that directions for use were not required. Aspirin lollipops, though, were a different matter, requiring a physicians prescription (99102). The application submission rate slowed during World War II and the early post-war years to about 300 annually. However, it picked up again in the 1950s to approximately 500 each year, when research funds flooded laboratories almost as fast as pathbreaking new medicines flooded the marketplace. Upon the end of hostilities in Europe, the Committee on Medical Research of the Office of Scientific Research and Development disbursed remaining wartime research funds to the National Institutes of Health (NIH). That, together with strong congressional support, launched in full force the modern era of autonomously peer-reviewed extramural funding of biomedical research at NIH (103). In addition, the pharmaceutical industry accelerated a trend that began in the period between the wars, pouring more and more revenue into research and development (104,105). That decision might have been made a little easier by the success of their wartime experience with penicillin, synthetic anti-infective agents, and other drugs. Thus, a host of antibiotics, diuretics, ataractics, corticosteroids, antispasmodics, and other classes of drugs proliferated during that decade (106,107). Of course, the number of supplements grew as the base number of NDAs increased. And then there were some drugs that yielded scores or even hundreds of NDAs, such as diethylstilbestrol and rauwolfia serpentina. David Cavers reports that the latter led to applications from 319 different firms and was included in 2500 different medicines (108).
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9. COMING TO GRIPS WITH EFFICACY BEFORE 1962 Another drug regulation policy was growing increasingly important in the 1950sthe relationship between drug safety and drug efficacy. The idea of federally mandated effectiveness in medicines was nothing new at this time. For example, regulations issued by the National Institute of Health (formerly the Hygienic Laboratory) in 1934 required that biologics had to work: [A] license for new products shall not be granted without satisfactory evidence of therapeutic or prophylactic efficiency (109). This formalized a policy that had been in place for years. In the late 1930s FDA promulgated a rule requiring manufacturers of oral or otherwise inert ovary, suprarenal, pituitary, prostate, pineal, and mammary extracts to label their products with a statement that such an article does not contain any known therapeutically useful constituent of the glands mentioned. Of course, even under the 1906 act, actions taken against patent medicines that made false therapeutic claims were implicitly driven by efficacy considerations (considerations that the Supreme Court believed were ahead of their time). The Insulin Amendment, Penicillin Amendment, and the other antibiotic amendments literally invoked efficacy as a prerequisite for certification by FDA. Reviews of certain NDAs that claimed to treat serious diseases such as pneumonia certainly took efficacy into account (110). The concept that in certain cases a drug could not be safe without being effective was employed but never pressed forward as an official policy until Hepasyn came along. The Hepasyn story began in the early 1930s, when various researchers observed that cancerous tissue bore a high concentration of the amino acid, arginine, which appeared to promote cell division in tumors. Some tried to exploit this observation by applying the liver enzyme arginase, which helps to hydrolyze arginine, as a possible treatment to control tumor growth. Success was fleeting for most. However, dentist Wesley G. Irons, working as an anatomist at the Schools of Pharmacy and Dentistry at the University of California at
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San Francisco in the 1940s, claimed to have success treating animal tumors with arginase. When his funding fell through at the university, Irons was offered funding and laboratory space at the San Francisco College of Mortuary Science, a source for cadavers in Ironss classes. The mortuary school reserved commercial rights to Ironss work and served as the manufacturing establishment for Hepasyn, the name they gave to arginase. In November 1950 the school arranged with a Hollywood clinician to test arginase, and within a year 100 patients had received the substance. Eventually the Hollywood physician began treating other cancer patients on an ambulatory basis once a week at the mortuary school. The story became even more curious after Irons and the school parted company, but the San Francisco school submitted an NDA late in 1953. FDA inspectors visited the mortuary school and found serious production problems, such as organoleptic sterility testing. The NDA itself, though the sponsors claimed to have data on 175 patients, contained results with only 10. FDA, not surprisingly, considered the application incomplete and requested more data. As problematical as the manufacturing operation was, FDA chose to focus on the clinical evidence submitted by the college (see Fig. 5). By October 1955 the application was deemed complete enough for a review. The agencys strategy was made clear to a medical officer in San Francisco: We have given considerable thought to the proper handling of this application and have decided in conjunction with [General Counsel William] Goodrich that since this preparation is ineffective in the treatment of malignant disease its use is not safe in such situations. In other words, while section 505 does not refer to efficacy we are going to try and take the position that efficacy is so intimately bound up in the use of this material that the lack of efficacy will make it unsafe for use (111). The Hepasyn review thus was not going to be just another NDA evaluation. Rather, it was to be a blatant stand on therapeutics and the law. FDAs expectation or hope was that the San Francisco College of Mortuary Science, its application denied on the basis of lack of efficacy, would appeal the decision in an administrative hearing.
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Figure 5 The San Francisco College of Mortuary Science served as the manufacturer, ambulatory clinic, and new drug application sponsor for a cancer treatment. FDA used this opportunity to press for a formalized policy mandating an efficacy requirement in some drugs. (Courtesy of the San Francisco History Center, San Francisco Public Library.)
In late December of that year, FDA Commissioner George Larrick informed the college that its NDA was denied because of misleading statements and omissions, because of inadequate manufacturing and control procedures, and because safety has not been proven because of lack of proof of efficacy in diseases that are invariably fatal unless treated with adequate
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efficacious means (112). While there was not a surfeit of bona fide treatments for the cancers Hepasyn claimed to benefit, there certainly were some. An approved yet ineffective Hepasyn, the reasoning went, would lead some patients to delay or possibly avoid treatment with established effective treatments. Larrick informed the mortuary school that if the NDA were not withdrawn, a hearing noticeas provided in the 1938 act to sponsors who wished to petition adverse NDA decisions by FDAwould be issued next month. Led by medical officer Barbara Moulton, FDA continued to assemble its case for a hearing. Medical director Albert Holland observed that this case may well be a precedent-establishing case no matter which way the courts decide it. But in the end the courts would not have the opportunity, as the San Francisco school withdrew the application rather than face the hearing (113). FDA had another chance to press the safety-efficacy policy a few years later, and this time the drug firm was more accommodating. On September 9, 1959, FDA approved Eaton Laboratories application for Altafur (furaltadone), a systemic antibacterial agent. However, FDAs reevaluation of the NDA as a rising number of neurological and other adverse reactions came to light led the agency to question the efficacy of Altafur (114). Among other issues, FDA believed there were insufficient reports in the application from experts in the treatment of infectious diseases, and certain claims would have required unattainable plasma levels even at triple the recommended dosage. The agency did not explain why these issues were not apparent at the time of the application. Eaton Laboratories submitted additional data, but FDA said that evaluation of those data should be done in the venue of a formal hearing over suspension of the Altafur NDA; its lack of effectiveness did not justify its toxicity. The hearing began in January 1961 and lasted several weeks. The hearing examiner was persuaded by the testimony of Maxwell Finland of Harvard, George Jackson of Illinois, and other experts on infectious diseases who disputed Altafurs claim of therapeutic value. The examiner decided that efficacy was indeed relevant to Altafurs safety considering the diseases treateddiseases amenable to effective treatment by other,
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less toxic drugs on the market. The NDA for Altafur was suspended in August 1962, less than 2 months before Congress passed the Kefauver-Harris Drug Amendments (115,116). 10. KEFAUVER, KEVADON, AND A NEW APPROACH TO DRUG REGULATION Estes Kefauver of Tennessee was not the first senator to voice concern about increasing cost of drugs. Fellow Democrat Warren Magnuson of Washington had heard complaints from constituents and also learned about the rising cost of drugs in America as a member of the Labor, Health, Education, and Welfare Subcommittee. But Kefauver, chairman of the Subcommittee on Antitrust and Monopoly since January 1957, was in a position to explore this development in depth. Thus, in December 1959, following an extensive investigation by his staff that began the previous year, Kefauver initiated hearings into administered prices in the pharmaceutical industry. The early testimony provided some headline-grabbing statistics into how the pharmaceutical industry arrived at drug prices. For example, the committee learned that the German firm Schering had purchased bulk estradiol progynon (for symptoms associated with menopause) from Roussell of France for resale in the United States. When the committee compared the cost of the bulk product and what Schering charged for tablets produced therefrom, they discerned a markup of 7000% (117). The Schering president objected that such a hyperbolic figure ignored the costs of manufacturing, advertising, distribution, and research on this drug. Kefauver replied that Schering would have incurred no research costs for this Roussell drug itself. When the hearings shifted into a study of drug costs as a function of research expenses in the industry, A. Dale Console, a former medical director at Squibb, testified that research indeed leads to many failures, but that the problem arises out of the fact that [firms] market so many of their failures (118). The hearings thus took on another dimension by investigating advertising practices of the pharmaceutical industry
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and the delivery of information about their drugs to doctors. Records subpoenaed by Kefauver from the 22 largest firms revealed that in 1958 they expended an average of one fourth of their gross income on advertising. Investment in detail men represented a considerable portion of that expense, as estimates for the same year indicated a detail force for the industry of 15,000, or one for every 10 doctors (119). The committee also heard about the relationship between FDA and the pharmaceutical industry. Former FDA medical officer Barbara Moulton, described an acquiescent agency, frequently and inappropriately deferring to the wishes of firms. The committees inquiry into Henry Welch, director of the Antibiotic Division at FDA, who developed a lucrative business in medical reprint sales with drug companies, revealed a highranking regulatory official who was, at minimum, far too cozy with regulated interests (120). After 10 months of hearings, Kefauvers committee had raised a number of concerns, concerns that soon would be reflected in proposed legislation, introduced by Kefauver on April 12, 1961 (121124). Kefauver first addressed patents in his bill, severely curtailing the monopoly that drug companies would have on their products (an outgrowth of another facet of the hearings). The bill also gave FDA increased authority over drug production, distribution, and advertising. Food and Drugs inspection authority would be enhanced to uphold stronger qualitycontrol standards in a system reminiscent of that applied to biologics. Advertising would include explicit and prominent warnings, again responding to problematical issues during the hearings. The law would extend FDAs role for batch certification of selected antibiotics to all such drugs, not just those covered by the amendments up to the early 1950s. The drug clearance provision of the 1938 act, in which a drug application became effective after 60 days unless prevented by specific FDA action, would be ended under this bill. Finally, sponsors would have to shows drugs to be effective as well as safe (125). Opposition emerged quickly. The AMA, for example, came out strenuously opposed to the effectiveness requirement, arguing that only the physician can make a determination if a drug works or not. The industry, operating in part through
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its trade association, the Pharmaceutical Manufacturers Association, worked vehemently against elements of the bill that would affect its profits and force firms to advertise a drugs adverse reactions as well as its indications. The support of the White House was tepid at best (126). The process of negotiation, dilution, and revision ensued once Kefauvers bill cleared his subcommittee, proceeded to a parent committee, and then to the full Senate. However, unbeknownst to Kefauver and his colleagues, at this time a drug disaster was developing that would have an impact on Kefauvers law analogous to the legislative effect of the Elixir Sulfanilamide tragedy. On September 12, 1960, the William S. Merrell Company of Cincinnati submitted an application for Kevadon, known generically as thalidomide. Merrell was the U.S. licensee for the German firm Chemie Grunenthal, which introduced this sedative in Europe in 1956. The application was routed to Frances Kelsey, who had replaced Barbara Moulton. Kelseys superiors believed this apparently straightforward NDA would be appropriate for a newcomer. However, Kelsey found the chronic toxicity data inadequate to support the safety of the drug and the labeling unsuitable. Merrell continued to append data to the application, which Kelsey continued to find inadequate to the task. The contacts between Merrell and Kelsey or her superiors thereafter occurred almost weekly until the spring, as the firm was rushing to make a March 1 launch date for Kevadon. At this time Kelsey also was deeply involved in FDAs administrative hearing with Eaton Laboratories over Altafur. But crucial news emerged in February 1961, when the medical officer read a report in the December 1960 issue of the British Medical Journal that associated long-term use of thalidomide with peripheral neuritis. When representatives from Merrell met with Kelsey in May to discuss this revelation (which Merrell believed rather inconsequential, assuming the effects were reversible), Kelsey requested evidence that Kevadon would be safe in pregnancy. Although the request was based on a theoretical consideration stemming from the neurological side effect, it was consistent with Kelseys own
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training as a pharmacologist at the University of Chicago, and it was shared by her medical officer colleagues at FDA. Merrell and outside clinical investigators representing the company continued to argue that Kevadon was effective and safe relative to the barbiturates, the firm now hoping to meet a November 1961 launch in time for the holidays. But on the last day of that month, Merrell reported to Kelsey that thalidomide had been withdrawn from Germany, where use of the drug had been correlated with severe congenital abnormalities. On March 8, 1962, Merrell withdrew its NDA for Kevadon. The United States narrowly escaped the fate of many other countries. But the agency learned in April for the first time the true scale of Merrells investigation. Over 1100 doctors received Kevadon (the agency had assumed from three to six dozen investigators were involved), and the investigation involved about 20,000 patients, 624 of whom were pregnant. Despite assurances by Merrell that a recall had been completed, field investigators discovered that over 25,000 doses were still unaccounted for in August, prompting an Elixir Sulfanilamidelike national search for outstanding samples of the drug. Seventeen cases of thalidomide-induced phocomelia occurred in the U.S., seven of which were documented to be caused by thalidomide obtained outside of the Merrell study (127129). The shock of what might have happened with thalidomide wrested the drug regulation reform bill from congressional inertia, and President Kennedy, surrounded by Kefauver, Kelsey, and others, signed the bill into law on October 10, 1962 (130) (see Fig. 6). Much had changed from the bill Kefauver introduced, but some elements remained. Attempts to cut costs via patent adjustments were long gone, as was the biologics-like system of licensing (although firms had to register). Manufacturers had to prove that their drugs were effective as well as safenot just drugs introduced from that point forward, but all new drugs introduced since 1938. FDAs control over the clinical investigation of drugs was clarified and strengthened, and a surprise provision required experimental subjects to give informed consent. Safety, effectiveness, and reliability of a drug would be further provided for by requiring
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Figure 6 President Kennedy hands Senator Kefauver one of the pens used to sign the 1962 Drug Amendments. Among those looking on is Frances Kelsey, standing second from left.
that production adhere to current good manufacturing practice, although that provision was made clear in FDA regulations as far back as the early 1940s (131). New drug clearance would no longer be based on an application becoming effective automatically after 60 days unless FDA action indicated otherwise; a new drug now could be marketed only with FDAs assent. Oversight of prescription drug advertising was transferred from FTC to FDA. And finally, drug inspectors would have enhanced access to establishment records other than financial or personnel documents (132). 11. CONCLUSION The 1962 law was a landmark in the history of drug regulation, and no law since has been as sweeping in its coverage of the
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pharmaceutical enterprise. But subsequent laws and regulations stand out, too, for many reasons. For example, the rise in the consumer movement certainly had an impact on drug regulation. The issuance of the first patient package insert in 1970, for oral contraceptives, followed pointed protest by womens health advocates against AMAs opposition to this precedent in patient education (133). The Vitamins and Minerals Amendment (Proxmire Amendment) of 1976, which prevented FDA from limiting potency of supplements or regulating them as drugs, was due in no small part by organized efforts of consumers to inundate their members of Congress and FDA with letters of protest on a scale unheard of at that time (134,135). The National Organization for Rare Disorders led the effort behind the Orphan Drug Act of 1983 to persuade pharmaceutical companies to develop drugs, otherwise unprofitable, for diseases with small patient populations (136,137). In the same year, as part of an overall revision of investigational new drug (IND) procedures (the IND rewrite), FDA proposed so-called treatment-use INDs, expanding physician and patient access to experimental drugs for therapeutic rather than investigational purposes in patients with serious diseases or conditions, for whom alternative therapies do not exist or cannot be used (138140). However, there were several restrictions to treatment INDs, such as the need to have a firm request treatment IND status, to be treated by a physician skilled in therapy of that disease, and to have no other therapies available. Activists representing HIV and AIDS victims, families, and friends engaged FDA directly on this issue and helped not only to relax these restrictions but refocus the overall drug development and evaluation process. FDA thereafter would consult with sponsors to plan more efficient clinical studies of drugs for life-threatening and severely debilitating diseases, modeled on the testing and evaluation of AZT (141,142). Moreover, continuing pressure by AIDS activists for expedited access to experimental therapies figured in a policy announced by FDA Commissioner Frank Young in July 1988. Individuals would be allowed to return to the country with a 3-month supply of any drug desired as long as the agency ensured that the product was not fraudulent, counterfeit, or harmful,
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and if the traveler presented the name and address of the physician responsible for the treatment. The volleying over IND and NDA policies between FDA and the AIDS community continued into the 1990s (143). The history of drug regulation has come full circle, from the second decade of the nineteenth century, when a Maryland physician persuaded Congress to pass a law to ensure genuine smallpox vaccine, to the first decade of the twenty-first century, when the United States again faced smallpox vaccination as a policy issue. In between we have witnessed a vast array of stimuli to changes in the way drugs are regulated. Therapeutic disaster and concomitant outrage, of course, are perhaps the most visible sources for tectonic shifts in policy. But political upheaval, organized social action, institutionalization of professional authority, the political and economic strength of the drug industry, the will and whims of all three branches of government, the manner in which the fourth estate captures and conveys regulatory issues, and basic shifts in therapeutics itself all have had an impact on the way this country regulates drugs. FDA often refers to itself as a science-based regulatory agency, but the context for drug regulation over the past 200 years has been and will always be much broader than science and law.
NOTES AND REFERENCES

1. AJ Wedderburn. A Compilation of the Pharmacy and Drug Laws of the Several States and Territories. Bulletin 42, Division of Chemistry, U.S. Department of Agriculture. Washington, DC: GPO, 1894, passim. G Sonnedecker, G Urdang. Legalization of drug standards under state laws in the United States of America. Food Drug Cosmetic Law Journal 8: 741760, 1953. PB Hutt, RA Merrill. Food and Drug Law: Cases and Materials. 2nd ed. Westbury, NY: Foundation Press, 1991, pp. 660661 (quote from p. 660). I am indebted to Peter Hutt for bringing this important development to my attention.
2.
3.
35
4. 5.
Pharmacopoeia of the United States of America. Boston: Charles Ewer, 1820, p. 17. G Sonnedecker. The Founding Period of the U.S. Pharmacopeia: I. European Antecedents. Pharmacy in History 35: 151162, 1993. G Sonnedecker. The Founding Period of the U.S. Pharmacopeia: II. A National Movement Emerges. Pharm. Hist. 36: 325, 1994. G Sonnedecker. The Founding Period of the U.S. Pharmacopeia: III. The First Edition. Pharm. Hist. 36: 103122, 1994. L Anderson, GJ Higby. The Spirit of Voluntarism, A Legacy of Commitment and Contribution: The United States Pharmacopeia. Rockville, MD: USP, 1995, pp. 725. Quoted in C Ridgway. Good Enough for America! The Drug Import Law of 1848. Seminar paper, University of Wisconsin, Madison, WI, 1986. Cited in: JH Young. Pure Food: Securing the Federal Food and Drugs Act of 1906. Princeton, NJ: Princeton University Press, 1989, p. 7. Young. Pure Food, pp. 67. Congressional Globe. 30th Cong., 1st sess., 1 December 1847 15 August 1848, p. 858. Drug Import Act. Public Law [3045]. 9 U.S. Stat. 237, 26 June 1848 (quote is from Sec. 1). Young. Pure Food, pp. 1417. M Okun. Fair Play in the Marketplace: The First Battle for Pure Food and Drugs. DeKalb, IL: Northern Illinois University Press, 1986, pp. 1415. G Sonnedecker. Contributions of the pharmaceutical profession toward controlling the quality of drugs in the nineteenth century. In: JB Blake, ed. Safeguarding the Public: Historical Aspects of Medicinal Drug Control. Baltimore: Johns Hopkins University Press, 1970, pp. 105111. HF Dowling. Fighting Infection: Conquests of the Twentieth Century. Cambridge, MA: Harvard University Press, 1977.
6.
7.
8.
9.
10. 11. 12. 13. 14.
15.
16.
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17.
HA. Lechevalier, M Solotorovsky. Three Centuries of Microbiology. New York: McGraw-Hill, 1965; New York: Dover, 1974. Treasury Department, Marine Hospital Service. Annual Report of the Supervising Surgeon-General of the Marine-Hospital Service of the United States for the Fiscal Year 1895. Washington, DC: GPO, 1896, p. 327. Treasury Department, Marine Hospital Service. Annual Report 1895, pp. 329335. RA Kondratas. Biologics Control Act of 1902. In: The Early Years of Federal Food and Drug Control. Madison, WI: American Institute of the History of Pharmacy, 1982, p. 11. The laboratory notebook that documents the Hygienic Laboratorys work (in the possession of the Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland) and a sample of the standard itself (in the possession of the Division of Science, Medicine, and Society, National Museum of American History, Smithsonian Institution, Washington, D.C.) were incorporated as part of an exhibit, Safety for Millions: The Biologics Control Act of 1902 Centennial, National Museum of American History, Smithsonian Institution, Washington, DC, September 2002. U.S. Congress, House. Sale of Viruses, Etc., in the District of Columbia. Report No. 2713, to Accompany H. R. 15289, 57th Cong., 1st sess., 27 June 1902, pp. 67 (testimony of George M. Kober, Acting Chairman, Medical Society of the District of Columbia, Washington, DC, 16 April 1902). Reproduced in: Legislative History of the Regulation of Biological Products. N. p.: Division of Biologics Standards, National Institutes of Health, Department of Health, Education, and Welfare, 1967. Biologics Control Act. Public Law 57244. 32 U.S. Stat. 728, 1 July 1902. Perhaps it is more accurate to say that any charges brought under the 1902 act or under its consolidation in the 1944 Public Health Service Act were not contested. The suit brought by the government against John P. Calise and the Westchester Blood Bank in 1962 for altering expiration dates appears to be
18.
19. 20.
21.
22.
23. 24.
37
the first litigated case of any kind under the 1902 Biologics Act. 25. JM Solomon. Legislation and regulation in blood banking. In: M Schaeffer, ed. Federal Legislation and the Clinical Laboratory. Boston: G. K. Hall, 1981, p. 150. PB Hutt, personal communication, 12 September 2002, who suspects that Calise might have been the first case. Kondratas. Biologics Control Act of 1902. Treasury Department, Public Health and Marine-Hospital Service. Annual Report of the Surgeon-General of the U.S. Public Health and Marine-Hospital Service of the United States for the Fiscal Year 1904. Washington, DC: GPO, 1904, p. 372. Treasury Department, Public Health and Marine-Hospital Service. Annual Report of the Surgeon-General of the U.S. Public Health and Marine-Hospital Service of the United States for the Fiscal Year 1908. Washington, DC: GPO, 1909, p. 44. Center for Biologics Evaluation and Research, Food and Drug Administration. Science and the Regulation of Biological Products: From a Rich History to a Challenging Future. N. p.: [CBER], 2002. 17 U.S. Stat. 322323, 18 June 1872. 28 U.S. Stat. 963, 2 March 1895. JH Young. The Medical Messiahs: A Social History of Health Quackery in Twentieth-Century America. Princeton, NJ: Princeton University Press, 1967; rev. ed., 1992, pp. 66 ff., 8687. LF Kebler. Public Health Conserved through the Enforcement of Postal Fraud Laws. Am J Public Health 12: 678683, 1922. Young. Medical Messiahs, pp. 122128. Young. Medical Messiahs, pp. 296315. Wheeler-Lea Amendments. Public Law 75447. 52 U.S. Stat. 111, 21 March 1938.
26. 27. 28.
29.
30.
31. 32. 33.
34.
35. 36. 37.
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38. 39.
M Handler. The control of false advertising under the WheelerLea Act. Law Contemp Problems 6: 91110, 1939. M Fishbein. A History of the American Medical Association. Philadelphia: W. B. Saunders, 1947, pp. 226227, 235236. A Smith. The Council on Pharmacy and Chemistry and the chemical laboratory. In: Fishbein. American Medical Association, pp. 876877, 884885. JG Burrow. The prescription drug policies of the American Medical Association. In: Blake. Safeguarding the Public, pp. 113114. P Starr. The Social Transformation of American Medicine. New York: Basic Books, 1982, p. 133. H Marks. The Progress of Experiment: Science and Therapeutic Reform in the United States, 19001990. Cambridge: Cambridge University Press, 1997, pp. 2341. Smith. Council on Pharmacy and Chemistry and the Chemical Laboratory, pp. 870 ff. AE Smith. The Council on Pharmacy and Chemistry. J Am Med Assoc 124: 434 ff., 1944. HF Dowling. Medicines for Man: The Development, Regulation, and Use of Prescription Drugs. New York: Alfred A. Knopf, 1970, pp. 170177. It was more than a possibility; see the case of Clarin (heparin potassium), as discussed in U.S. Congress, Senate, Subcommittee on Antitrust and Monopoly of the Committee on the Judiciary. Drug Industry Antitrust Act. Hearings pursuant to S. Res. 52 on S. 1552, 87th Cong., 1st sess., 13 and 15 September 1961 and 1213, 1829 December 1961, Part 5. Washington, DC: GPO, 1962, pp. 25872588. Reproduced in: A Legislative History of the Federal Food, Drug, and Cosmetic Act and Its Amendments 20: 329330. J Bishop. Drug evaluation programs of the AMA, 19051966. J Am Med Assoc 196: 122123, 1966. New program of operation for evaluation of drugs. J Am Med Assoc 158: 11701171, 1955.
40.
41.
42. 43.
44. 45. 46.
47.
48. 49.
39
50.
HF Dowling. The impact of the new drug laws on the Council on Drugs of the American Medical Association. Clin Res 13: 162165, 1965. MK Weikel. Research as a function of pharmaceutical industry: The American formative period. M. S. thesis, University of Wisconsin, Madison, WI, 1962, pp. 2936. DL Cowen. The role of the pharmaceutical industry. In: Blake. Safeguarding the Public, p. 73. J Liebenau. Medical Science and Medical Industry: The Formation of the American Pharmaceutical Industry. Baltimore: Johns Hopkins University Press, 1987, passim, but especially, pp. 5778. JP Swann. Academic Scientists and the Pharmaceutical Industry: Cooperative Research in Twentieth-Century America. Baltimore: Johns Hopkins University Press, 1988, pp. 923. JH Madison. Eli Lilly: A Life, 18851977. Indianapolis: Indiana Historical Society, 1989, pp. 27, 52. JH Young. Even to a sucking infant: nostrums and children. In: American Health Quackery: Collected Essays by James Harvey Young. Princeton, NJ: Princeton University Press, 1992, pp. 135, 138. GL Nelson, ed. Pharmaceutical Company Histories, vol. 1. Bismarck, ND: Woodbine, 1983, p. 161. J Liebenau. A case unresolved: Mrs. George vs. Dr. Hand and his colic cure. Pharm Hist 31: 135138, 1989. The best source on the history of patent medicines remains JH Young. The Toadstool Millionaires: A Social History of Patent Medicines in America before Federal Regulation. Princeton, NJ: Princeton University Press, 1961. Youngs Medical Messiahs and his American Health Quackery also address this subject. Young. Pure Food, pp. 5051. Wiley typically emphasized the problem of food adulteration as a more serious public health issue than drug adulteration, perhaps in part because of his scientific background.
51.
52. 53.
54.
55. 56.
57. 58. 59.
60. 61.
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62. 63.
On Wiley and his time, see HW Wiley. An Autobiography. Indianapolis: Bobbs-Merrill, 1930. OE Anderson. The Health of a Nation: Harvey W. Wiley and the Fight for Pure Food. Chicago: University of Chicago Press, 1958. Young. Pure Food. Food and Drugs Act of 1906. Public Law 59-384. 34 U.S. Stat. 768, 30 June 1906. A Thackray, JL Sturchio, PT Carroll, RF Bud. Chemistry in America, 18761976: Historical Indicators. Dordrecht: D. Reidel, 1985, pp. 126131. For bibliographic information on the variety of regulations issued by the bureau at this time, see A Guide to Resources on the History of the Food and Drug Administration: Published Primary Sources: Sources on Regulation and Enforcement. <http://www.fda.gov/oc/history/resourceguide/ sources.html>, 18 January 2002. A Sellers, ND Grundstein. Administrative Procedure and Practice in the Department of Agriculture under the Federal Food, Drug, and Cosmetic Act of 1938. 308-page typescript in 2 parts. Part I: 12 (files, FDA History Office, Rockville, MD). MG White, OH Gates. Decisions of Courts in Cases under the Federal Food and Drugs Act. Washington, DC: GPO, 1934, pp. 267269 (quote is from p. 268). Quoted in Young. Drugs and the 1906 Law, p. 149. Sellers, Grundstein. Administrative Procedure and Practice. 1: 1415, n. 31. Sherley Amendment of 1912. Public Law 62-301. 37 U.S. Stat. 416, 23 August 1912. RdeF Lamb. American Chamber of Horrors. New York: Farrar and Rinehart, 1936, pp. 6468. Young. Drugs and the 1906 Law, pp. 147152. Young, Drugs and the 1906 Law, pp. 149152. JP Swann. FDA and the practice of pharmacy: prescription drug regulation to 1951. Pharm Hist 36: 5759, 1994.
64. 65. 66.
67.
68.
69.
70. 71. 72. 73. 74. 75. 76.
41
77. 78.
Young. Drugs and the 1906 Law, pp. 153156. On the effort by FDA to promote the need for a new law, see G. Kay. Healthy Public Relations: The FDAs 1930s Legislative Campaign. Bull Hist Med 75: 446487, 2001. The standard source on the construction of the 1938 Food, Drug, and Cosmetic Act is CO Jackson. Food and Drug Legislation in the New Deal. Princeton, NJ: Princeton University Press, 1970. An excellent source on the Elixir Sulfanilamide disaster is JH Young. Sulfanilamide and diethylene glycol. In: J Parascandola, JC Whorton. Chemistry and Modern Society: Historical Essays in Honor of Aaron J. Ihde. American Chemical Society Symposium Series 228. Washington, DC: American Chemical Society, 1983, pp. 105125. Elixir of Death. RubinTarrant Productions, History Channel, 11 December, 2003. The letter quoted is reproduced in the files, FDA History Office, Rockville, MD. Food, Drug, and Cosmetic Act. Public Law 75717. 52 U.S. Stat. 1040, 25 June 1938. A recent article has shed light on this provision of the act, largely forgotten by those who would believe a requirement for good manufacturing practices began in 1962 (or even later). DE Cooper. Adequate Controls for New Drugs: Good Manufacturing Practice and the 1938 Federal Food, Drug, and Cosmetic Act. Pharm. Hist. 44: 1223, 2002. DF Cavers. The Evolution of the Contemporary System of Drug Regulation under the 1938 Act. In: Blake. Safeguarding the Public, pp. 167168. Warning Statements for Drug Preparations. TC-14, 1 November 1940. Reproduced in: VA Kleinfeld, CW Dunn. Federal Food, Drug, and Cosmetic Act: Judicial and Administrative Record, 19381949. Chicago: Commerce Clearing House, c. 1949, pp. 574578; quote is from p. 577. HM Marks. Revisiting The Origins of Compulsory Drug Prescriptions. Am J Public Health 85: 109115, 1995.
79.
80.
81. 82. 83. 84.
85.
86.
87.
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Swann
88. 89.
Swann. FDA and the Practice of Pharmacy. To Distributors of Sulfanilamide and Related Drugs. TC-1, 26 August 1938. Reproduced in: Kleinfeld, Dunn. Federal Food, Drug, and Cosmetic Act, p. 561. The generalization about prescription drugs applies, of course, only to nonnarcotic drugs. The latter could be dispensed only under a doctors authorization under the Harrison Narcotic Act of 1914. An Act to Amend the Federal Food, Drug, and Cosmetic Act. Public Law 82-215. 65 U.S. Stat. 648, 26 October 1951. The illegal trade in amphetamines and barbiturates in the trucking industry received dramatic treatment on television in the early 1960s: 330 Independence SW. The Dick Powell Theater, NBC, 20 March 1962. Drug Abuse Control Amendments of 1965. Public Law 89-74. 79 U.S. Stat. 226, 15 July 1965. JP Swann. Drug abuse control under FDA, 19381968. Public Health Rep 112: 8386, 1997. Insulin Amendment of 1941. Public Law 77-366. 55 U.S. Stat. 851, 22 December 1941. Penicillin Amendment of 1945. Public Law 79-139. 59 U.S. Stat. 462, 6 July 1945. Streptomycin Amendment. Public Law 80-16. 61 U.S. Stat. 11, 10 March 1947. Aureomycin Amendment of 1949. Public Law 81-164. 63 U.S. Stat. 409, 13 July 1949, which accounted for chlortetracycline, chloramphenicol, and bacitracin. Cavers. In: Blake. Drug Regulation under the 1938 Act, p. 167. Directions for Use. TC-426, 22 January 1945. Reproduced in: Kleinfeld, Dunn. Federal Food, Drug, and Cosmetic Act, p. 746. Lollipops Containing Aspirin. TC-130, 7 March 1940. Reproduced in: Kleinfeld, Dunn. Federal Food, Drug, and Cosmetic Act, p. 620.
90.
91. 92.
93. 94. 95. 96. 97. 98.
99. 100.
101.
43
102. 103.
Specific NDAs were collected from NDA summary data, files, FDA History Office, Rockville, MD. RH Mandel. A Half Century of Peer Review, 19461996. Bethesda, MD: Division of Research Grants, National Institutes of Health, 1996, especially pp. 16 ff. Swann. Academic Scientists and the Pharmaceutical Industry. R Landau, B Achilladelis, A Scriabine. Pharmaceutical Innovation: Revolutionizing Human Health. Philadelphia: Chemical Heritage Press, 1999, pp. 72 ff. P de Haen. Compilation of New Drugs, 1940 thru 1975. Pharmacy Times 1976; 42 (no. 3): 4075. P de Haen. New Drug Parade: A Historical Minireview, 19541982. Poster exhibit presentation. Drug Information Association Annual Meeting, Washington, D.C., 28 July 1983. Englewood, CO: Paul de Haen International, 1983. Cavers. Drug Regulation under the 1938 Act, pp. 164 (rauwolfia), 167 (NDA submission rates). U.S. Department of the Treasury, Public Health Service. Regulations for the Sale of Viruses, Serums, Toxins and Analogous Products in the District of Columbia and in Interstate Traffic. Misc. Publication No. 10, Approved 13 March 1934. Washington, DC: GPO, 1934, p. 3. JP Swann. Sure cure: public policy on drug efficacy before 1962. In GJ Higby, EC Stroud. The Inside Story of Medicines: A Symposium. Madison, WI: American Institute of the History of Pharmacy, 1997, pp. 228232, 235237. GA Granger to RW Weilerstein, 14 October 1955, NDA 9214, Misc. File IV, FDA Records, Rockville, MD. Quoted in Swann. Sure Cure, p. 244. The Hepasyn case is drawn from Swann. Sure Cure, pp. 237246 (Holland quote is from p. 244). Around the same time, an HEW-requested review of antibiotic decisions made by FDA in the wake of the Henry Welch affair, conducted by the National Research Council, led to a similar conclusion. See Swann. Sure Cure, p. 248.
104. 105.
106. 107.
108. 109.
110.
111. 112. 113. 114.
44
Swann
115. 116. 117. 118. 119. 120.
M Mintz. The Therapeutic Nightmare. Boston: Houghton Mifflin, 1965, pp. 5456. Swann. Sure Cure, pp. 246250. R Harris. The Real Voice. New York: Macmillan, 1964, pp. 5964. Quoted in Harris. The Real Voice, pp. 7879. Harris. The Real Voice, pp. 8891. RE McFadyen. FDAs Regulation and Control of Antibiotics in the 1950s: The Henry Welch Scandal, Felix Mart-Ibanez, and Charles Pfizer and Co. Bull. Hist. Med. 53: 159169, 1979. Harris. The Real Voice, captures the hearings succinctly, though weighted toward Kefauvers perspective; the preceding description draws from pp. 5116. RE McFadyen. Estes Kefauver and the drug industry. Ph.D. dissertation, Emory University, Atlanta, GA, 1973. The complete hearings are reproduced in A Legislative History of the Federal Food, Drug, and Cosmetic Act and Its Amendments 17: 178558 (Report No. 448, pursuant to S. Res. 52, a study of administered prices in the drug industry, 27 June 1961); 17: 559807 (Hearings, Part 1; 5, 6, 18 21, 25 July 1961); 18: 1212 (Hearings, Part 1; cont.); 18: 213944 (Hearings, Part 2; exhibits and appendices); 19: 1 799 (Hearings, Part 3; 1618, 31 October 1961 and 1, 9 November 1961); 19: 800899 (Hearings, Part 4; 79 December 1961); 20: 1313 (Hearings, Part 4; cont.); 20: 314797 (Hearings, Part 5; 13, 15 September 1961, 1213 and 1820 December 1961). In addition, the hearings before the Committee on Interstate and Foreign Commerce in the House of Representatives on the Drug Industry Act of 1962 (H. R. 11581 and 11582), under Chairman Oren Harris of Arkansas, 1922 June 1962 and 2023 August 1962, are reproduced in A Legislative History of the Federal Food, Drug, and Cosmetic Act and Its Amendments 21: 170883. On Kefauver in general, see CL Fontenay. Estes Kefauver: A Biography. Knoxville: University of Tennessee Press, 1980.
121.
122. 123.
124.
45
125.
U.S. Congress, Senate. S. 1552. A bill to amend and supplement the antitrust laws with respect to the manufacture and distribution of drugs, and for other purposes, 87th Cong., 1st sess., 12 April 1961. Reproduced in: A Legislative History of the Federal Food, Drug, and Cosmetic Act and Its Amendments 17: 121144. Harris. The Real Voice, pp. 123153. The preceding account is drawn from U.S. Congress, Senate, Subcommittee on Reorganization and International Organizations of the Committee on Government Operations. Interagency Coordination in Drug Research and Regulation. Hearings pursuant to S. Res. 276, 87th Cong., 2d sess., 1, 9 August 1962, Part 1 of 2. Washington, DC: GPO, 1963, pp. 75 ff. RE McFadyen. Thalidomide in America: a brush with tragedy. Clio Med 11: 7986, 1976. P Knightley, H Evans, E Potter, M Wallace. Suffer the Children: The Story of Thalidomide. New York: Viking Press, 1979, which provides the most detail to this story. Two months earlier Kennedy conferred on Kelsey the Presidents Award for Distinguished Federal Civilian Service (the highest award for federal civilian service) for work that . . . prevented a major tragedy of birth deformities in the United States . . .; Presentation of The Presidents Award for Distinguished Federal Civilian Service. Program, the White House, 7 August 1962, files, FDA History Office. See the report that made public Kelseys role in the Kevadon review: M Mintz. Heroine of FDA Keeps Bad Drug Off Market. Washington Post, 15 July 1962. JP Swann. The 1941 sulfathiazole disaster and the birth of good manufacturing practices. PDA J Pharmaceut Sci Technol 53: 148153, 1999. Drug Amendments of 1962. Public Law 87781. 76 U.S. Stat. 780, 10 October 1962. See LV Marks. Sexual Chemistry: A History of the Contraceptive Pill. New Haven, CT: Yale University Press, 2001, pp. 150152.
126. 127.
128. 129.
130.
131.
132. 133.
46
Swann
134. 135. 136. 137.
Health Research and Health Services Amendments of 1976. Public Law 94278. 90 U.S. Stat. 401, 22 April 1976. RD Apple. Vitamania: Vitamins in American Culture. New Brunswick, NJ: Rutgers University Press, 1996. Orphan Drug Act. Public Law 97414. 96 U.S. Stat. 2049, 4 January 1983. LR Basara, M Montagne. Searching for Magic Bullets: Orphan Drugs, Consumer Activism, and Pharmaceutical Development. New York: Haworth Press, Pharmaceutical Products Press, 1994, pp. 143 ff. 48 Fed Reg 26721, 26728-26730, 2674226743, 9 June 1983. Cf. 52 Fed Reg 88508857, 19 March 1987. 52 Fed Reg 1946619477, 22 May 1987, which reproposed and then finalized the proposalafter 4 years. This citation itemized several diseases as illustrations of those normally considered immediately life-threatening, including advanced AIDS cases, advanced congestive heart failure, and severe combined immunodeficiency syndrome, as well as examples of serious diseases, such as Alzheimers disease, advanced Parkinsons disease, and active advanced lupus. Treatment INDs would not apply to those suffering the latter group of serious diseases (p. 19467). 53 Fed Reg 4151641524, 44144. The Presidents Task Force on Regulatory Relief certainly had a significant role as well in this reappraisal of the drug approval process. For a summary of investigational drug revisions and the role of AIDS activists, see JH Young. AIDS and the FDA. In: C Hannaway, V Harden, J Parascandola. AIDS and the Public Debate. Amsterdam: IOS Press, 1995, pp. 5466.
138. 139. 140.
141. 142.
143.
2
The New Drug-Approval Process Before and After 1962
MICHAEL P. PESKOE Palmer & Dodge Boston, Massachusetts, U.S.A.
1. INTRODUCTION The history of the regulation of pharmaceuticals in the United States has been an evolving one, shaped by both historical events and perceptions of medical need. It has also been affected significantly by the ongoing tensions between the various societal components involved either directly or indirectly in the process: what are now commonly known as stakeholders. These include the pharmaceutical industry; the government [mostly as represented by the U.S. Food and Drug Administration (FDA) and its predecessor agencies]; the consuming public (either represented by proxy by the government,
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or by self-appointed consumer groups, but rarely by consumers themselves); and the medical profession. It has also been shaped in part by the general evolution of administrative and regulatory practice during the past 40 years. Although the regulation of pharmaceuticals predates significantly the regulation of the subject matter of many other modern regulatory agencies, such as the Environmental Protection Agency (EPA), the Federal Aviation Administration (FAA), the National Traffic and Motor Vehicle Safety Agency (NHTSA), the Consumer Protection Safety Commission (CPSC), and the Federal Trade Commission (FTC), its recent evolution has been affected by the development of modern tenets of American administrative law and practice. While the need for federal government approval of pharmaceuticals prior to their marketing has been a fundamental part of the regulatory landscape for more than 60 years, it was not always so. Notwithstanding the greatly diminished controversy over this policy that exists today, particularly with respect to governments prior approval of drug effectiveness, pressures continue to be applied to the approval system. These pressures result from both external events and market forces. As a consequence, the countrys drug approval regulatory system still presents an interesting study of the evolution of a regulatory system almost 100 years old, yet still fluid and subject to continuing change.
2. THE FEDERAL FOOD AND DRUGS ACT OF 1906 Known as the Wiley Act, in honor of Henry A. Wiley, the first director of the governments Office of Chemistry in the Department of Agriculture, and also as the Pure Food and Drugs Act, this first foray into actual government regulation of drugs embodies concepts that still remain in the current legislation, though in a secondary role. The act proscribed the manufacture and interstate shipment in the United States of adulterated or misbranded drugs (or foods), making both
Drug-Approval Before and After 1962
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criminal (a misdemeanor). 1. Adulterated and misbranded were defined in the law, in a manner more limited than today. The former was defined essentially as noncompliance with the United States Pharmacopeia or National Formulary, or generally if strength or purity fell below the professional standard or quality under which the drug was sold. 2. The latter proscribed any statement in either the package or label of a drug regarding the article or its ingredients that was false or misleading in any particular, or if the drug were an imitation of another drug, or if the packaging were removed, or failed to contain a statement on the label of the quantity of any alcohol or other named potentially toxic substances. 3. No prior approval requirements were contained in the statute, nor is there any suggestion they were entertained. Rather, the act was essentially a truthin-labeling statute, directed in part at controlling the manufacture and sale of worthless and potentially dangerous patent medicines and requiring the government to find illegal conduct after the fact if it wished to prosecute.
3. THE 1912 SHIRLEY AMENDMENT In a 1911 Supreme Court decision, United States v. Johnson (4), involving a criminal indictment for the interstate shipment of medicine falsely labeled as a cure for cancer, the Court found that the proscription in the 1906 law against the misbranding of drugs dealt only with false statements as to characteristics of identity, such as strength, quality, or purity, but not with claims of effectiveness. As a result, in 1912 Congress added language to the misbranding provisions that proscribed, in the case of drugs, any statement regarding curative or therapeutic effect, which is false and fraudulent (5). Although
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extending the statutes enforcement reach to fraudulent claims of efficacy, the amendment gave FDA no premarket approval power over drugs or related products. 4. 1938 FEDERAL FOOD, DRUG AND COSMETIC ACT 4.1. Statutory Drug-Approval Provisions In 1933, Congress began a 5-year effort at amending the 1906 Act that would ultimately create the framework of human drug regulation that exists today. Between the initiation of congressional debate and passage, over 100 children died from taking a drug called Elixir Sulfanilimide, in which a manufacturer placed a well-known and accepted drug, sulfanilimide, into a new vehicle, diethylene glycol (now used in antifreeze), that was unfortunately fatally toxic to those who took it. As enacted, the new Federal Food, Drug and Cosmetic Act of 1938 added the first requirements for premarket approval of drugs. It defined both drugs and new drugs in a manner still utilized today: the former to encompass the wide range of medicants sold or likely to be sold to alleviate human disease, and the latter in a manner that would effectively subject to prior approval every new drug entity and product and, after the agencys lawyers were through interpreting the law, older ones as well. As enacted in 1938, new drug was defined as follows (6):
Sec. 201 . . . (p) The term new drug means (1) Any drug the composition of which is such that such drug is not generally recognized, among experts qualified by scientific and experience to evaluate the safety of drugs, as safe for use under the conditions prescribed, recommended, or suggested in the labeling thereof, except that such a drug not so recognized shall not be deemed to be a new drug if at any time prior to enactment it was subject to the Food and Drugs Act of 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use; or
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(2) Any drug the composition of which is such that such drug, as a result of investigations to determine its safety for use under such conditions, has become so recognized, but which has not, otherwise than in such investigations, been used to a material extent or for a material time under such conditions.
At the same time that it defined new drug, the new law prohibited the introduction or delivery for introduction into interstate commerce of any new drug unless an application filed pursuant to the new act was effective with respect to such drug (7). This was the initial premarket approval requirement for drugs. A new drug application (NDA) was required to contain full reports of investigations which have been made to show whether or not such drug is safe for use (8), as well as articles used as components, a full statement of composition, methods used in and facilities and controls used for manufacturing, processing and packing the drug, samples of the drug as required by the Secretary, and specimens of labeling (9). An application would become effective on the sixtieth day after filing, unless the effective date was postponed in writing to such time, not to exceed 180 days, as the agency determined necessary to study and investigate the application (10). In other words, an application would become effective without further action by the agency within 60 days unless the agency stopped it from becoming so. The agencys ability to so forestall an application from becoming effective was limited to 180 days (11). Provisions were also included establishing requirements for the agencys decision not to approve an application (12). These included provisions that the investigations did not include adequate tests by all methods reasonably applicable to show whether or not the drug was safe for use under the conditions set forth in labeling, that such tests show that the drug is unsafe for use under those conditions, that the methods for manufacture, processing or packing are inadequate to preserve identity, strength, quality, and purity, or whether the information submitted in the application or on the basis of any other information was insufficient to determine whether the drug was unsafe for use. However, the
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agency was required, in reaching any such conclusion, to provide both notice and an opportunity for hearing to any applicant whose application was determined not worthy of approval (13). The new statute also empowered the agency specifically to suspend the effectiveness of an approved application, again following notice and opportunity for hearing, if it found that clinical experience, new test methods, or even methods not thought applicable at the time of approval showed the drug to be unsafe for use under its labeled indications or that the application was found to contain any untrue statement of material fact (14). Should a manufacturer contest the agencys order suspending the effectiveness of an application, its recourse was filing an action in federal district court (15). In keeping with what are now modern tenets of administrative law, any new factual matters were required to be presented to the agency before any adjudication by the court. The agency conclusions as to any findings of fact were deemed conclusive (16). Finally, the new law imposed an obligation on the agency to develop regulations exempting drugs solely for investigational use from the above restrictions (17). The statutory framework enacted in 1938 is still the model in use today, with additions and modifications as outlined in the remainder of this chapter up to 1997. In establishing global criteria for premarket approval contained in the concept of new drug, the new law all but assured from that time forward that government would now evaluate drugs prior to their marketing. Definitions were written broadly: not only new drug but the definition of drug itself was written to be inclusive (18). Moreover, by including within the new drug definition the concept of general recognition, requiring that a determination of safety be recognized based on the views of experts, Congress gave the agency power to establish high barriers to market entry. On the other hand, the new law gave significant credence to an approval earned under the statute; withdrawal of an application, once approved, was not made particularly easy for the government to accomplish.
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4.2. The 1938 Grandfather Provisions and Old Drug Status Two provisions deserve special comment. The statute did exempt or grandfather certain drugs from the new drug requirements. This exemption included any drug marketed under the 1906 act whose labeling had not changed (19). Thus, at least in this respect, the law did not portend to reach backwards unless an existing drugs labeling had at some point been changed. The second exemption concerned those drugs that might be determined to be not new, that is, where general recognition of safety might already exist. In that the exemption from new drug status was obviously desirable to drug manufacturers, this would be a future area of contention. Finally, the new drug definition also seemed to create a situation in which new drug status was fluid, in which a drug that might be new today would at some point no longer be so and would no longer be subject to the myriad requirements applicable only to new drugs. This was contained in the second new drug definition, which stated, in essence, that a drug recognized by experts as safe for labeled conditions on the basis of tests conducted to establish safety, but not otherwise, and not used to a material extent or for a material time under such conditions, would nonetheless still be a new drug (20). The converse of this, that such a drug used for a material extent or for a material time would no longer be a new drug, suggests that such a drug might ultimately graduate to a postnew drug status. To date, no post-1938 prescription drug has done so. 4.3. Regulation of Antibiotics and Insulin In 1941 Congress added new special approval provisions to the 1938 act regarding drugs composed wholly or partly of insulin. Unlike the existing provisions, section 506 required that, prior to distribution, insulin be batch-certified by the agency if such drug has such characteristics identity . . . strength, quality and purity . . . as necessary to insure safety and efficacy of use(21). This was essentially a requirement that the agency itself test a sample of each batch of insulin prior to release by the manufacturer and stemmed from concern that insulin manufactured
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from live organisms required further protections compared to other drugs. Similarly, in 1945 batch-certification requirements for penicillin were added in a new section 507 and were modeled after the insulin requirements (22). Over the next several years, the requirements were extended to additional antibiotics, culminating in an extension to all antibiotics in 1962 (23). The added requirements stemmed from the fact that antibiotics were derived from microorganisms, resulting in a concern that actual batch testing by the government should be required as a condition of marketing. Although these sections included a specific requirement for effectiveness, it was assumed as part of the certification process that appropriate proof of identity, strength, quality, and purity would necessarily permit a conclusion regarding effectiveness. Ultimately, due to the added expense to the agency of supporting a batch-certification laboratory and growing confidence in the manufacturing processes of both insulin and antibiotics, both products were exempted from certification. Later, as part of legislation adopted in 1997, both sections were repealed (24). Insulin and antibiotics are now regulated like other new drugs.
5. THE DRUG EFFECTIVENESS AMENDMENTS OF 1962 5.1. Approval Provisions The modern era of drug regulation begins with the drugeffectiveness amendments of 1962. These amendments added the requirement that all new drugs be proven effective as well as safe and far more detailed requirements for the safety testing of new drugs prior to marketing, the latter as a direct result of the thalidomide tragedy that occurred in Europe (and almost in the United States) in the latter 1950s and early 1960s. The addition of an effectiveness requirement was made exceedingly complicated by the added requirement that all drugs whose safety and effectiveness were established between 1938 and 1962 would be made retroactively subject to the new effectiveness standard.
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The 1962 amendments accomplished these objectives in several ways. Initially, the statutory definition of new drug in section 201(p) of the act was amended by adding the words and effectiveness following safety where it appeared in the section (25). Thus, any drug whose effectiveness was not a matter of general recognition by experts qualified by scientific training and experience to evaluate effectiveness would be a new drug for that additional reason and subject to premarket approval requirements for effectiveness as well as safety. The requirement for general recognition of effectiveness has been the cornerstone of the agencys now generally accepted interpretation of the section that once a new drug, always a new drug. As noted previously, section 201(p)(2) of the act provided an alternative new drug definition: a drugs safety or effectiveness could be recognized (as opposed to generally recognized) on the basis of investigations, but the drug would still be a new drug if it had not been used to a material extent or for a material time. This suggested a possibility that new drugs ultimately could graduate from new drug status over time, ending their need to be subject to an effective new drug application and similarly ending their obligation to comply with numerous requirements applicable to new drugs, but not to not new drugs. It is this potential statutory movement from new drug to not new drug status that has not been acknowledged by FDA, nor sought by manufacturers, at least for the past three decades; nor has the issue been given publicity in the numerous statutory amendments to the act that have occurred during the past 15 years. Other significant changes in the FDA approval process were also implemented by the 1962 amendments. Perhaps most importantly, the amendments replaced the passive approval mechanism of the 1938 act, which permitted an NDA to become effective automatically after a 60-day period, with an active approval scheme. Section 505(c) of the act provided that (20):
Within one-hundred and eighty days after the filing of an application under subsection (b), or such additional period as
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may be agreed upon by the Secretary, and the applicant, the Secretary shall either
(A) approve the application if he then finds that none of the grounds for denying approval . . . applies, or (B) give the applicant notice of an opportunity for hearing before the Secretary . . . on the question whether such application is approvable. The new legislation also expanded significantly the provisions of the 1938 act regarding the statutory bases for refusing to approve a submitted application [section 505(d)] and for withdrawing approval of an approved application [section 505(e)]. With respect to the refusal to approve an application, the statute left the existing provisions regarding lack of safety intact, but added to them the following proscription regarding the new effectiveness requirement (27):
If the Secretary finds that, evaluated on the basis of the information submitted to him as part of the application and any other information before him with respect to such drug, there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof . . . he shall issue an order refusing to approve the application. . . . As used in this subsection . . . the term substantial evidence means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.
Thus, unlike the statutory safety test, which required simply that studies demonstrate safety, the statutory test of effectiveness, set forth ironically in the statutory section containing criteria for withholding approval, was legislated as one of substantial evidence requiring adequate and wellcontrolled investigations, including clinical investigations by
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experts qualified . . . to evaluate the effectiveness of the drug involved (28). This requirement of substantial evidence of effectiveness would play a paramount role in the decades following the 1962 enactment in enabling FDA to set the bar high before approving a drug as safe and effective (29). With respect to those provisions concerning the withdrawal of an approved (i.e., effective) application, the amendments added provisions for the withdrawal of an application should there be new information, evaluated together with the evidence available when the application was approved, that there was a lack of substantial evidence that the drug would have the effect it was represented to have according to its labeling (30). The amendments also added new provisions for the immediate suspension of the effectiveness of an application should the Secretary find an imminent hazard to the public health. The authority to implement this section was reserved to the Secretary, and was not delegable to the FDA (31). In response to the then recent thalidomide episode, Congress also greatly expanded the statutory provisions regarding the investigation of drugs. While the 1938 act had simply authorized the promulgation of regulations exempting such drugs from the prohibition against interstate shipment of unapproved new drugs, the 1962 amendments directed that the regulations consider including the submission to FDA, before the undertaking of any clinical tests using such a drug, reports of preclinical tests (including animal tests) adequate to justify the proposed animal tests (32), signed agreements between investigators and sponsors of investigations that patients to whom the drug administered will be under the investigators direct or indirect supervision(33), and the establishment and maintenance of records obtained as a result of the investigational use that will enable the Secretary to evaluate the safety and effectiveness of the drug in the event of the filing of a new drug application (34). What was not optional under the amendments, however, was that any such clinical trial exemption be conditioned on the requirement that investigators certify to sponsors that any study subjects be informed that the drugs were investigational
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and obtain their consent (except where not feasible or contrary to the best interests of the study subjects) (35). As a result of these provisions and the regulations that followed, and notwithstanding the regulatory provision that such an exemption will become effective automatically after 30 days unless delayed by the agency (36), there is no area of FDA regulation where the agency has more unrestricted power than in its oversight of clinical investigations. 5.2. The 1962 Grandfather Clause The amended new drug definition also extended the category of drugs not subject to the new drug provisions, i.e., those considered grandfathered. First, in section 201(p), it essentially extended the 1938 grandfather clause through the 1962 enactment so that a drug that was subject to the 1938 clause (because it was subject to the 1906 Act and its labeling had not been changed) and exempt thereby from the new drug provisions would continue to be exempt, now from the new effectiveness requirement as well, if its labeling had continued to remain unchanged. The number of drugs that continue to meet these criteria has never been fully documented; it is safe to say that FDA views the category as an anachronism and, to the extent that it is required to focus on any such drugs as part of a regulatory event, it has had little difficulty arguing successfully that grandfather status is no longer applicable. A new grandfather provision was enacted in 1962 that would, when the criteria were met, exempt such a drug from the effectiveness but not the safety provisions of the act. Section 107(c)(4) of the 1962 amendments specified a fourpart test: on the day immediately preceding the enactment date, October 10, 1962, the drug was commercially sold in the United States, was not a new drug as defined by then in effect section 201(p) (meaning that it was generally recognized as safe on that date), was not subject to a new drug application on that date (meaning under the 1938 act), and was intended for use solely for its labeled indications as they existed on that day (in short, its labeling could not have changed).
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5.3. The DESI Review and the Imposition of Effectiveness on Pre-1962 Drugs The addition of an effectiveness requirement in 1962 was made more complicated for the agency by the added requirement that all new drugs approved solely for safety under the 1938 Act be subject to the new effectiveness standard unless grandfathered (see above). Transitional amendments enacted as section 107(c) implemented this legislative scheme in the following manner (37). First, any new drug application that was effective on the day before the new amendments were enacted (the enactment date) was deemed approved as of the enactment date (38); the new effectiveness amendments did not apply to any such deemed approved application as long as the application was not withdrawn or suspended when intended solely for use under its preenactment date indications (but not as to any changed indications) (39), and the provision permitting withdrawal of an approved application for a lack of substantial evidence of effectiveness as to existing uses was determined not to apply until one of the following events occurred: the expiration of a 2-year period beginning on the enactment date or the withdrawal or suspension of the application (40). These provisions effectively applied the new effectiveness standard on October 10, 1964, to all drugs approved under the 1938 Act and permitted their withdrawal if effectiveness had not been established. All post-1938approved applications had been simply deemed approved under the 1962 amendments for a 2-year grace period (41). While withdrawal for lack of effectiveness was not automatic, first requiring the agency to initiate and conduct withdrawal proceedings under section 505(e), the premarket approval requirements of the statute permitted the agency to allege that effectiveness had not been established, shifting the burden on pre-1962 applicants to then produce the necessary information to demonstrate substantial evidence of effectiveness in order to prevent withdrawal. Due to administrative difficulties attendant to implementation of this section, FDA ultimately contracted with outside groups, notably the National Academy of Sciences and
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National Research Council, to review the available data, usually as compiled by manufacturers, on all pre-1962approved drugs, and to make recommendations to FDA on whether there existed for those drugs the substantial evidence of effectiveness now required by the statute. This process became known as the Drug Efficacy Review Implementation, or DESI Review, and took the better part of 25 years, until the mid-1980s, to complete, though even to this day certain drugs remain on the market in a state of regulatory limbo, with no final determinations having been made as to their effectiveness under the 1962 standard (42). 5.4. Important Legal Developments Regarding the 1962 Amendments The 1962 amendments to the drug-approval process, particularly the increased burdens for prior approval for new drugs, generated significant efforts by various components of the pharmaceutical industry to avoid the added regulation imposed by the new amendments, particularly insofar as they rewrote the rules applicable to drugs already on the market. This also resulted from the significant procedural protections written into the earlier law, and continued in the new law, for applications that had already become effective. Over the next two decades, certain disagreements involving the agencys interpretation of the amended new drug, grandfather, and effectiveness provisions of the statute wound their way through the courts, culminating in several court decisions that ultimately both supported the agencys strict high bar and inclusive interpretation of the new amendments and set the tone of the agencys review policies for the next several decades. In USV Pharmaceutical Corp. v. Weinberger (43), decided in 1973, the issues were the scope of the grandfather and transitional amendments enacted in 1962. This manufacturer had products containing the same active ingredient, some of which were covered by pre-1962 NDAs, and some of which were not. Of the criteria found in the 1962 grandfather exemption, one was that the drug not be covered by an effective application on the effective date. The Court found that, while new drug
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applications were intended and applied to individual products, in this instance it would consider none of the products to be lawfully subject to the exemption even though they were literally not subject to an NDA at the time, as the exemption was intended to treat all products whether or not of different manufacturers containing the same active ingredient the same, that is, as either new or not new. The court also found that a manufacturer was not capable of deactivating an existing NDA so as to also avail himself of the exemption. The net effect of the opinion was to include any drug that had at any time been subject to the new drug provisions enacted in 1938 to also be subject to the effectiveness requirements enacted in 1962. In Weinberger v. Bentex Pharmaceuticals, Inc. (44), decided at the same time as USV, the Court squarely faced the question of who decided what constituted general recognition of effectivenessFDA or the courts. In this case, the Court interpreted the Act as authorizing FDA, subject to judicial review, as the locus of jurisdiction on the new drug question for both individual drugs and classes of drugs, determining that such questions were to be administratively determined by the agency, and not de novo in the courts. In Ciba Corp. v. Weinberger (45), again decided at the same time as USV and Bentex, the Court further established FDA, in the context of its withdrawal of pre-1962 NDAs for the manufacturers failure to establish effectiveness, as the administrative agency responsible for making new drug determinations in an administrative setting, reviewable in the Court of Appeals, but not subject to having the new drug issue litigated in other court proceedings. Finally, in the last and probably the most important case, Weinberger v. Hynson, Westcott & Dunning (46), also decided with the other cases noted, the Court reviewed the withdrawal of the NDA of a drug subject to the transitional amendments of the 1962 Act, that is, one approved under the 1938 Act for safety but ostensibly lacking substantial evidence of effectiveness, and thus subject to proceedings for NDA withdrawal. In so doing, it sustained the validity of FDAs then new Summary Judgment regulations, which permitted the agency, following publication of a Notice of Opportunity for Hearing, to then
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deny a hearing and summarily withdraw the NDA when the applicant did not tender information in response sufficient to make a prima facie showing that it could demonstrate substantial evidence of effectiveness through the statutory standard requiring adequate and well-controlled clinical investigations. In addition, the Court also sustained FDAs view that whether a drugs effectiveness was supported by substantial evidence was part of the new drug determination, and not simply requirements that must be met following a new drug determination. This case and the others decided with it effectively made all post-1938 drugs new drugs subject to NDA requirements for effectiveness and largely closed the door on the efforts of companies to avoid the requirements for adequate and wellcontrolled studies by claiming not-new-drug status under the new-drug definition. This 1973 grand slam for FDA in the U.S. Supreme Court regarding the scope of the 1962 amendments was the beginning of a multidecade trend in which the agency seemed relatively invincible in its efforts to expand the statute, in both its old and new drug provisions, particularly regarding the effectiveness requirements of the Act (47). Under the rubric of protecting the public health, FDA was able to establish and maintain through several significant court victories its expansionist view of its mandate to control the new drug process at both the macro and micro levels. Other cases decided in the next several years further solidified that mindset. In 1975, the Supreme Court decided United States v. Park (48). While involving a criminal prosecution of a senior manager of a national food company for sanitation failures, it affirmed earlier cases establishing strict criminal liability for senior company managers for violations of the Act, including, theoretically, violations involving the drug provisions of the act. In 1979, in United States v. Rutherford (49), the Supreme Court held that drugs for terminally ill patients whose safety or effectiveness were unproven were subject to the new drug provisions of the Act. In this case, notwithstanding that all parties conceded that the cancer patients involved were surely to die from their disease, and that no other remedies were available, the Court refused to allow the sale of laetrile, an
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unproven cancer remedy, by finding an implied exception to the safety and effectiveness requirements. In 1983, in United States v. Generix Drug Corp. (50), the Court resolved the additional question of the application of the new drug definition to generic versions of approved drugs. While innovator drugs were subject to NDAs, generic versions were not, and the question before the Court was whether the new drug definition applied to them. Specifically, did the new drug definition apply only to the active ingredient, potentially exempting generic products from new drug regulation, or each specific product, both innovator and generic, thereby subjecting all versions of the drug to the new drug provisions. Again, the Court sustained FDAs expansive reading of the new drug definition, concluding that the new drug-licensing provisions were applicable to individual products, including each separate generic product, and not merely the active ingredient. It relied in its opinion on the fact that each generic product would be different, at least in inactive ingredients or excipients, from the innovator, raising issues of safety and effectiveness warranting premarket review. By the time the Generix case was decided, FDAs view of the regulatory world of new drugs was essentially institutionalized. The new drug provisions were seen to apply to all prescription drug products, both brand and generic, and once applied to a drug product, were attached indefinitely. Little attention was paid then, or has been paid since, to the notion that drugs in new drug status could evolve to a post-, nonregulated, old drug status, notwithstanding inferences both in the new drug definition as well as in several court opinions that such was Congresss original intent.
6. THE POST-1962 ERA The two decades after 1962 were not ones of substantial legislative attention to the new drug-approval process. Other issues were more prominent. The growth in public financing of drug purchases under Medicaid caused a revolution in the publics perception of the value of generic drugs. While industry
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complained continuously about delays in getting drugs through FDAs approval mechanism, Congress did not engage the issue. Efforts to rewrite the Federal Food, Drug and Cosmetic Act that were initiated in the late 1970s came to naught, while FDA revised its own IND and NDA regulations in a manner that, while clarifying certain concepts such as compassionate INDs and adverse drug reporting, embraced the notion that FDAs requirements for proof of safety and effectiveness would not be relaxed in order to promote innovation or for drugs for use in treating serious and fatal diseases, notwithstanding the lack of alternatives for either patients or doctors. 6.1. The Orphan Drug Act of 1983 In 1982, recognizing that certain diseases involved only small numbers of patients and were thus being largely ignored by pharmaceutical companies due to the lack of financial incentives to development, Congress initiated legislation specifically directed at this problem. The Orphan Drug Act of 1983 provided federal financial incentives for drug development heretofore unavailable and also presaged other significant legislative developments that would come years later (51). As enacted, the Orphan Drug Act applied to drugs for any disease or condition which occurs so infrequently in the United States that there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States for such drug. It provided two major financial incentives to companies that would undertake to develop these products. First, the act provided a tax credit based on clinical trial expenses. Second, it provided a 7-year exclusivity for any nonpatentable drug, during which time FDA would be unable to approve an NDA or biological product license for the same drug for the same disease or condition. On a nonfinancial level, and to some extent foretelling later legislative developments, FDA was mandated to provide prospective orphan drug candidate applicants with written recommendations for the non-clinical and clinical investigations that the agency believed would be necessary for approval. This
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provision dented, perhaps for the first time, FDAs view that manufacturers were entirely responsible for the development of the studies required for approval, and that it was not FDAs role to prejudge trial design, and by inference data produced from such design, prior to submission of the data for approval (52). In 1984 and 1985, Congress further amended the act to make its enticement provisions more appealing. To reduce complexity regarding qualifications for orphan drug exclusivity, the test was made far more objective and inclusive: an orphan disease was defined as any disease or condition that affected fewer than 200,000 persons in the United States, or that affected more than 200,000 persons but for which there was still no reasonable expectation that development costs could be recovered from sales (53). Second, the exclusivity provision was changed to no longer be contingent on the availability of patent protection; all orphan drugs approved would receive a 7-year exclusivity under which FDA would not be permitted to approve the same drug for the same disease or condition (54). At the same time, FDA took the position that, while it would assist in the development of appropriate trials for approval, and while the law did provide incentives previously unavailable to development initiatives, it did not in any way reduce the scientific burden on manufacturers to establish effectiveness based on adequate and well-controlled clinical trials (55). 6.2. The Era of Shifting Priorities Two events merged in the latter years of the 1980s and continued through the early 1990s that, together, significantly altered the FDAs implementation of the requirements for investigation and approval of new drugs. The AIDS crisis was one; while FDA was able to fend off the demands of cancer patients in the 1970s and 1980s who desired access to unproven cancer drugs, it was not able to curtail access to unproven AIDS therapies by patients afflicted with an unexpected, and unremittingly lethal, new disease. The second event was more subtle. For years the industry
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had relentlessly criticized the Agency for what it perceived as the delay in getting it to act on pending applications. Review and approval times could stretch into years, for no apparent reason, despite a long-standing legislative provision requiring Agency action on pending NDAs within 180 days of filing. Comparisons were frequently made during this period to approval times in other developed countries, mostly the United Kingdom, where it was often said drug-approval times were substantially less for the same drugs than in the United Statesa so-called drug lagwith no apparent loss in safety. Unlike the cancer population, AIDS victims were young people who were suffering egregiously before invariably losing their lives in their prime, rather than, as with most cancer patients, if not in old, than at least in middle age. They also shared other characteristics. Many were homosexual males from middle class families living in the same neighborhoods in major urban areas and were able to coalesce into an active political force, no doubt enhanced by the support of their healthy, or at least not-yet-sick, colleagues. A further distinction from the cancer patients of the previous decade was the position of the medical establishment, always a force in FDA decisions and policy, if not always an apparent force. Unlike the cancer scenario, where doctors at least had some drugs and procedures to offer, for AIDS they had none that were remotely promising, leaving them as hopeless as their patients. FDAs adherence to the regulatory system that had served well for two decades, a reliance on scientific proof of safety and effectiveness prior to permitting the marketing of any drug no matter how serious the disease or the availability of alternative therapies, did not play well to an audience of suffering and dying young men and their frustrated physicians. FDA relied initially on its traditional safety valve for making available unproven drugs, the compassionate IND, under which drugs under investigation could be made available with the sponsors consent to individual practitioners for individual patients outside of study protocols. This, however, was woefully insufficient in scope to deal with a growing national epidemic, and FDAs initial reliance became problematic. The combination of pressures from constant criticism based on supposed drug
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lag together with the Agencys inability to handle the AIDS crisis fostered two reform movements that have altered its approval processes, perhaps permanently. On the issue of drug lag, and to respond to agency representations that at least some of that issue was based on limited resources, Congress undertook to impose, against the agencys will, at least initially, user fees. These fees, common elsewhere in government, are simply the governments charging for the performance of its servicesin this particular case, its licensing function. Resisted initially by FDA as a potential intrusion of its independence, it has now become an accepted part of the new medical product landscape, providing funds to the Agency to enhance its approval performance, though at some cost to the traditional opaqueness of the approval processes that had previously existed. While not necessarily impacting the actual requirements for approval, the user fee legislation (56) did tacitly recognize, if not validate, the industrys dissatisfaction with the approval process, and essentially required FDA, in return for its new funding source, to make the process more responsive to industry desires in two fundamental waysthe time required for agency action on applications, and providing industry with more awareness of the status of applications and access to the agency during the process. 6.3. The User Fee Act of 1992 The Prescription Drug User Fee Act of 1992 (PDUFA), beginning with fiscal year 1993 and continuing for 5 years, required set fees for each new drug application (and biological product licenser supplement containing clinical data, though not bioequivalence data), to be paid in part at the time of submission and prior to approval. These fees were not insignificant, set at the outset in 1993 at $100,000 for a full NDA, and half that for a supplement, to $233,000 in 1997. Certain exemptions, such as one for certain small businesses, were included. It also required certain establishment fees and product fees. Documentation on the concessions (euphemistically referred to as performance goals) made by FDA in 1992 is not readily available; however, documentation provided with the
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renewal of user fees in 1997 indicates that both review times and more transparency in the approval process were uppermost in the minds of reformers. Action was expected on 90% of standard applications within 12 months, and on priority applications, those for serious diseases, within 6 months. Actual approval was not necessarily expected but, rather, FDAs initial review of the application and the issuance of an approval letter. Other measurements involved 12-month review of standard efficacy supplements, 6-month review of priority efficacy supplements, and 6-month review of manufacturing supplements. These criteria were made more restrictive in the years following 1997. Other actions involved responses to requests for meetings, scheduling meeting dates, issuance of minutes following meetings, responding to sponsor clinical hold responses, dispute resolution, study protocol assessments, and simplifying action letters, all of which were designed to give manufacturers a more reliable sense of the agencys actions on pending applications, as well as make it more difficult for the agency to modify its views or position on such applications (57). The dynamic of the user fee legislation seems to be universally seen as positive. Similar legislation has now been enacted for both animal drugs and medical devices. For detailed information on the effects of this legislation and for subsequent changes in the approval requirements resulting from the AIDS epidemic see the chapters in this book regarding PDUFA and the FDA Modernization Act of 1997.
REFERENCES AND NOTES

1. 2. 3. 4. 5. 6. Wiley Act, Pub. L. 59384, 34 Stat. 768 (1906), sec. 1, 2. Wiley Act, sec. 7. Wiley Act, sec. 8. 221 U.S. 488 (1911). 37 Stat. 416 (1912). 1938 Act, Pub. L. No. 75717, 52 Stat. 1040 (1938), sec. 201( p).
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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
1938 Act, sec. 505(a). 1938 Act, sec. 505(b)(1)(A). 1938 Act, secs. 505(b)(1)(B)505(b)(1)(F). 1938 Act, sec. 505(c). Id. 1938 Act, sec. 505(d). Id. 1938 Act, sec. 505(e). 1938 Act, sec. 505(h). Id. 1938 Act, sec. 505(i). 1938 Act, sec. 201(g). 1938 Act, sec. 201(p). 1938 Act, sec. 201(p)(2). 55 Stat. 851 (1941). 59 Stat. 463(1945). 76 Stat. 780, 785(1962). See Hutt and Merrill, Food and Drug Law, Cases and Materials, Foundation Press (1991), pp. 521522. Pub. L. 105115 (1997). Federal Food, Drug and Cosmetic Act, (FDCA) sec. 201(p)(1), sec. 201(p)(2), 21 U.S.C. 321(p)(1), (p)(2); Pub. L. 87781 (1962). FDCA, sec. 505(c); 21 U.S.C. 355(c). FDCA, sec. 505(d); 21 U.S.C. 355(d). Id. As with the 1938 Act, the act provided significant procedural protections to manufacturers whose applications were not deemed worthy of approval, including notice, and opportunity for hearing, which, if granted, was contemplated to be a full administrative hearing.
24. 25.
26. 27. 28. 29.
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30.
The requirement for new information is considered by the agency to include a reevaluation of existing information, rather than requiring wholly new information as a prerequisite for withdrawal. FDCA, sec. 505(e), 21 U.S.C. 355(e). See, also, 21 CFR 2.5. FDCA, sec. 505(i)(1), 21 U.S.C. 355(i)(1). FDCA, sec. 505(i)(2), 21 U.S.C. 355(i)(2). FDCA, sec. 505(i)(3), 21 U.S.C. 355(i)(3). FDCA, sec.505(i), 21 U.S.C. 355(i). See 21 CFR 312.40. Sec. 107(c), pub. l. 87781 (1962). Sec. 107(c)(2). Sec. 107(c)(3) Sec. 107(c)(3)(B) Secs. 107(c)(2) and 107(c)(3)(B). A News Along the Pike publication of FDA dated December 3, 2003, reports that, under the DESI review, FDA evaluated 3,443 drugs having 16,000 claims, removing 1,099 of them from the market. 412 U.S. 655 (1973). 412 U.S. 645 (1973). 412 U.S. 640 (1973). 412 U.S. 609 (1973). FDA did not win every case. Nor does this discussion begin to discuss the judicial history. Rather, it includes the two cases that best reflect the agencys success at persuading the Court, under the mantra of protecting the public health, to read the new drug definition expansively. One significant loss by the Agency involved its efforts, through regulation, to control the distribution of the drug methadone. FDA believed that safe under section 505 included the potential for possible misuse, rather than simply inherent safety, and could thus regulate post-approval distribution of a new drug. In American
31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.
43. 44. 45. 46. 47.
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Pharmaceutical Assn. v. Weinberger, 530 F.2d 1054 (D. C. Cir.1976); affirming 377 F. Supp. 824 (D.C. D.C., 1974), the courts disagreed, interpreting safety to mean inherent safety for the uses in labeling, thus invalidating postapproval distribution restrictions. Regardless of this opinion, FDA has successfully controlled postapproval distribution of certain potentially toxic drugs through voluntary arrangements with manufacturers reached during the approval process. 48. 49. 50. 51. 421 U.S. 658 (1975). 442 U.S. 544 (1979). 460 U.S. 453 (1983). 96 Stat. 2049 (1983). The diseases used as examples were not necessarily obscure. Muscular distrophy, for example, widely known through annual telethons, was a principal example, and was particularly noteworthy in that a well-known actor, Jack Klugman, whose brother suffered from the disease, used his then significant celebrity status to promote the legislation and enhance its passage. Another example, amytrophic lateral sclerosis, was also well known as Lou Gherigs disease. The orphan drug provisions are codified at sections 525528 of the FDCA, 21 U.S.C. 360aa360dd. In providing for tax credits and exclusivity, this legislation presaged similar, but far more controversial provisions in the 1984 Drug Price Competition and Patent Term Restoration Act, and later in the Pediatric Exclusivity Act. It appears that such provisions are now routinely considered appropriate to entice and reward manufacturers to develop new drugs or new uses for existing drugs. 98 Stat. 2815 (1984). 99 Stat. 387 (1985). In an attempt to provide some additional level of competition, FDA has taken the position that it will not consider orphan drugs to be the same, despite similarities, if a second manufacturer can show clinical benefit, and will thereby permit such a manufacturer to break the 7-year exclusivity. See 21 CFR 316. P. L. 102571 (1992). See letter from Donna Shalala to Thomas Bliley, November 12, 1977.
52.
53. 54. 55.
56. 57.
3
FDA Regulation of Biological Products
JAMES N. CZABAN and NATASHA LESKOVSEK Heller Ehrman White & McAuliff LLP Washington, D.C., U.S.A.
1. INTRODUCTION Federal regulation of biological products (or simply biologics) is paradoxical in that biologics encompass some of the most advanced, cutting edge medical technology, yet they are regulated in significant part under the framework of the oldest U.S. law governing therapeutic products. For a variety of scientific, historical, legal, and political reasons, the federal regulatory scheme for biological products has been, and to some extent remains, fragmented and unsettled. For example, the fact that, legally speaking, most biologics also meet the statutory definitions for other product classes (i.e., drugs, medical devices) has
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resulted in the U.S. Food and Drug Administration (FDA) approving and regulating different types of biologics in all of its organizational Centers [the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), the Center for Food Safety and Applied Nutrition (CFSAN), and the Center for Veterinary Medicine (CVM)], with some products being regulated in different respects by more than one Center simultaneously. Also, advances in medical technology have spawned new and previously unimagined product categories that have posed classification conundrums which challenge FDAs ability to determine how (or if ) the new products may be regulated under the often rigid legal constraints posed by regulatory statutes. In addition, public and congressional responses to public health crises have periodically shed an unflattering light on existing regulatory processes and the responsible administrative organizations, leading to sometimes abrupt changes in the oversight scheme for biological products. And, more recently, pressure from patients and regulated industry for greater responsiveness and accountability in the review and approval of biotechnology-derived products has led FDA itself to, once again, consolidate most therapeutic product review and approval authority within one organizational unit. The legal and regulatory category known as biologics comprises a broad and diverse array of products for curative, preventative, and diagnostic purposes. The purpose of this chapter is not, and could not be, to present a detailed scientific discussion of all, or any one, of the many products or technologies within the biologics category. Nor will there be an extended focus on the most common pathway for biologic review and approval, because under the modern regulatory scheme most therapeutic biologics follow the same approval pathway as traditional pharmaceuticalsan IND, followed by phase 1, 2, and 3 clinical trials, a marketing application (for biologics a BLA as opposed to the NDA for pharmaceuticals), and postapproval oversight of safety, marketing, and good manufacturing compliance. This common approval pathway is discussed in Chapter 2.
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Rather, this chapter will present an historical overview of how biologics have been regulated in the past, and how those regulatory processes have evolved over time. Where regulation of certain biological products (e.g., blood, tissue, gene therapy technology) differs from the standard model, those differences will be explained and discussed. One area of particular focus will be the inherently overlapping nature of most biologics as both biologics and as drugs or devices (i.e., combination products) and the unique regulatory challenges this overlap poses. This chapter will conclude with a few observations and predictions about future trends in the regulation of biological products in the twenty-first century. 1.1. What Are Biologics? The term biologic is subject to several different meanings, depending upon the scientific or legal context in which the term is used. Generally speaking, from a scientific standpoint a biologic is a compound consisting of, or derived from, all or part of a living organism, and used for therapeutic or diagnostic purposes. However, to determine whether it may regulate a particular product as a biologic (as opposed to as a drug, a device, a combination product, or a nonregulated article), FDA must first look to the governing statutory provisions of the Public Health Service Act (PHSA) and the Federal Food, Drug and Cosmetic Act (FDCA). Because these statutes definitions are not comprehensive nor always clear, FDA also relies upon its own regulations and internal policies to determine the nature and scope of its regulatory authority in particular situations. 1.2. Statutory and Regulatory Definitions Legally speaking, the term biologic is somewhat ill-defined and is subject to overlapping definitions and regulatory schemes within FDAs jurisdictional purview. As discussed in greater detail later in this chapter, these definitional distinctions and vagaries result in many difficult but intriguing product-specific questions, the answers to which can have a profound impact
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on the nature and degree of FDA oversight of a particular product. The Public Health Service Act (PHSA) defines biological product as
a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings (1).
FDA has, by regulation, further defined the types of products included within the PHSA definition of biologic as follows (2): A virus is interpreted to be a product containing the minute living cause of an infectious disease and includes but is not limited to filterable viruses, bacteria, rickettsia, fungi, and protozoa. 2. A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells. 3. A toxin is a product containing a soluble substance poisonous to laboratory animals or to man in doses of 1 milliliter or less (or equivalent in weight) of the product, and having the property, following the injection of nonfatal doses into an animal, of causing to be produced therein another soluble substance which specifically neutralizes the poisonous substance and which is demonstrable in the serum of the animal thus immunized. 4. An antitoxin is a product containing the soluble substance in serum or other body fluid of an immunized animal which specifically neutralizes the toxin against which the animal is immune. In addition, trivalent organic arsenicals are defined by FDA to mean arsphenamine and its derivatives (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of diseases or injuries of man (3). 1.
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Radioactive biological products are biological products labeled with a radionucleotide or intended solely to be labeled with a radionucleotide (4). FDA has also established regulatory criteria by which products will be deemed analogous to a biologic listed in the PHSA, and therefore also deemed to be a biologic. Specifically, FDA has established that a product is analogous to a virus if it is prepared from or with a virus or agent actually or potentially infectious, without regard to the degree of virulence or toxicogenicity of the specific strain used (5). Products are analogous to a therapeutic serum if they are composed of whole blood or plasma or contain some organic constituent or product other than a hormone or an amino acid, derived from whole blood, plasma, or serum (6). And products are analogous to a toxin or antitoxin if they are intended, irrespective of its source of origin, to be applicable to the prevention, treatment, or cure of disease or injuries of man through a specific immune process (7). The FDCA does not include a definition of biologic, although it does include numerous provisions by which FDA exercises regulatory oversight of such products. Significantly, virtually all biologics as defined by the PHSA also fall within drug and/or device definitions under the FDCA. 1.3. Applicable to Versus Intended Use Under the FDCA, a drug includes any article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man (8), and a device includes an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part or accessory, which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease (9). Both drugs and devices include other articles intended to affect the structure or any function of the body of man, but drugs do not include food or dietary supplements (which are regulated separately), and devices do not include an article which achieve[s] its primary intended purpose through chemical
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action within or on the body . . . and which is not dependent upon being metabolized for the achievement of its primary intended purpose (such articles would be regulated as drugs). Moreover, certain products that are, in a sense, biologics can be dietary supplements, for example, dried animal blood products intended for ingestion to supplement the diet. The PHSA definition of biologic does not explicitly include the critical legal concept of a products intended use, which is a key element of the drug and device definitions of the FDCA. Under the traditional intended use concept, a companys own statements about its product, especially in the products labeling (whether approved or not) will affect the products status as a drug, device, food, cosmetic, or other. Generally speaking, a product that is not intended for therapeutic, curative, or diagnostic purposes cannot be a drug or a device. The PHSA uses the arguably broader concept of whether the product is applicable to the prevention, treatment, or cure of disease such that a companys actual intent is not dispositive if the product itself could be used for such purposes. Moreover, unlike the FDCAs drug and device definitions, the PHSA definition of biological does not mention diagnosis, but FDA has filled this definitional gap by expanding the applicability concept to encompass diagnostic uses as a basis for falling within the biologic definition. Specifically, FDAs regulations provide that (10): A product is deemed applicable to the prevention, treatment, or cure of diseases or injuries of man irrespective of the mode of administration or application recommended, including use when intended through administration or application to a person as an aid in diagnosis, or in evaluating the degree of susceptibility or immunity possessed by a person, and including also any other use for purposes of diagnosis if the diagnostic substance so used is prepared from or with the aid of a biological product. 1.4. Tissue An increasingly important area of biologic development involves the use of human tissue and derivatives or components thereof. However, tissue is not defined by statute as a biological, even
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though it meets the general lay definition. Yet FDA currently regulates some tissue, and has clearly signaled its intent to assert broader jurisdiction over such products. The agencys current approach, as of the time of this writing, to regulating such products is highly fragmented, as its existing tissue regulations are narrow in scope, applying only to human tissue intended for transplantation that is recovered, processed, stored, or distributed in a manner that does not change the tissues function or characteristics. Establishment registration and listing regulations for human cells, tissue, and cellularand tissue-based products became effective on January 21, 2004, 21C.F.R. Part 1271. Moreover, FDAs tissue regulations do not apply to tissue products that are otherwise regulated as drugs, biologics, or medical devices. In addition, vascularized human organs for transplantation, blood and blood products, secreted or extracted human products such as milk, collagen, and cell factors (but not including semen), minimally manipulated bone marrow for homologous use (i.e., for use in the tissue donor)(so long as such tissue is not combined with a drug or device), and nonhuman cells, tissues, and organs, are not considered tissues for purposes of FDAs existing and proposed tissue regulations (11). 1.5. Gene Therapy FDA also regulates the use of gene therapy, which can be broadly defined as a medical intervention based on modification of the genetic material of living cells. Such cells may be modified ex vivo for subsequent administration, or may be altered in vivo by administration directly to the patient. Gene therapy may be intended to prevent, treat, cure, diagnose, or mitigate disease or injuries in humans, and the intended effects of gene therapy can be permanent or short term, depending on the condition being treated or cured (12). FDA asserts regulatory jurisdiction over gene therapy in much the same way as it regulates drugs and therapeutic biologics, but due to the novelty and difficulty of gene therapy technology, no gene therapy product has yet been approved by FDA for commercialization. Several highprofile scandals in leading gene therapy research centers, as
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well as periodic scares regarding the incidence of leukemia in gene therapy recipients, have led FDA to halt all gene therapy trials at various times. The repeated need to deal with interruptions in the research process and respond to high-profile findings in an area of intense public scrutiny have delayed the development of approvable gene therapies. 1.6. Transgenic Animals and Xenotransplantation Transgenic animals include genetically and cellularly modified food animalsfish, dairy cows, and meat-producing animals that are engineered to grow faster, resist disease, produce milk containing therapeutic drugs or vaccines, etc. FDA will regulate transgenic animals and their products under the theory that such animals contain a new animal drug or biologic as defined by law or regulations (13). Thus, primary regulatory oversight is being handled by the Center for Veterinary Medicine, with input by other Centers as appropriate. In evaluating transgenic animals, issues of food safety, environmental safety, target animal safety, effectiveness claims, quality controls, and labeling and promotional activities will be important (14). Similar concerns, and especially food safety concerns, are being considered by FDA in connection with the cloning of livestock for commercial purposes. The National Academy of Sciences has played an important role in assessing the safety of animal biotechnology (15). Xenotransplantation is defined by FDA as any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs (16). FDA has been on the global forefront of xenotransplantation regulation, with its 1996 issuance of a Xenotransplantation Action Plan. Recent guidance has provided more specific direction with respect to the safety concerns surrounding source animal screening and testing, Good Manufacturing Practices, and long-term clinical safety evaluation. The potential for cross-species infection,
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as with transgenic animal food and drug products, remains of paramount concern. 1.7. Human Cloning The myriad social, ethical, and legal questions surrounding the legality and regulation of human cloning is approaching FDA at an ever-faster pace. FDA has consistently taken the approach that all cloning studies involving human subjects require an IND and that the major unresolved safety questions pertaining to the use of cloning technology to create a human being, [require that] until those questions are appropriately addressed in the IND, FDA [will] not permit any such investigation to proceed (18,19). FDAs approach, together with multilateral bans on human cloning in other countries, have presently pushed any human cloning research off-shore where any report of successful results must be carefully scrutinized.
2. STATUTORY HISTORY OF BIOLOGICS REGULATION Federal regulation of biologics dates back to 1902, with passage of the Biologics Control Act (also known as the Virus-Toxin Law) (Table 1). The Biologics Control Act authorized the precursor of the National Institutes of Health (NIH) to regulate the commercial production of vaccines, serums, toxins and antitoxins, and similar products to ensure their safety, purity, and potency (20). These statutory standards for biologics approval safety, purity, and potencystill apply today and are a primary distinguishing factor in the regulation and approval process for biologics versus drugs (efficacy, as discussed below, was added as an approval criterion in 1934). The Biologics Control Act also required products to be labeled with the product name, the name, address, and license number of the manufacturer, and an expiration date. The Hygienic Laboratory enforced the Act by setting product standards, conducting establishment inspections and analyses of marketed samples, and revoking licenses in the case of
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Table 1
1894 1901 1902 1906 1912 1930 1937 1938 1940 1941 1944 1948 1950 1955 1962 1972 1973 1980s 1982 1988 1992 1997 2003
History of Biological Products Regulation

Public health labs produce diphtheria antitoxin Thirteen children die of tetanus due to contaminated diphtheria antitoxin Biologics Control Act The Food and Drug Act Public Health Service created National Institutes of Health Division of Biologics Control Food, Drug and Cosmetic Act Rh blood group system Cohn fractionation of blood The Public Health Service Act (Laboratory of Biologics Control) National Microbiological Institute First live polio vaccine in humans Cutter polio vaccine incident; Division of Biologics Standards created Kefauver-Harris drug amendments Bureau of Biologics to FDA New provisions of PHS Act Biotechnology era National Center for Drugs and Biologics Center for Biologics Evaluation and Research Prescription Drug User Fee Act Food and Drug Administration Modernization Act ???
Source: Adapted from Ref. 20.
violations. The Act also gave the Hygienic Laboratory rulemaking authority. Early regulations dealt with procedures for licensing and inspection, but in 1934 regulations were promulgated requiring a showing of efficacy as a condition for granting of new biologics licenses (21). The earliest licensed products included smallpox and rabies vaccines and diphtheria and tetanus antitoxins. 2.1. The Public Health Service Act The Biologics Control Act was recodified and incorporated into the Public Health Service Act in 1944 without significant substantive change. However, the PHSA established the Laboratory of Biologics Control as the licensing authority for biological products and required for the first time that biologics
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establishments also be subject to separate licensure (22). In 1948 the National Microbiological Institute at NIH took administrative control over the regulation of biological products. As a result, the regulation of biological products was integrated with the scientific research at NIH. The strong influence of the Public Health Service medical corps, who staffed and continue to staff the biological regulatory administration, and the influence of science at NIH have been strong factors in the cultural environment of the regulatory evaluation and approval processes for biological products. The Laboratory of Biologics Control became a political victim of medical tragedy in 1955. In the spring of 1955, defective polio vaccine batches resulted in hundreds of cases of polio, in what became known as the Cutter incident. As a result, regulatory authority over biological products was transferred to the Division of Biologics Standards, a newly created division of NIH. Concurrently, vaccine testing regulations were strengthened, particularly those concerning manufacturing and testing requirements for marketed biological products. In 1972 the NIH Division of Biologics Standards was transferred to FDA and renamed the Bureau of Biologics. The PHS Act lacked many of the analogous statutory provisions of the federal Food, Drug, and Cosmetic Act (then known as the Food and Drug Act) which pertained to drugs. Therefore, FDA promulgated regulations for various activities of biologic manufacturers under the Food and Drug Act, including the investigational new drug process (IND), good manufacturing practices (GMPs), advertising and promotion, and the legal concepts of adulteration and misbranding of biologics (23), effectively applying the new drug substantial evidence criteria to biological products (24). The ability to regulate biological products through both the PHSA and FDCA provisions is especially important because of the difficult nature of characterization for some biological products. The emphasis on manufacturing controls and the ability to impose rigorous lot release requirements enables FDA to fulfill its mandate of protecting the public health. In 1982 the Bureau of Biologics merged with the Bureau of Drugs to form the National Center for Drugs and Biologics
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(NCDB). In 1987 the Center for Biologics Evaluation and Research name was coined. Thus, throughout its history, CBER has been strongly linked with science and research, but the complexity of the regulatory subject matter for which it is responsible has kept this federal entity a regulatory hot potato. 2.2. Food, Drug And Cosmetic Act Applicability to Regulation of Biologics As described above, with the 1972 transfer of biologics regulatory authority to the Bureau of Biologics, FDA incorporated Food and Drug Act principles in the regulation of biologics. However, Section 351 of the PHSA (42 U.S.C. x 262) has remained the primary source of FDA authority to regulate biologics, particularly for the standards of safety, purity, and potency. Both FDA and the federal courts have interpreted the FDCA statute and implementing regulations to read on to the PHSA requirements for biologics. Federal courts have upheld FDAs position that biologics under the PHS Act are also drugs under the Food and Drug Act. For example, in a 1962 criminal indictment under the FDCA, a federal district court in New York held that . . . whole human blood referred to in the indictment [against the defendants] would constitute a drug within the meaning of the [Federal Food, Drug, and Cosmetic Act] statute (25). Over time, biological products have been made subject to FDCA statutory provisions including advertising, the IND process, establishment registration and product listing, inspections, exports, and user fees (26). A number of legislative amendments to the FDCA since 1972, although titularly focused on drugs, have in fact included biologics within their scope, such as the Orphan Drug Act of 1982 and the Prescription Drug User Fee Act (PDUFA) of 1992 (27). Most notably, the Food and Drug Administration Modernization Act of 1997 (FDAMA) (28) made significant revisions to the biologics approval process and regulations. Section 123 of FDAMA eliminated the separate need for licensure of biologics establishments and products
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(ELAs and PLAs), codifying the singular Biologics License Application (BLA) in use today. 2.3. FDA Enforcement for Biologics Inspection of biologics-manufacturing facilities and processes is of critical importance since the manufacturing process often defines the biological product. In 1998, FDA began a Team Biologics initiative (29), which has brought regulators and technical specialists together for the efficient inspection of licensed biologics manufacturers. The Team Biologics model has been imported to other FDA inspectional activities and permits comprehensive, consistent approaches when assessing compliance from regulated industry. Factors such as the history of the master and working cell bank (for cellular or gene therapy) are highlighted in the Team Biologics approach in order to ensure that the statutory requirements of safety, purity, and potency are being met. Other inspectional areas of concern for biologics manufacturers are environmental monitoring, bioburden control, area classification, and training. FDA enforcement activity related to a Team Biologics inspection can take a number of forms, owing to the ability of biologics regulators to choose from either PHSA or FDCA tools or both. If a biological product may pose a danger to the public health, the FDCA as a criminal statute lends enforcement tools of injunction and seizure, which are complemented by PHSA authority to suspend licenses immediately.
3. REGULATORY APPROVAL PROCESSES FOR BIOLOGICS On June 30, 2003 FDA was nearing completion of its efforts to consolidate responsibility for the review of certain therapeutic biological products into the Center for Drug Evaluation and Research (30). This latest in the history of transferring control of biologics regulatory authority was intended for the purported benefits of regulatory consistency and efficiency.
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CDER now has oversight of monoclonal antibodies, cytokines, growth factors, enzymes, interferons (including recombinant versions), proteins intended for therapeutic use that are extracted from animals or microorganisms, and immunotherapies. Vaccines, blood, blood derivatives, and blood products, gene therapy, cell therapy, and tissue transplantation remain with CBER. The characteristics of biologics that contribute to their specific areas of regulatory concern include the fact that they are created by or extracted from living organisms; they are less defined physicochemically than pharmaceutical drugs (and are less pure); they have higher molecular weights; most are sterile injections; they are less stable, while their degradation is more complex; and finally, they are often immunogenic, which limits the relevance of preclinical testing in animals to the human experience. For biologics, the manufacturing process defines the product, and for this reason there are few categorical regulatory guidances on classes of biologics and great emphasis on an individual products chemistry, manufacturing, and control information. Thus, in the regulatory approval process for Biologics License Applications (BLAs), reviewers have heightened concern regarding new safety information and previously unseen adverse events. This translates into a higher rate of clinical holds for biologic INDs relative to drug INDs. In other respects, the BLA-approval process runs parallel to the NDAapproval process, emphasizing the same objectives for phase I (safety and toxicity), phase II (dose ranging), and phase III (indication, safety, and efficacy) studies. 3.1. Biologic Combination Products On December 31, 2002, FDA launched its Office of Combination Products specifically to handle the regulatory complexities associated with drug, biologic, and medical device combinations (31). Examples of biologic combination products include lumbar fusion cages containing genetically engineered human protein bone grafts (biologic/device) (32) or the use of Peg interferon alfa-2a with ribavirin for the treatment of patients with chronic hepatitis C (biologic/drug) (33).
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Designation of a primary review center for a combination product is based upon the primary mode of action of the product. The primary mode of action is currently determined by the Office of the Ombudsman in response to a Request for Determination (RFD), as outlined in 21 C.F.R. Part 3. If the primary mode of action is that of a biologic, then CBER has primary jurisdiction for reviewing the combination and receives collaborative input from CDER or CDRH as relevant (34). The primary mode of action determination is based upon a number of different factors, including chemical, physical or biological composition, manufacturing and formulation process, mechanisms of action of each moiety, proposed clinical indication and effects induced, and schedule of use, dose, and administration. 3.2. Therapeutic Biologics As discussed above, FDAs statutory authority for the licensure of biologics for commercial use is pursuant to Section 351 of the Public Health Service Act. Prior to licensure, the clinical investigation of these products is regulated under the drug investigation (IND) or medical device investigation (IDE) regulations. While there are no separate regulations governing investigational biologics, CBER controls the regulatory oversight of biologics INDs (35). The regulations governing the use of investigational biologics are set forth in Part 312 of Title 21 of the Code of Federal Regulations. The IND process culminates in the filing of a BLA, which is similar to an NDA in both content and format but places greater emphasis on product-manufacturing processes to assure the purity of the product and that specific standards are met. The fundamental standard for approval of a BLA is the same as for an NDA: a showing that the product is safe and effective for its labeled indication, as demonstrated in human clinical trials. The process for BLA submission and review is also the same as for an NDA. FDA has 60 days following BLA submission to determine whether an application is filed, and thereafter 180 days to review the application and either approve or refuse to approve the application (36). Upon completion of review,
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FDA issues either an approval letter or a letter requesting additional information (approvable, not approvable, or complete response) (37). Often final labeling needs to be negotiated prior to an approvable letter being superceded by final approval. The basic BLA includes all preclinical and clinical information concerning the biologic, as well as a full description of the manufacturing methods employed (38). Manufacturing process description must include, as relevant: complete description of the source material (including characterization of relevant cell banking systems) and the product; complete description of bulk substance production of bulk, including fermentation, harvest and purification procedures, process validation, and testing; complete description of manufacturing steps for production through finishing, including formulation, filling, labeling, and packaging [including all steps performed at outside (e.g., contract) facilities]; data demonstrating consistency of manufacture; formulation development studies, where appropriate, or rationale for selection of formulation; complete description of lots and manufacturing process utilized for clinical studies; data demonstrating absence or removal of adventitious agents where such agents are potentially present; and complete data demonstrating equivalency to clinical trial product when significant changes in manufacturing processes or facilities have occurred. FDA approval of therapeutic biologics often involves input from the public and the advisors and consultants on CBERs product categoryspecific Advisory Committees. Advisory committee membership can be set to include experts in the particular therapeutic area of a candidate product, promising a robust discussion of the BLA. 3.3. Vaccines Vaccine products within CBERs regulatory jurisdiction include live attenuated vaccines, DNA vaccines, and tumor vaccines. While most people are familiar with childhood preventive vaccines that have contributed to a significant reduction in vaccine-preventable diseases, new therapeutic vaccines
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for the treatment of cancer and other diseases are also being reviewed by CBER. The review and approval process for vaccines is tailored, as with all therapies, to the ultimate indication being sought by a sponsor. The size of the patient database requiredi.e., the number and duration of experience with human exposure can vary from several hundred to several thousand, depending upon the intended use. The general BLA process regulations are codified at 21 C.F.R. Part 601, while the IND regulations of 21 C.F.R. Part 312 apply to the investigational use of biologics. Vaccine clinical development follows the same general pathway as for drugs and other biologics. A sponsor who wishes to begin clinical trials with a vaccine must submit an IND to FDA. The IND describes the vaccine, its method of manufacture, and quality-control tests for release. Also included are information about the vaccines safety and ability to elicit a protective immune response (immunogenicity) in animal testing, as well as the proposed clinical protocol for studies in humans. Premarketing (prelicensure) vaccine clinical trials are typically done in three phases, as is the case for any drug or biologic. Initial human studies, referred to as phase 1, are safety and immunogenicity studies performed in a small number of closely monitored subjects. Phase 2 studies are dose-ranging studies and may enroll hundreds of subjects. Finally, phase 3 trials typically enroll thousands of individuals and provide the critical documentation of effectiveness and important additional safety data required for licensing. At any stage of the clinical or animal studies, if data raise significant concerns about either safety or effectiveness, FDA may request additional information or studies or may halt ongoing clinical studies. If successful, the completion of all three phases of clinical development can be followed by the submission of a BLA. To be considered, the license application must provide the multidisciplinary FDA reviewer team (medical officers, microbiologists, chemists, biostatisticians, etc.) with the efficacy and safety information necessary to make a risk/benefit assessment and to recommend or oppose the approval of a vaccine. Also
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during this stage, the proposed manufacturing facility undergoes a preapproval inspection during which production of the vaccine as it is in progress is examined in detail. Following FDAs review of a license application for a new indication, the sponsor and the FDA may present their findings to FDAs Vaccines and Related Biological Products Advisory Committee (VRBPAC). This non-FDA expert committee (scientists, physicians, biostatisticians, and a consumer representative) provides advice to the Agency regarding the safety and efficacy of the vaccine for the proposed indication. FDA is very involved with its external constituents when it comes to vaccine review, approval, and postmarketing risk assessment. Vaccine approval requires the provision of adequate product labeling to allow health care providers to understand the vaccines proper use, including its potential benefits and risks, to communicate with patients and parents, and to safely deliver the vaccine to the public. FDA and CBER rely heavily upon the CDC and childhood vaccine experts in setting the vaccine schedule for childhood immunizations, and FDA works closely with CDC also to annually choose the constituents of the influenza vaccine, which varies seasonally. Postmarketing risk assessment also factors heavily for vaccine approvals, since all adverse events cannot be anticipated until a larger population is inoculated. CBER and the U.S. Centers for Disease Control and Prevention (CDC) jointly manage the Vaccine Adverse Event Reporting System (VAERS), a cooperative program for vaccine safety. VAERS is a postmarketing safety surveillance program, collecting information about adverse events (side effects) that occur after the administration of U.S. licensed vaccines. In the postmarketing phase, FDA continues to oversee the production of vaccines in order to ensure continuing safety. After licensure, monitoring of the product and of production activities, including periodic facility inspections, must continue as long as the manufacturer holds a license for the product. If requested by FDA, manufacturers are required to submit to FDA the results of their own tests for potency, safety, and purity for each vaccine lot. They may also be required to submit samples of each vaccine lot to FDA for testing.
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However, if the sponsor describes an alternative procedure that provides continued assurance of safety, purity, and potency, CBER may determine that routine submission of lot release protocols (showing results of applicable tests) and samples is not necessary. 3.4. Biologic Devices In addition to the Public Health Service Act and Food Drug and Cosmetic Act, biologic devices are also subject to devicerelated FDA statutes. For instance, in vitro diagnostics and medical devices used in blood banks to process biological products (such as kits used to screen for HIV and hepatitis) are delegated to CBER by the Intercenter Agreement between CBER and the Center for Devices and Radiological Health (39) and are regulated under the Medical Device Amendments of 1976 and 1992 and the Safe Medical Devices Act of 1990 (40). The review and approval of biologic devices is interactive between CBER and CDRH, particularly with respect to in vitro diagnostic devices. The Medical Device User Fee and Modernization Act of 2002 imposes commitments for 510(k) and PMA review times on both CBER and CDRH for biologic devices. The regulatory framework that pertains to devices includes the Investigational Device Exemption (IDE) and Humanitarian Use Device (HUD). Clinical investigations of certain in vitro diagnostic biologic devices are exempt from IND regulations if the products are intended to be used in diagnostic procedures that confirm the diagnoses made by other, medically established diagnostic products or procedures and they are labeled and shipped in conformance with FDA regulations (see 21 C.F.R. x312.160 for labeling and shipping requirements) (41). 3.5. Tissue and Somatic Cell Therapy CBER regulates human tissue intended for transplantation under 21 C.F.R. Part 1270. The Part 1270 regulatory scheme is limited to requiring tissue establishments to screen and test donors, prepare and follow written procedures for the
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prevention of the spread of communicable disease, and maintain records (42). Cellular and tissue-based products at this time are on the cusp of full regulation. Under a Reinventing Tissue Regulation plan begun in 1997, new regulations are set to be codified at 21 C.F.R. Part 1271 (43). The plan produced several proposed rules, beginning in 1998, which described a new approach to the regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps). This new approach included, among other things, requirements for donor suitability screening (effective May 25, 2005) (44), registration and listing of tissue establishments (effective January 21, 2004) (45), and the development of Good Tissue Practices (not finalized as of this writing) (46) (collectively, the 21 C.F.R. Part 1271 regulations). The HCT/P establishment registration and listing rule became effective on January 21, 2004 (47). HCT/P research sponsors and product developers have to consider whether their products meet the minimal manipulation and homologous use standards, since IND and licensure requirements were being phased in to permit the development of licensing standards for those products where possible (48). 3.4. Blood and Blood Products Blood product regulation is one area in which FDA significantly regulates both the product and process of marketing a therapeutic. CBER regulates the collection of blood and blood components used for transfusion or for the manufacture of pharmaceuticals derived from blood and blood components, such as clotting factors, and establishes standards for the products themselves (49). Many CBER standards for blood products are presently published as guidance documents but are in the process of being updated through notice and comment rulemaking, under the Blood Action Plan, as described below. While whole blood is not subject to FDA approval, it is subject to a range of other regulatory requirements designed to ensure the safety of transfusion recipients from bloodborne infectious diseases such as human immunodeficiency virus (HIV), hepatitis, Creutzfeld-Jakob disease (CJD, the human
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variant of bovine spongiform encephalopathy), etc. Bloodderived products are subject to heightened regulatory requirements, including preapproval for therapeutic and diagnostic products. CBER also regulates blood banking devices, as described above, including cell separators, blood collection containers, and HIV screening tests. In addition to licensing blood products, CBER develops and enforces quality standards, inspects blood establishments, and monitors reports of errors, accidents, and adverse clinical events. FDA has significantly increased its oversight of the blood industry in recent years, particularly with the 1997 Blood Action Plan (50). The Blood Action Plan is focused on FDAs ability to respond to emerging infectious diseases (such as West Nile virus) and the updating of its regulations to reflect greater coordination with CDC, thus increasing safety of the blood supply while at the same time maintaining sufficient supply in an era of increased donor deferral. FDA requires all blood and blood component manufacturers to adhere to current Good Manufacturing Practices (cGMP), as outlined at 21 C.F.R. Part 606. FDA inspects all blood facilities at least every 2 years, and problem facilities are inspected more often. Blood establishments are now held to quality standards comparable to those expected of pharmaceutical manufacturers; in years past, exemptions of certain practices were more frequent. All owners or operators of establishments that engage in the manufacturing of blood products are required to register, pursuant to Section 510 of the FDCA (51). CBER works closely with other parts of the PHS to identify and respond to potential threats to blood safety, to develop safety and technical standards, to monitor blood supplies, and to help industry promote an adequate supply of blood and blood products. 3.7. Gene Therapy Gene therapy is one area where CBERs historical roots in the NIH are continued. While FDA has primary jurisdiction for review and approval of gene therapy products, NIHs Recombinant DNA Advisory Committee (RAC) is responsible
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for oversight and public discussion of clinical gene transfer research. NIH also evaluates the quality of the science involved in human gene therapy research and funds gene transfer research. Although more than 200 gene therapy trials were purportedly being conducted under INDs as recently as 2002, no BLA for gene therapy has yet been submitted or approved. CBERs 1998 Guidance for Human Somatic Cell Therapy and Gene Therapy remains the most formal representation of FDAs requirements for gene therapy clinical trials and product approval (52). As with most true biologics, the absence of categorical class requirements makes both guidance and rulemaking in this area difficult, with much regulatory discretion being exercised by the regulatory scientists within CBER. Safety issues continue to be of paramount concern in the oversight of gene therapy trials, as discussed above. 3.8. Generic Biologics Although the subject of increasing debate, FDAs ability to approve a generic biologic, me-too biologic, comparable biologic or biogenericunder any nameremains unsettled at present. Spiraling health care costs, particularly prescription drug costs, have placed increasing pressure on FDA regulators to permit approval of generic biologics. From a statutory perspective, the PHSA does not contain provisions that relate to approval of generic biologics in the way that the HatchWaxman Amendments changed the FDCA. However, the convergence of economic pressure and scientific advances in developing generic versions of innovator biologics, is both pushing and supporting FDAs intent to release a guidance document that address scientific approval standards for certain generic biologic products. Lester Crawford, Acting FDA Commissioner, recently confirmed in 2004 Congressional testimony, the Agency is getting ready to release a guidance document on approval criteria for generic versions of certain biologics. Most likely, this anticipated guidance document will specifically address standards for approval of generic human growth hormone products. The guidance is also expected to draw on FDAs September 2003 draft guidance concerning
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comparability protocols for Chemistry, Manufacturing, and Control (CMC) changes to protein drug products and biological products. Comparability protocols are used, and have historically been used, for post approval changes to a products manufacture. In the case of a biologic product, CMC changes can theoretically and actually create an entirely new product that would otherwise require approval of a full BLA. Therefore, comparability protocols have traditionally been used by BLA sponsors to gain approval for CMC changes without having to repeat clinical studies, and are thus an attractive regulatory precedent to the approval of a generic biologic (53). The most significant impediment to the approval of a generic biologic is the absence of many analytic standards that are available for drugs. Specifically, product characterization/ identity, purity, the assessment of pharmacokinetic parameters, manufacturing, and analytic processes will be critical for a sponsor to demonstrate if FDA is to approve a biologic without product-specific clinical data. It would seem that the most likely candidates for the first generic biologics would be those products that fit the definition of biologics but that have historically been regulated as drugs by CDER, including fibrinolytics, somatotropins, and insulin. The FDCA Section 505(b)(2) approval pathway, under which sponsors may rely upon the agencys prior findings of safety and efficacy for a product but which permits FDA to require clinical evidence, has been considered one potential mechanism for the approval of generic biologics without legislative change. The need for a bridging clinical trial to demonstrate safety and lack of immunogenicity for the generic biologic is understood even among most proponents of generic biologics. The recent integration of CBERs Office of Therapeutics Research and Review (OTRR) could be a harbinger of more unified review standards for biologics and drugs, and ultimately for the approval of generic biologics. FDAs interest in developing mechanisms to support approval of generic biologics has garnered the attention of the biotechnology industry and individual companies, who have already launched direct attacks on FDAs authority to pursue such policies. In 2003 the Biotechnology Industry Organization (BIO) filed a Citizen Petition with FDA
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challenging the Agencys legal authority, and the scientific feasibility, of FDA approval of generic biologics under 505(b)(2) NDAs. FDA affirmed its previously asserted general authorities under section 505(b)(2), but deferred a response on BIOs scientific arguments to a later date. More recently, on April 8, 2004, Genentech filed a petition directly aimed at preventing FDA from even issuing the expected similarity guidance. Genentechs position is that any FDA guidance document would inherently and unlawfully reflect the agencys use of Genentechs proprietary trade secret data previously submitted to FDA for the sole and limited purpose of seeking approval of Genentech products. More specifically, Genentech attacks the FDAs ability lawfully to approve specific generic versions of Genentech products under a comparability guidance, because to do so would require FDA to specifically refer to, and compare, Genentechs crucial proprietary manufacturing processes to the proposed generic companys processes. As FDA pursues its pending guidance and addresses the mounting legal challenges thereto, key members of Congress, including Senator Hatch, are expressing growing interest in pursuing a statutory pathway for generic biologic approvals. While specific Congressional proposals have not been widely circulated at the time of this writing, a legislative approach would not be expected to address detailed scientific questions, but rather to establish a general pathway, giving FDA authority to consider appropriate information as necessary to approve generic biologics. New Congressional authorization would effectively blunt many, but perhaps not all, legal objections in ways that agency action alone could not. But, as in the case of past legislative reforms to FDA authority and processes, the agency and Congress appear to be pursuing the issue of generic biologics in parallel, and at some point in the perhaps not too distant future, those paths will converge and result in concrete legislation.
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Czaban and Leskovsek P.L. 105-115. Compliance Program Guidance 7341.001 Inspection of Licensed Therapeutic Drug Processors. At the time of writing, the CBER/CDER consolidation is finished through phase II. See http://www.fda.gov/bbs/topics/ANSWERS/2003/ ANS01188.html http://www.fda.gov/bbs/topics/NEWS/2002/NEW00862.html http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01155.html http://www.fda.gov/cber/approvltr/pegihof120302L.htm 21 U.S.C. x353(g)(1)(C). 21 C.F.R. xx312.2(a), 601.21. FDCA Section 505(i) exempts from the new drug approval requirements of the Food and Drug Act, investigational drugs, thus permitting their shipment in interstate commerce, subject to limitations imposed by FDA. The FDAs regulations specifically provide that investigational biologics also fall within this exemption from the new drug regulations. 21 C.F.R. x 314.100(a). Id. 21 C.F.R. 601.2(a). Available at http://www.fda.gov/oc/ombudsman/bio-dev.htm P.L. 94-295 (1976 Amendments), P.L. 102-300 (1992 Amendments) and P.L. 101-629 (the SMDA). 21 C.F.R. x 312.2(b)(2)(i) 21 C.F.R. Part 1270. 66 Fed Reg 1508 (January 8, 2001). 64 Fed Reg 52696 (September 30, 1999) (Donor Suitability proposed rule). 66 Fed Reg 5447 (January 19, 2001) (Establishment Registration and Listing final rule). 66 Fed Reg 1508 (January 8, 2001) (Good Tissue Practices proposed rule). 68 Fed Reg 2689 (January 21, 2003). Id at 2985. 21 C.F.R. Parts 606 and 640. http://www.fda.gov/cber/blood/bap.htm 21 C.F.R. x607.7(a) (Establishment Registration and Product Listing of Blood Banks and Other Firms Manufacturing Human Blood and Blood Products). http://www.fda.gov/cber/gdlns/somgene.htm Comparability protocols: chemistry, manufacturing and controls information (February 2003); available at http://www.fda. gov/cber/gdlns/ cmprprot.htm
31. 32. 33. 34. 35.
36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.
52. 53.
4
Generic Drug Approval Process: Pre-1984 History Concerning Generic Drugs
DAVID L. ROSEN Gray Cary Ware & Freidenrich, LLP Washington, DC, U.S.A.
1. INTRODUCTION Before enactment of the Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman Act), Abbreviated New Drug Applications (ANDAs) were permitted for duplicate versions of drug products, though only for drugs first approved by the U.S. Food and Drug Administration (FDA) between 1938 and 1962. Generally, such drugs were subject to the Drug Efficacy Study Implementation (DESI) program and were determined to be both safe and effective or were otherwise removed
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from the market. Products were eligible candidates for ANDAs if they were the same as an already approved drug in terms of dosage form, route of administration, strength, active ingredient, indication(s), and other conditions for using the drug product. Certain drug products were required to demonstrate bioequivalence if they were determined by FDA to have an actual or potential bioavailability problem and if appropriate methodology and standards were available to conduct such testing. In addition, FDA regulations permitted the submission of ANDAs for similar and related products only if the Agency made a specific determination, following a companys specific inquiry, letter, or citizen petition, that an ANDA was appropriate for the particular product. FDA made such a determination upon evaluating the nature of the proposed product in view of the efficacy and safety of the product initially marketed between 1938 and 1962.
2. THE 1938 FEDERAL FOOD, DRUG, AND COSMETIC ACT The Federal Food, Drug, and Cosmetic Act (FD&C Act) as enacted by the U.S. Congress in 1938 established a premarket clearance system for new drugs under which companies seeking FDA approval were required to submit new drug applications (NDAs), including, among other items, data demonstrating the safety of the respective drug products. The FD&C Act provided that the NDAs would automatically become effective if a brandname drug was proven to be safe so that the drug product could be legally marketed within a specific time period unless the FDA affirmatively refused to approve the specific NDA. In addition to drug products marketed under an NDA that had been approved or become effective, many brand-name and generic products marketed without an effective NDA were identical, similar, or related to drug products having effective NDAs. Drug manufacturers who were marketing such drug products had determined that their products were generally recognized as safe (GRAS) or had received an advisory opinion
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from the Agency that an NDA was not required because their products were GRAS and determined by FDA not to be new drugs.
3. THE 1962 AMENDMENT TO THE FD&C ACT In 1962 Congress amended the FD&C Act to require affirmative approval by FDA of NDAs before marketing of drug products. The 1962 Kefauver-Harris amendment required that drug companies demonstrate the effectiveness of a drug product in addition to safety requirements imposed under the 1938 FD&C Act. Under x505(b) of the amended Act, NDAs were (and still are) required to contain, among other items, full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective. For products marketed prior to 1962, drug companies were required to submit data to demonstrate the effectiveness of their drug products. Congress also instructed FDA to review all drug products that obtained NDA approval from 1938 to 1962 in order to evaluate whether such products were effective. The evaluation of these drug products and the implementation of the findings of the evaluation were carried out under the DESI program. FDA contracted with the National Academy of Sciences/National Research Counsel (NAS/NRC), which established expert panels to review the submitted clinical data and make recommendations to FDA about the effectiveness of the specific drug products included in the DESI program, based on the data submitted, as to whether a drug product should be considered effective, probably effective, possibly effective, or ineffective, but not an approved form of treatment since other treatments are better, safer, or more convenient. FDA reviewed and considered the recommendations of the NAS/NRC expert panels concerning the effectiveness of DESI drug products and published its conclusions in the Federal Register. The Federal Register notices, commonly referred
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to as DESI notices, set forth revised conditions for marketing specific drug products. The revised conditions for marketing set forth in the Federal Register notices not only applied to the specific brand-name product for which efficacy data were generated but also provided conditions for obtaining FDA approval to market a duplicate generic version of the product. FDA administratively established the policy to approve generic versions of DESI-reviewed drug products without express statutory authority for such an abbreviated approval process, but no one ever challenged the Agencys authority in this matter. If a drug manufacturer had a pre-1962 new drug application in effect for a brand-name drug product, FDA processed the application to approval if the manufacturer submitted a supplemental NDA that provided revised labeling to conform the products indications for use to those determined to be effective in the DESI review. The manufacturer also was required to comply with other revised conditions for marketing the product as set forth in the Federal Register notice. Such conditions could include reformulation of the ingredients contained in the product, changes in strength of individual ingredients, changes in dosage form, and other revisions of the labeling. As noted above, however, many drug products on the market were identical in active ingredient(s) and indication(s) or very similar or in some manner related to the drug products found effective in the DESI review but for which no new drug application had ever been submitted. With respect to products for which no NDA was ever submitted and duplicate or generic versions thereof, in implementing the DESI program, FDA concluded that each such drug product was a new drug that required its own approved new drug application before it could be legally marketed (3). (The definition of new drug under the FD&C Act applies to the drug product rather than to the generic active ingredient.) FDA also issued a statement of policy that revoked the earlier advisory opinions that drugs could be marketed without preclearance by the agency. FDAs policy revoking earlier advisory opinions concerning the marketing of products earlier deemed not to be new drugs was published in the Federal Register in 1968 (4).
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4. THE ABBREVIATED NEW DRUG APPLICATION PROCEDURE FOR PRE-1962 DRUGS To provide a mechanism for approval of duplicate generic products based on the DESI evaluation, FDA established a procedure for submission of ANDAs. This procedure was set forth in Federal Register notices (4,5). After FDA had reviewed the conclusions of the NAS/NRC experts and found that a particular drug product was effective and suitable for ANDAs, FDA published in the Federal Register a DESI notice announcing these conclusions. Subsequently, any manufacturer of a duplicate of the drug not already holding an approved NDA was then required to submit an ANDA to obtain approval to market the duplicate version of the approved drug within a defined period of time (2). Approval of an ANDA was based on the proposition that the evidence of effectiveness necessary for approval of an NDA had been provided by the brand-name company, reviewed, and accepted during the DESI process. The evidence of safety of the drug had been determined on the basis of information included in the brand-name company NDA and through the subsequent postmarketing experience with the drug. The information required for an ANDA must demonstrate the generic drug applicants ability to manufacture a product meeting appropriate standards of identity, strength, quality, and purity equivalent in both safety and effectiveness to the brand-name drug whose safety and effectiveness was established during the course of the DESI review. The ANDA was required to contain information on the generic drug products formulation, manufacture, quality control procedures, testing, facilities, stability, dissolution profile (where applicable), and labeling. In addition, the DESI notice also identified other data and information that FDA required in an ANDA for a specific drug product, typically data on the in vivo bioavailability of the proposed generic drug product comparing it to the brand-name drug product. The criteria used to establish bioequivalence was known as the 75/75 rule, where 75% of the subjects were required to have concentrations in the plasma between 75 and 125%
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when the proposed generic drug product was compared to the brand-name drug product. The data required to be submitted, reviewed, and determined by FDA to support approval of the ANDA was the same kind of chemistry, manufacturing and controls, labeling, and related product quality information required for a full NDA but did not include the reports of investigations establishing the safety and effectiveness of the drug, which was already established through the DESI program. For brand-name drug products approved by FDA after 1962, however, FDA declined to establish an abbreviated review process. These drug products had not been subject to the DESI review. As a condition of approval for brand-name drug products introduced after 1962, companies were required to submit adequate and well-controlled studies to establish both the safety and effectiveness of the drugs. There was no statutory provision for an abbreviated process for generic versions of brand-name drug products approved after 1962, and FDA therefore required a full NDA in order to approve a generic version of a post-1962 brandname drug. Just prior to the passage of the Drug Price Competition and Patent Term Restoration Act (commonly referred to as the Hatch-Waxman Amendments to the FD&C Act), the Federal Circuit issued a significant decision affecting patent infringement (7). The court held that using a drug to perform the necessary tests for generic approval of a drug constituted infringement of the patent if that testing was performed prior to the expiration of the patent. This decision had the effect of essentially extending the monopoly associated with drug patents, since under the Bolar rule (7), generic companies could not even begin testing a brand for the purposes of developing a generic copy (for example, beginning formulation development or performing bioequivalence testing) until after the expiration of the patent. In the Hatch-Waxman Amendments, Congress explicitly overturned this decision and included an express legislative provision that it would not be an act of infringement to make, use, or sell any patented invention solely to develop and submit applications for approval of drugs.
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5. LITERATURE-SUPPORTED NDAs FOR GENERIC VERSIONS OF POST-1962 BRAND-NAME DRUGS In the 1970s FDA recognized that requiring applicants to repeat costly and time-consuming preclinical and clinical research for duplicate versions of certain brand-name drug products initially approved after 1962 with long marketing histories and extensive published support in the literature was not an efficient use of scarce research resources. FDA established a paper NDA policy whereby a company could obtain approval of an NDA for these certain generic versions of brand-name drugs under x505 based solely upon the existence of published scientific literature to provide safety and efficacy information in conjunction with bioequivalence data. Companies seeking approval through the paper NDA route were required to review and evaluate both preclinical and clinical literature to establish safety and effectiveness. This information satisfied/met the full report of investigation requirements of x505(b) of the FD&C Act. FDA announced the paper NDA policy via a memorandum without following notice-and-comment rulemaking procedures. FDA claimed that it was just interpreting the NDA submission and approval requirements of x505 of the FD&C Act. The paper NDA policy was later challenged in court on both substantive and procedural grounds, and found to be lawful (8,9). While the paper NDA process provided an alternative route to obtain approval for drug products, including duplicates of certain brand-name drugs first approved by FDA after 1962, this approval route ultimately proved to be of limited long-term applicability and usefulness to the generic industry since there was not enough published literature deemed by FDA to meet the statutory requirement of full reports of adequate and well-controlled studies to establish safety and effectiveness for the vast majority of post-1962 drug products. In fact, only approximately 11 drug products approved after 1962 were deemed by FDA to satisfy the full report requirements for approval. As a result of the limited applicability and utility of the paper NDA process to be a viable mechanism for approval of
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duplicate versions of brand-name drugs approved after 1962, Congress and FDA received significant pressure from the generic industry and healthcare and patient advocates to establish a broader policy to authorize generic drug approvals for post-1962 NDA-approved drug products to reduce drug costs. In 1983 FDA began drafting proposed regulations to establish an abbreviated new drug application review process for post1962 generic drugs. FDA, however, delayed issuing proposed regulations. The National Association of Pharmaceutical Manufacturers, representing generic drug manufacturers, then instituted a lawsuit seeking declaratory judgment that FDA could lawfully establish a post-1962 generic drug policy. Before the lawsuit was adjudicated, Congress enacted the Drug Price Competition and Patent Term Restoration Act of 1984, which statutorily established an abbreviated review process for post1962 generic drug approvals under x505(b)(2) of the FD&C Act.
REFERENCES
1. Chief, Review Support Branch, Division of Generic Drugs, Office of Drug Standards, Bureau of Drugs, personal communication. 35 Fed Reg 11273, July 14, 1970. United States v. Generix Drug Corp., 460 U.S. 453 (1983). 33 Fed Reg 7758, May 28, 1968. 34 Fed Reg 2673, February 27, 1969. 35 Fed Reg 6574, April 24, 1970. Roche Products, Inc. v. Bolar Pharmaceuticals Co., Inc., 733 F.2d 858 (Fed. Cir.), cert. denied, 469 U.S. 856 (1984). Burroughs Wellcome Co. v. Schweiker, 649 F. 2d 221 (4th Cir. 1981). Upjohn Mfg. Co. v. Schweiker, 681 F. 2d 480 (6th Cir. 1982). Beers DO. Generic and Innovator Drugs: A Guide to FDA Approval Requirements, 5th ed.
2. 3. 4. 5. 6. 7. 8. 9. 10.
5
Generic Drug Approval Process, Post-1984: Hatch-Waxman Reform
MARC S. GROSS, S. PETER LUDWIG, KRISTIN BEHRENDT KOSINSKI, and ATUL R. SINGH Darby & Darby, P.C. New York, New York, U.S.A.
1. OVERVIEW OF GENERIC DRUG APPROVAL PROCESS UNDER HATCH-WAXMAN The regulatory scheme for approval of generic drugs changed in April 1984 with the enactment of the Drug Price Competition and Patent Term Restoration Act of 1984, commonly known as the Hatch-Waxman or Waxman-Hatch Act (1). The Act was intended to balance the interests of consumers, the brand-name/(innovator) pharmaceutical industry, and the generic drug industry to make available more low cost generic
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drugs [and] to create a new incentive for increased expenditures for research and development of certain products which are subject to pre-market approval (2). In fewer than 20 years since enactment of the statute, generic drugs increased from 19 to 47% of prescriptions filled for pharmaceuticals and even in 1994 accounted for savings to consumers of $810 billion (3). Breaking new ground, Title I of Hatch-Waxman authorized the marketing of generic drugs upon approval of Abbreviated New Drug Applications (ANDAs) (4). Under the Act, an ANDA can be approved upon submission of evidence that the active ingredient of the generic drug is the bioequivalent of a drug previously approved by the U.S. Food and Drug Administration (FDA) after submission of a full New Drug Application (NDA), without having to submit studies establishing the safety and efficacy of the drug (5). Hatch-Waxman contains similar provisions respecting ANDAs and so-called 505(b)(2) applications, or paper NDAs, for which evidence of safety and efficacy of the drug must be submitted but can be based on third-party published data rather than full safety and efficacy testing (6). Title II of Hatch-Waxman provided for specific extensions of patents covering drugs (and other products) subject to regulatory review by the FDA and other governmental agencies (7). This provision was intended to balance the benefits of ANDA practice by providing brand-name drug companies with the restoration of portions of the terms of their drug patents lost during the testing period required for approval of the drugs. Patent term adjustments under 35 U.S.C. x156 (Section 156 extensions), as well as patent extensions implemented 10 years after enactment of Hatch-Waxman pursuant to the Uruguay Round of Negotiations under the General Agreement on Tariffs and Trade (8), authorized extended drug patent terms providing patent marketing exclusivities to innovator companies. The Hatch-Waxman statutory scheme incorporates several provisions relating to the submission and approval of both ANDAs and 505(b)(2) applications subject to such patent and other marketing exclusivities for listed drugs granted to brandname companies. Thus, the Act specifically provides that it is not an act of patent infringement to use a patented invention
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solely for uses reasonably related to the development and submission of information for FDA or other governmental approval (9). On the other hand, Hatch-Waxman provides that an applicant for an ANDA or a 505(b)(2) applicant must make an appropriate certification respecting marketing of the generic ` drug vis-a-vis any patents for the same drug that are listed by the brand-name NDA holder in the FDAs list of Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) (10). Where the generic applicant certifies that there are no patents listed in the Orange Book (Paragraph I Certification) or that any listed patents have previously expired (Paragraph II Certification), it may enter the marketplace immediately upon FDA approval. Where the applicant certifies that any listed patent has not yet expired but will expire on a particular date (Paragraph III Certification), the FDA may approve the ANDA and make it effective as of the patent expiration date. Where the applicant for generic approval intends to market the drug prior to expiration of any patent(s) listed in the Orange Book, it makes a certification that, in its opinion, the patent(s) are not infringed or are invalid (Paragraph IV Certification), and it notifies the NDA holder and patent owner accordingly (11). In such instance the statute provides that the NDA holder/patent owner may then initiate a patent infringement action against the applicant for generic approval and the FDA must suspend approval of the ANDA or Section 505(b)(2) application for up to 30 months (the 30-month stay), subject to an earlier court determination, or the listed patent(s) expire (12). In an effort to encourage generic drug entry into the pharmaceutical market, the Hatch-Waxman Act provides a commercial incentive to those generic companies who are the first to file ANDAs incorporating Paragraph IV Certifications challenging infringement or validity of Orange Booklisted brand-name pharmaceutical patents. Thus, in the event the listed brand-name patent(s) are adjudged to be invalid or not infringed prior to their normal expiration date(s), the first generic filer entitled to approval of its ANDA receives a 180-day exclusivity period, during which no other ANDA can be approved
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for the same product (13). In such circumstances, the first entity to file an ANDA can be the only generic marketer for 180 days. In addition, Hatch-Waxman incorporates several provisions limiting the filing or approval of ANDAs and 505(b)(2) applications in view of marketing exclusivities previously obtained by a brand-name NDA holder. Chief among such limitations is a 5-year bar on submitting an application for generic drug approval following approval of an NDA on a new chemical entity (NCE) (14) and a 3-year bar on obtaining approval of a generic drug application following approval of an NDA based on new clinical investigations respecting a previously approved drug (15). The FDA approval scheme for ANDAs containing Paragraph I, II, III, or IV Certifications is illustrated in Figures 1 and 2 (16). As of the preparation of the present text, substantial administrative and statutory modifications have recently been incorporated in the Hatch-Waxman regulatory scheme in an
Figure 1
ANDA patent certifications.
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Figure 2
Paragraph IV certifications.
effort to speed the approval and marketing of generic drugs. The principal change made is designed to limit brand-name companies to the opportunity to obtain a single 30-month stay of approval of ANDA or 505(b)(2) applications for the resolution of patent infringement litigation respecting listed drug patents. The recent changes are considered in detail below. Accordingly, the discussion in this chapter includes Applications for FDA Approval to Market a New Drug: Patent
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Submission and Listing Requirements and Application of 30Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug Is Invalid or Will Not Be Infringed, effective as of August 18, 2003 (the 2003 Rule Changes) (17). The FDA anticipated that some of the 2003 Rule Changes might be challenged; however, as of this writing they remain in effect in their published form save for certain modifications required for consistency with the subsequent statutory amendments noted below (18). The following discussion also references the amendments to the Hatch-Waxman Act enacted as part of Title XI of the Medicare Prescription Drug Improvement, and Modernization Act of 2003, signed into law by President Bush on December 8, 2003 (the 2003 Statutory Changes) (19).
2. LISTING PATENTS IN THE ORANGE BOOK 2.1. Requirements In 1984, Hatch-Waxman required for the first time, each NDA applicant to identify any patent that claims the drug for which the NDA was submitted or a method of using such drug that the applicant believed could reasonably be asserted against potential generic infringers (20). The patent information must be submitted in or during the pendency of the NDA or, if a patent eligible for listing in the Orange Book is granted after approval of the NDA (or even after the filing of an ANDA seeking approval of a generic equivalent of the listed product), within 30 days after grant of the patent (21). Under HatchWaxman, the generic applicant must make a patent certification as to each such listed patent (22) and, if the patent is not listed until after filing of the ANDA, amend its application accordingly (23). On the other hand, if the brand-name company fails to submit the patent information for listing in the Orange Book within the 30-day period after the grant of the patent, the generic applicant need not submit an amended certification and the patent owner may not initiate an infringement suit under 35 U.S.C. x271(e)(2) (24).
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The patents for which information must be submitted in connection with an NDA include those directed to the drug substance (active ingredient), the drug product (formulation or composition), and methods of use (indications) approved for the listed drug product (25). The patents thus submitted to FDA are listed by it in the Orange Book (26); these are the so-called listed patents or Orange Book patents. Since enactment of Hatch-Waxman, brand-name companies have submitted patents for listing in the Orange Book directed to a wide range of subject matter, including different forms of the active drug substance, e.g., anhydrous or hydrated forms, salts, enantiomers or crystal forms of the active substance, different formulations of the drug, metabolites formed in patients after administration of the drug, and methods of use of the drug whether or not previously approved by FDA (27). The listing of multiple patents in the Orange Book has compelled ANDA and 505(b)(2) applicants to make multiple patent certifications and, in some instances, has resulted in the imposition of multiple 30-month stays of generic product approvals, with consequent delays of generic entry into the market. Under present practice, FDA does not review the propriety of patents submitted by NDA holders for listing in the Orange Book on the ground that it does not have the expertise to review patent information (28). Rather, if the accuracy or relevance of patent information submitted for listing in the Orange Book is disputed by an ANDA or 505(b)(2) applicant, it must notify FDA, and the agency will then ask the NDA holder to confirm the correctness of the patent information and, unless the NDA holder withdraws or amends its patent information, FDA will not change the patent information in the . . . [Orange Book] (29). The agencys failure to review patent listings in the Orange Book for possible delisting has provoked substantial controversy and prompted proposals for reform. The 2003 Rule Changes embodied FDAs response to previous criticisms of its procedures respecting patent listings. Under the new regulations, drug substances that contain the same active ingredients as the subjects of NDAs but in different physical forms, i.e., polymorphs (30), must be submitted
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for listing in the Orange Book. An NDA holder or patent owner must, however, establish that a polymorph claimed in a patent will perform the same as the drug product described in the NDA with respect to such characteristics as dissolution, solubility, and bioavailability (31) for listing. To establish such sameness for a polymorph, the NDA holder or patent owner must submit detailed test data in five different categories, utilizing forms specified in the 2003 Rule Changes (32). Further in accordance with the 2003 Rule Changes, the listing of product-by-process patents (33) is permitted, provided, however, that to be submitted for listing the productby-process patent must claim the drug product that is the subject of the NDA and the drug product must be novel (34). In addition, the 2003 Rule Changes prohibit the submission for listing of patents that claim packaging, metabolites, or intermediates [in addition to the previous prohibition against the submission of process patents claiming methods of making drug substances (active ingredients)] (35). Packaging is distinct from finished dosage forms for approved drug products, which must be submitted for listing (36). A metabolite is defined by FDA as a chemical compound that results after the active ingredient of the drug has broken down inside the body; metabolites may not be submitted for listing since they are not the active ingredients described in NDAs (34). Finally, intermediates, materials that are produced during preparation of the active ingredient and are not present in the finished drug product, may not be submitted for listing (34). FDA considers intermediates as in-process materials, as distinguished from drug substances or components in a finished drug product (34). 2.2. Challenges to Listing In several cases ANDA applicants have sought to compel FDA to delist patents improperly listed in the Orange Book. Those efforts have been without success, the Court of Appeals for the Federal Circuit holding that delisting is a private right of action both barred by the FDCA and not a recognized defense to a claim of patent infringement (37). While the Federal
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Circuit held out the possibility that a generic company might secure federal jurisdiction on some other basis (38) (e.g., by an action against the listing company in a counterclaim to a patent infringement suit), any attempt by a generic company to seek delisting would involve substantial additional delays, during which it would be barred from the market by reason of the continued patent listing in the Orange Book. In its 2003 Rule Changes, FDA declined to create any administrative procedures for challenging patent listings or for delisting patents. Instead, it affirmed its long-standing view that it has only a ministerial role in overseeing Orange Book listings (39). However, in an effort to reduce confusion and help curb attempts to take advantage of this process [the Hatch-Waxman administrative scheme](40), the agency has restricted the types of patents and supporting evidence required for listing (Sec. 2.1) and permitted NDA holders/patent owners one 30-month stay of approval of an ANDA filed after Orange Book listings (Sec. 9.1.2). In the 2003 Statutory Changes, no changes were made in the types of patents that must be submitted for listing in the Orange Book; however, the amendments provide a remedy for improper listings. Thus, in the event of the filing of a patent infringement action based on an ANDA or 505(b)(2) application, the applicant may assert a counterclaim to correct or delete the patent listing if the patent does not claim the approved drug or an approved method of use (41). The counterclaim may not include an award for damages. No such action for improper listing may be brought in the absence of a patent infringement action brought by the patent owner or NDA holder. This provision is effective as to any proceeding under Section 505 that was pending on or after December 8, 2003, regardless of the date on which the proceeding was commenced (42).
3. ABBREVIATED NEW DRUG APPLICATIONS 3.1. The Listed Drug Under Section 505( j) of Hatch-Waxman, an ANDA may be filed for a generic version of any listed drug (43). Any drug
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for which an NDA has previously been approved is deemed to be a listed drug and is listed by FDA in the Orange Book (44). Drugs previously approved under ANDAs are regarded as listed drugs (45). Antibiotics are also regarded as listed drugs (46). An ANDA must include all of the information required in an NDA exceptsignificantly, full reports of investigations demonstrating that the drug is safe and effective in use. Additionally, the ANDA must show (a) that the labeling of the drug for which the ANDA is sought is the same as the approved labeling for the listed drug, (b) that the generic drug, its route of administration, dosage form, and strength are the same as the listed drug or supply such information respecting any differences as the FDA may require, (c) that the generic drug is bioequivalent to the listed drug, and (d) that information is supplied regarding the status of any Orange Booklisted patents on the approved drug (47). 3.2. Establishing Equivalence to the Listed Drug Initially, an ANDA filer must show that the conditions of use identified in its proposed labeling have been previously approved for the listed drug on which the ANDA is based (48). According to the statute, the ANDA must incorporate the same labeling as that previously approved for the listed drug, except for any changes required because of differences approved on the basis of a suitability petition (see Sec. 3.4) or because the generic drug and the listed drug are produced or distributed by different manufacturers (49). Changes in the proposed labeling that may be approved under the FDA regulations include the listing of differences in expiration date, formulation, bioavailability, pharmacokinetics, or revisions made to comply with current FDA labeling guidelines (50). Consistent with the case law, the current regulation also specifically authorizes the omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under section 505( j)(4)(D) of the act (51). This provision, coupled with a Section (viii) Statement (see Sec. 7.1), has provided a mechanism for avoiding infringement of listed method-of-use patents for which generic applicants do not seek approval.
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In addition to the labeling requirement, an ANDA applicant must establish, if the listed drug has only one active ingredient, that its new drug is the same as that of the listed drug (52) or, if the listed drug has more than one active ingredient, that its active ingredients are the same as those of the listed drug or, if one of the active ingredients is different, that FDA has approved a suitability petition for the new drug and that the different active ingredient is both an active ingredient of a different listed drug or of a drug that is not a new drug within the meaning of Hatch-Waxman (53). Finally, the ANDA must show that the new drug is bioequivalent to the listed drug (54). As defined in the statute, a generic drug is considered to be bioequivalent to a listed drug if (a) the rate and extent of absorption of the respective drugs do not significantly differ from one another or (b) there is no significant difference in the extent of absorption of the respective drugs and the rate of absorption of the respective drugs is intentional, reflected in the proposed labeling of the generic drug, not essential to achieving effective concentrations, and is considered medically insignificant (55). FDA may exercise discretion in determining whether the evidence submitted to show bioequivalence is adequate (56) and in a proper case may waive the requirement for proof of bioequivalence (57). 3.3. Additional Requirements Although FDA does not require safety testing data in support of an ANDA, it may consider safety questions associated with the identity or concentrations of the inactive ingredients of the generic drug. Thus, approval of an ANDA may be denied if the agency finds that the inactive ingredients are unsafe under the conditions set forth in the proposed labeling for the drug or the composition of the drug is unsafe because of the type or quantity of the inactive ingredients in the composition (58). The regulations specify a number of changes in the inactive ingredients of a generic product on which the agency may predicate a reasonable basis to conclude that one or more of the inactive ingredients of the proposed drug or its composition
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raises serious questions of safety (59) and refuse approval. The FDA thus has considerable latitude in determining whether the identity or amounts of inactive ingredients in a generic drug may adversely affect the safety of the drug. 3.4. Suitability Petitions for Drugs That Differ from a Listed Drug If a party wants to submit an ANDA for a new drug that differs in specific respects from the listed drug to that the ANDA refers, it may submit a suitability petition to FDA seeking permission to file such an application (60). Such petitions may be filed where the new drug has (a) a different active ingredient, (b) a different route of administration, (c) a different dosage form, or (d) a different strength from the listed drug (60). Any different active ingredient must be within the same pharmacological or therapeutic class as the active ingredient in the listed drug, and the modified drug must be expected to have the same therapeutic effect as the listed drug (61). When the party filing a suitability petition seeks approval to incorporate a different active ingredient in a listed drug having more than one active ingredient, it must establish that the other active ingredients of the new drug are the same as the active ingredients of the listed drug, that the different active ingredient is an active ingredient of a different listed drug, or that the different active ingredient is an active ingredient of a drug that is not a new drug under the FDCA (62). Consistent with the statutory provisions, a suitability petition should be granted unless FDA finds that investigations must be conducted to show the safety and efficacy of the modified drug or of any of (i) its active ingredients, (ii) route of administration, (iii) dosage form, or (iv) strength, which differ from the listed drug, or that the drug may not be adequately evaluated for approval as safe and effective on the basis of the information required in an ANDA (63). The procedure for submitting a suitability petition is set forth in the FDA regulations (64). The petition must identify the listed drug, incorporate a copy of the proposed labeling for the generic product (as well as a copy of the approved labeling
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for the listed drug), and make the several specific showings outlined in the regulation. Under the statute, a suitability petition must, in theory, be either approved or disapproved within 90 days of the date the petition is submitted (65). 3.5. Removal of Orange Book Listing of a Drug Hatch-Waxman specifies that listing of a drug in the Orange Book will be terminated if its approval is withdrawn or suspended or it is withdrawn from sale for safety or efficacy reasons (66). FDA will not approve an ANDA when the approval of the NDA for the reference-listed drug has been withdrawn or suspended and the FDA has published a notice of opportunity for hearing to withdraw approval of the listed drug or when the Secretary has determined that the listed drug has been withdrawn from sale for safety or efficacy reasons (67). Withdrawal of approval of a listed drug may occur where, after due notice and opportunity for hearing, FDA finds that the drug is unsafe for use under the conditions for which it was approved, that there is a lack of substantial evidence that the drug is effective under the conditions set forth in the product labeling, or that the NDA contained any untrue statement of material fact (68). An ANDA holder may submit written comments on the notice of opportunity for hearing issued on the proposed withdrawal of the related listed drug, and, in the event it is granted a hearing, the ANDA holder may participate as a nonparty participant (69). If the Secretary of Health and Human Services finds that continued use of the drug presents an imminent hazard to the public health (70) and the FDA enters a final decision withdrawing approval of the listed drug, any ANDA whose holder submitted such comments will be withdrawn (71).
4. APPROVAL OF GENERIC DRUGS UNDER SECTION 505(b)(2) This section of Hatch-Waxman provides for approval of certain drugs for which full safety and efficacy investigations required
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for NDAs under Section 505(b)(1) are not required. The applications may apply to situations in which the applicant has not obtained a right of reference or use from the party for which the full safety and efficacy investigations were previously conducted (72). FDA interprets the provisions of Section 505(b)(2) to sanction reliance by a generic applicant on the safety and/or efficacy data submitted in a prior NDA for the related listed drug (73). Hence the paper NDA denomination, because the applicant relies on laboratory and clinical data from a third party. As of this writing, a number of 505(b)(2) applications have been filed for approval of salts differing from the NDA-approved salts of the same active ingredients, the generic applicants relying on data previously submitted to FDA by the NDA holders (74). In one such instance, the NDA holder/patent owner unsuccessfully challenged the foregoing FDA interpretation by Citizen Petition (75). As noted below, 505(b)(2) applicants must make patent certifications and comply with patent notice provisions analogous to those required for ANDA applicants (76). Because of the similar requirements, FDA may refuse to accept 505(b)(2) applications for drugs that are duplicates of listed drugs and are eligible for approval of ANDAs under Section 505( j) (77). 4.1. Reliance Upon Literature Investigations relied upon by a 505(b)(2) applicant may include both studies that it owns and reports from studies owned by third parties. Such studies may include both clinical and animal safety and efficacy tests. FDA views all such tests submitted in a 505(b)(2) application as having been relied upon by the 505(b)(2) applicant (78). 4.2. Variants of Listed Drugs 505(b)(2) applications are necessary for new generic drugs that differ sufficiently from the prior listed drugs that suitability petitions for filing ANDAs (Sec. 5.2.3) would not be approved. For example, this is the case where the listed drug has only one active ingredient (79). Accordingly, as indicated above, the filing
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of a 505(b)(2) application is appropriate where, for example, the generic drug for which approval is sought is a different salt from one that is the active ingredient of a listed drug (60).
5. FDA ACTION ON ANDAs AND 505(b)(2) APPLICATIONS In general, an ANDA or 505(b)(2) application may not be submitted within 5 years after the approval of an NDA for a New Chemical Entity (NCE), unless the application contains a Paragraph IV Certification (in which case the application may be submitted on the fourth anniversary of the approval of the NDA) (80). FDA interprets the term new chemical entity as set forth in this section of Hatch-Waxman as referring to the active moiety of the previously approved NDA, i.e., the molecule or ion (excluding the groups that form an ester or salt or other noncovalent derivative of the molecule) that is responsible for the physiological or pharmacological action of the drug (81). An ANDA or 505(b)(2) application may, however, be filed after the fourth anniversary of the NDA approval for an NCE where the application contains a Paragraph IV Certification of noninfringement or invalidity of a listed patent relating to the approved drug (82). Under Hatch-Waxman, FDA must approve an ANDA unless it finds that the methods and facilities of the applicant are inadequate to assure the identity, strength, quality, and purity of the drug or the information submitted in the application is insufficient to meet the further statutory requirements (83). On the other hand, since a 505(b)(2) application is basically an NDA, it must meet each of the requirements for an NDA save that it may rely upon investigations of safety and efficacy that were not conducted by the applicant and for which it has not obtained a right of reference (78). The statute provides the agency must complete its review of the sufficiency of an ANDA or 505(b)(2) application within 180 days of initial receipt of the application (84). During the review period FDA may either approve or disapprove the
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application. If it disapproves the application, it must give the applicant notice (a not approvable letter) and provide it with the opportunity to amend the application, withdraw it, or request a hearing to challenge the agencys grounds for denying approval (85). The opportunity to request a hearing is designed to provide the applicant with the opportunity to contest the grounds asserted by the agency for denying approval of the application (86). Alternatively, if FDA approves the ANDA or 505(b)(2) application, the effective date of approval may be delayed (14) on any of the various grounds indicated below.
6. PATENT CERTIFICATIONS 6.1. Types of Certifications An applicant for an ANDA or a Section 505(b)(2) NDA must certify to FDA that, in its opinion and to the best of its knowledge, with respect to each listed patent that claims the drug or a use of the drug for which the applicant is seeking approval (22): 1. The patent information which the NDA holder is required to file (including the identification of any listed patent) has not in fact been filed (a Paragraph I Certification), 2. The listed patent has expired (a Paragraph II Certification) 3. The listed patent will expire on some specified date and the ANDA or 505(b)(2) applicant does not intend to commence marketing the drug for which it seeks approval until after that date (a Paragraph III Certification) 4. The listed patent is invalid or will not be infringed by the manufacture, use, or sale of the drug for which the ANDA or 505(b)(2) application is submitted The FDA regulations provide that Paragraph IV Certification may be based on unenforceability of the listed patent as well as noninfringement or invalidity thereof (87).
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6.2. Content of Certifications Paragraph I Certification simply permits the ANDA or 505(b)(2) applicant to inform FDA that the NDA holder has not listed any patents that might affect the agencys approval of the application (88). Similarly, Paragraph II Certification serves to inform FDA that a previously listed Orange Book patent has expired and would not have any effect on approval by the agency. In like manner, a Paragraph III Certification informs FDA when a listed patent will expire, thus providing notice to the agency that the ANDA or 505(b)(2) application should not be approved prior to that date (see Fig. 2). Paragraph IV Certification, on the other hand, imposes certain obligations on (a) the ANDA or 505(b)(2) applicant, (b) the owner of the listed patent, and (c) FDA. The initial obligation is imposed on the applicant, who must include a statement in its application that it will provide notice of its application and the basis for its position to the owner of each listed patent and the holder of the NDA for the listed drug or the representatives thereof (89).
7. NOTICE TO PATENT OWNER AND HOLDER OF NDA FOR LISTED DRUG The notice required of the ANDA or 505(b)(2) applicant must state that an application containing bioavailability or bioequivalency data has been submitted to FDA to obtain approval to engage in the commercial manufacture, use, or sale of the listed drug before the expiration of the patent as to which the certification has been made (90). The notice must include a detailed statement of the factual and legal basis of the applicants opinion that the patent is not valid or will not be infringed (90). FDA regulations provide that the notice of factual and legal basis must set forth a detailed statement for each claim of the listed patent for which a Paragraph IV Certification is submitted and provide a full and detailed explanation of why the claim is not infringed and/or such an explanation of the
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grounds supporting the allegation of invalidity (or, alternatively, unenforceability) of each such claim (91). The regulations further require that the notice given by the ANDA applicant must identify the ANDA number, the established name, if any, of the proposed drug product, the active ingredient, strength and dosage form of the proposed drug product, and the patent number and expiration date of each of the listed patents believed to be invalid, unenforceable, or not infringed (92). Under the 2003 Rule Changes, a generic applicant who submits an amended or supplemental Paragraph IV Certification is not required to provide a notice of the factual and legal basis for its certification to the listed patent owner or NDA holder (93). On the other hand, under the 2003 Statutory Changes, when an amended or supplemental Paragraph IV Certification is made, the applicant must give the notice of factual and legal basis to the patent owner/NDA holder (90). The amendment to the Act essentially reverses the 2003 Rule Changes with respect to providing notice of an amended or supplemental Paragraph IV Certification. Under the 2003 Statutory Changes, when Paragraph IV Certification is in the ANDA or 505(b)(2) application, the notice must be given no later than 20 days after the postmark date on the notice from FDA of filing of the application (94). When the certification is in an amendment or supplement to the generic application, the notice must be given at the same time as the submission of the amendment or supplement (95). Assuming compliance with the procedural requirements, FDA presumes the notice to be effective upon receipt by the patent owner and NDA holder and counts the day following the date of receipt as the first day of the 45-day period provided in Hatch-Waxman for possible commencement of infringement litigation, as described below (96). Brand-name companies have in some infringement actions (predicated on Paragraph IV Certifications) asserted that ANDA applicants have not satisfied the requirement to provide sufficient notice of the factual and legal basis for asserting noninfringement or invalidity of listed patents and sought court orders remedying allegedly deficient notices. To date, no such orders have been issued (97).
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7.1. Section viii Statement of Listed Use Patents That Do Not Cover Indications for Which Approval Is Sought Hatch-Waxman provides that Paragraph IV Certifications need not be made in ANDAs or 505(b)(2) applications with respect to Orange Booklisted use patents which do not claim a use for which the applicant seeks approval. In this instance, the statute (and the FDA rules) provides that the applicant may file a statement that the use patent does not claim such a use (98). A Section viii Statement is significant since it may avoid the submission of a Paragraph IV Certification and thus preclude the patent owner from commencing an infringement suit and invoking the 30-month stay of approval of the generic drug. FDA has disclaimed any role in assessing whether a use patent covers an indication for which an ANDA or 505(b)(2) applicant seeks approval (99). Moreover, it has taken the position that it must accept the representations by the NDA holder as to the scope of the use patent and, in a number of instances, held that Section viii Statements are improper and instead required Paragraph IV Certifications (100). FDAs approach has been specifically endorsed by the courts (101). In another case, however, a trial court ordered FDA to accept an ANDA applicants Section viii Statement in lieu of a Paragraph IV Certification (102). This court did not take issue with FDAs policy of deference to NDA holders characterizations of the scope of use patents but found on the facts of the specific case that the patent owner had consistently distinguished the use claimed in the method patent in question from the indication for which the ANDA applicant sought approval. In order to refine its treatment of Section viii Statements, FDA, in its 2003 Rule Changes, modified the declaration required of an NDA holder for listing of a method-of-use patent. It now requires that the declarant must . . . describe each individual method of use [and identify the related patent claim(s)] for which a patent is submitted for listing, and identify the corresponding language found in the labeling of the approved NDA that corresponds to that method of use (103). By requiring greater particularity in the declaration,
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FDA may take a more substantive role in evaluating the pro` priety of Paragraph IV Certifications vis-a-vis Section viii Statements. 7.2. Amending ANDAs or 505(b)(2) Applications to Make Paragraph IV Certifications When an ANDA or 505(b)(2) applicant amends its application to make a Paragraph IV Certification, the statute requires it to notify the listed patent owner and NDA holder accordingly (90). Under previous regulations, this requirement is made if the generic applicant amends a Paragraph III Certification to a Paragraph IV Certification or adds a Paragraph IV Certification when a patent is listed in the Orange Book during the pendency of the application (104). A notice of the factual and legal basis for the Paragraph IV Certification must be sent at the same time that the amendment . . . is submitted to FDA (104). FDA regulations do not require ANDA or 505(b)(2) applicants to amend their prior certifications if the NDA holder failed to provide the requisite patent information within 30 days after patent issuance or if their applications originally contained appropriate patent certifications (105). In accordance with the 2003 Rule Changes, an ANDA or 505(b)(2) applicant that amends its application to add a Paragraph IV Certification is only required to provide notice to the NDA holder and patent owner if (a) the application did not already contain a Paragraph IV Certification; or (b) there was not a full opportunity for the NDA holder to obtain a 30-month stay (106). The FDA suggested that when the ANDA or 505(b)(2) applicant is not required to provide notice of its subsequent Paragraph IV Certification(s) to the NDA holder and patent owner, multiple 30-month stays may be avoided (107). However, as pointed out above, the 2003 Statutory Changes still require notice of amended or supplemental Paragraph IV Certifications; the 2003 Act provides, however, for only a single 30-month stay of FDA approval upon the initiation of an infringement suit based on a patent listed in the Orange Book prior to the filing as to which a Paragraph IV
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Certification was made in the ANDA or 505(b)(2) application not the amendment or supplementationof such application (112) (see Sec. 9.1.2).
8. SUBMISSION OF AN ANDA OR 505(b)(2) APPLICATION AS AN ACT OF PATENT INFRINGEMENT As part of the effort to balance the rights of brand-name and generic pharmaceutical manufacturers, the Hatch-Waxman Act provided that the development of information by or for generic drug companies for the purpose of preparing ANDAs or 505(b)(2) applications does not constitute patent infringement. Thus, Hatch-Waxman amended the patent statute to provide that [i]t shall not be an act of infringement to make, use, offer to sell, or sell . . . a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs (108). On the other hand, Hatch-Waxman provided that the submission of an ANDA or 505(b)(2) application asserting noninfringement or invalidity of a listed patent (requiring a Paragraph IV Certification) may be treated as (what the Supreme Court has characterized as) an artificial act of infringement (109). Thus, the patent statute was amended to specify that [i]t shall be an act of infringement to submit . . . [an ANDA or 505(b)(2) application] . . . if the purpose of such submission is to obtain [FDA] approval . . . to engage in the commercial manufacture, use, or sale of a drug . . . claimed in a patent before the expiration of such patent (110). Hatch-Waxman provides that a patent owner has 45 days after receiving notice of a Paragraph IV Certification to sue the ANDA (or 505(b)(2)) applicant for infringement (12). The applicant is required to notify FDA immediately upon the filing of suit within the 45-day period (111). If the patentee does not file an infringement action within the 45-day period, FDA may immediately approve the ANDA or 505(b)(2)
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application; if, on the other hand, the patent owner initiates suit, FDA cannot approve the application until the expiration of the 30-month stay for resolution of the litigation, as more fully set forth below (12). Accordingly, upon receipt of notice of Paragraph IV Certifications, brand-name pharmaceutical companies have frequently sued ANDA and 505(b)(2) applicants during the 45-day notice period to forestall generic competition in the marketplace for the 30-month period(s) sanctioned by Hatch-Waxman (112). 8.1. Scope of Infringement Actions Commenced Under 35 U.S.C. x271(e)(2) The artificial act of infringement under 35 U.S.C. x271(e)(2) is limited to the assertion of infringement based on Paragraph IV Certifications (12). In turn, Paragraph IV Certifications are directed to Orange Booklisted patents which claim the referenced listed drugs or uses for the listed drugs for which the applicant seeks approval. Thus, the statute cannot be relied upon as a basis for jurisdiction of infringement actions predicated on patents directed to methods of manufacture of listed drugs. Nor is it an act of infringement under x271(e)(2) to submit an ANDA for approval to market a listed drug for a different indication from one covered in a listed use patent (113). NDA holders/patent owners are authorized to list patents in the Orange Book that they believe could reasonably be asserted . . . [against an unlicensed party] engaged in the manufacture, use or sale of the drug . . . (20). In the past, ANDA or 505(b)(2) applicants could not seek patent delisting in infringement suits based on Orange Booklisted patents (114). A number of antitrust suits were, however, commenced predicated on the mala fides of Orange Book listings (115). Moreover, as indicated in Sec. 2.2, under the 2003 Statutory Changes an ANDA or 505(b)(2) filer sued on the basis of a Paragraph IV Certification may file a counterclaim seeking an order requiring the NDA holder to correct or delete the listing (41).
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8.2. Right of ANDA or 505(b)(2) Applicants to Seek Declaratory Judgments Hatch-Waxman precludes an ANDA or 505(b)(2) applicant from initiating a declaratory judgment action for noninfringement or invalidity of a listed patent within the 45-day period after receipt of its notice of the factual and legal basis for its Paragraph IV Certification (116). This provision facilitates initial commencement of a patent infringement suit and the consequent 30-month stay in accordance with the statutory scheme. On the other hand, it has been held that an ANDA or 505(b) (2) applicant may seek a declaratory judgment during the 45-day period on other grounds or file a counterclaim in the infringement suit for a declaratory judgment that it is not infringing other, unlisted patents (117). In either instance, it need only be shown that there is an actual controversy between the parties. The 2003 Statutory Changes further sanction the commencement of an action for declaratory judgment of noninfringement of a patent for which a Paragraph IV Certification has been made, provided that: (a) the NDA holder or, patent owner did not file an infringement suit within 45 days after receiving notice of such certification (118) and (b) in any case in which the notice from the ANDA or 505(b)(2) applicant asserts noninfringement, the notice is accompanied by a document offering confidential access to the ANDA or 505(b)(2) application for the sole purpose of determining whether an infringement action should be brought (119). The document offering confidential access must contain such restrictions as to persons entitled to access and the use and disposition of any information accessed as would apply had a protective order been entered to protect trade secrets and confidential business information. A request for access under an offer of confidential access is considered an acceptance of the terms and restrictions in the offer and creates an enforceable contract. Any ANDA or 505(b)(2) application to which confidential access is provided may be redacted by the applicant to remove information not relevant to any issue of patent infringement. Any action for declaratory judgment brought subject to the foregoing provisions must meet the case or controversy requirements of
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28 U.S.C. 2201 (120) and can only be commenced in the judicial district in which the defendant has its principal place of business or a regular and established place of business (121). The propriety of such declaratory judgment actions may well be the basis for future litigation. As stated in an explanatory statement in the conference committee report preceding enactment of the 2003 Statutory Changes, it was intended that the courts apply the reasonable apprehensions test for determining whether a suit presents a case or controversy supporting jurisdiction in a manner that provides generic drug manufacturers appropriate access to declaratory judgment relief to the extent required by Article III of the Constitution (122).
9. DELAYS IN THE APPROVAL OF ANDAs AND 505(b)(2) APPLICATIONS 9.1. Patent-Related Delays 9.1.1. Delays Attributable to Patent Term Extensions Delays in approval of ANDAs or 505(b)(2) applications may be prolonged because of extensions of the listed patents on which Paragraph IV Certifications must be made. Such extensions may be obtained because of patent term adjustments under 35 U.S.C. x156 or because of the 20-year term provisions under the URAA. Section 156 Term Adjustments To be eligible for a term adjustment under Section 156: 1. A patent relating to a drug product must be in force when the application for term adjustment is filed in the U.S. Patent and Trademark Office (123) 2. The term of the patent must not have been previously extended (124) 3. An application for the adjustment must be filed by the patent owner or its agent and must meet certain formal requirements (125)
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The drug product covered by the patent must have been subject to an FDA review period before its commercial marketing or use (126) 5. The FDA approval for commercial marketing or use after such review period must be the first commercial marketing or use of the drug product (127) The scope of any drug product patent extended under Section 156 shall, during the extension period, be limited to any use approved for the product (a) under the FDA law (128) (b) on or after the expiration of the review period on which the extension was based (129). The period of term extension may not exceed 5 years (130), but may be shorter depending upon the delay in obtaining regulatory approval as determined by a specific calculation (131). Under this provision, the period of the extension is reduced by any delays in the regulatory review procedure attributable to the NDA applicant (132). In any case, the patent term may not be extended for more than 14 years after the date of approval of the NDA for the drug product (133). The scope of a patent claiming a drug product is limited during the period of term extension to any FDA-approved use(s) (134). One court held that, during the extension period, a patent is also limited to the specific approved form of an approved drug, e.g., to the approved salt, notwithstanding generic product claims (that embraced other active agents effective for the same use as the approved product) incorporated in the extended patent (135). On appeal, however, the Federal Circuit held that, during the extension period, the generic product claims were not so limited (136). URAA Extensions The URAA conformed U.S. patent law with foreign law by providing that the term of a U.S. patent issued on or after June 8, 1995, extends 20 years from its effective filing date, rather than 17 years from its issue date. Thus, a patent issuing after June 8, 1995, claiming an effective U.S. filing date less than 3 years before its issue date is entitled to a term of 20 years from the effective filing date. On the other hand, a patent issued on an application filed after June 8, 1995, but claiming
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an effective filing date more than 3 years before its issue date is entitled to the 20-year term from the effective filing date (and will thus be in force less than the historical 17-year patent term from the issue date) (137). Accordingly, the effect of a prior listed patent on an ANDA or 505(b)(2) application may depend on its term under the URAA provisions. 9.1.2. The 30-Month Stay As illustrated in Figure 1, when an ANDA or a 505(b)(2) applicant certifies that patent information on a listed drug has not been submitted to FDA (a Paragraph I Certification) or that the patent or patents claiming the listed drug or the use of the drug for which the applicant seeks approval have previously expired (a Paragraph II Certification), FDA may approve the application immediately (138). On the other hand, when an ANDA or 505(b)(2) applicant certifies that the patent or patents listed in the Orange Book for the listed drug will expire on a specified future date (a Paragraph III Certification), the approval will be made effective as of that date (139). Last but not least, when an ANDA or 505(b)(2) applicant certifies that the patent or patents listed in the Orange Book respecting the drug would not be infringed by the proposed generic drug product or that the patent or patents are invalid or unenforceable, the FDA will, if an infringement action is commenced by the patent owner or NDA holder within the 45-day notice period, defer approval for the 30-month stay period, as discussed below (12). By delaying approval of an ANDA or 505(b)(2) application under which a generic applicant seeks to enter the market prior to expiration of a listed patent or patents, the stay provision protects the brand-name companys exclusive market pending completion of the infringement litigation. At the same time, the 30-month stay enables the generic applicant to obtain a judicial determination of infringement and validity of any listed patents without incurring the liability it might otherwise risk were it marketing the generic drug and facing a possible award of damages based on the patent owners lost profits. (As a general matter, this potential liability could be more
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than the generic companys total revenue from the sales of its drug, in view of the typical differences in the prices and profits of brand-name and generic products.) The 30-month stay is in fact somewhat of a misnomer. Hatch-Waxman provides that if an infringement action is initiated during the 45-day notice period, approval of an ANDA or 505(b)(2) application is delayed until the earlier of expiration of the 30-month period, or the date of a district court decision holding the patent(s) invalid or not infringed (12). Alternatively, the 30-month stay may be modified if before the expiration of that period the court hearing the infringement action determines that the patent is valid and infringed, grants a preliminary injunction, or determines that one of the parties has not reasonably cooperated in expediting the action (140). Prior to the effective date of the 2003 Rule Changes and enactment of the 2003 Statutory Changes, the generic filer was required to submit a Paragraph IV Certification as to each later-issued patent listed in the Orange Book subsequent to the filing of its application, subject to certain conditions (104). When the generic applicant submitted a Paragraph IV Certification as to the newly listed patent(s), upon commencing an infringement suit within the requisite period the brand-name company could obtain a new 30-month delay of FDA approval (141). Nor was it necessary for the multiple 30-month stays to run consecutively; it was possible for gaps to exist between sequential stays (142). The grant of multiple 30-month stays of generic entry and consequent abuse of the Hatch-Waxman regulatory scheme, coupled with continuing dramatic increases in prescription drug costs (143), led to several proposals for change. Thus, an FTC study in 20012002 culminated in the July 2, 2002, report (3) which made the following principal recommendation: Permit only one automatic 30-month stay per drug product per ANDA to resolve infringement disputes over patents listed in the Orange Book prior to the filing date of the generic applicants ANDA (144). On July 31, 2002, the U.S. Senate passed the McCainSchumer Bill (145), which proposed, among other changes, eliminating the automatic 30-month stay of approval of ANDAs
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or 505(b)(2) applications after suit by a brand-name company based on a Paragraph IV Certification and, subject to other qualifications, restricting such stay to patents listed within 30 days after approval of the NDAs. On October 21, 2002, the White House announced presidential action to lower prescription drug prices by improving access to generic drugs (146). President Bush referred to proposed regulatory action by FDA to implement the prior FTC recommendations, among other things, to allow one 30-month automatic stay based on infringement suits involving ANDAs. During the same week, FDA issued a detailed memorandum outlining its proposed rule making (147). Specifically, it proposed that an ANDA or 505(b)(2) applicant would not have to provide a notice of invalidity or non-infringement of a patent when the ANDA or 505(b)(2) application already contained a Paragraph IV Certification as to another patent, and the patent owner would thus only be entitled to a single 30-month stay for the resolution of infringement litigation based on the previous Paragraph IV Certification. As discussed above (Section 7.2), in accordance with the 2003 Rule Changes an NDA holder/patent owner could not obtain multiple 30-month stays provided it had one full opportunity to obtain a single 30-month stay after receiving notice from an ANDA or 505(b)(2) applicant of its Paragraph IV Certification. The one full opportunity proviso was intended to preclude avoidance of the 30-month stay provision by an ANDA or 505(b)(2) filer who (a) makes a Paragraph IV Certification but withdraws its application or changes to a Paragraph III Certification after giving notice but before the 45 days for filing an infringement action expires and before suit is filed or (b) makes a Paragraph IV Certification but changes its certification after it has been sued and the 30-month stay has commenced. On the other hand, the full opportunity provision would have precluded a second 30-month stay where an ANDA or 505(b)(2) applicant changed its Paragraph IV Certification to a Paragraph III Certification after an infringement suit was filed and the 30-month stay had commenced (e.g., following a
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court order finding infringement) and thereafter amended its application to add a new Paragraph IV Certification (148). The 2003 Statutory Changes have simplified and further restricted the grant of the 30-month stay. Thus, the stay may now only be obtained with respect to patents listed in the Orange Book prior to the filing of the ANDA or 505(b)(2) application; no 30-month stay will be triggered as to any patents listed after the filing date of the ANDA or 505(b)(2) application (12). 9.1.3. 180-Day Marketing Exclusivity for ANDAs
Hatch-Waxman provides a specific incentive to generic drug companies to file ANDAs seeking approval to market generic forms of listed drugs prior to expiration of brand-name companies patents for such drugs, namely the right to 180 days of ` marketing exclusivity vis-a-vis later ANDA filers (13). There is no comparable exclusivity accorded a 505(b)(2) applicant who may successfully challenge the validity or infringement of an asserted listed patent. Interpretation of the 180-day exclusivity provision has led to considerable controversy (and changes in agency positions), as discussed below. 9.1.4. Separate Exclusivity Periods for Different Dosage Forms and Different Listed Patents Before the 2003 Statutory Changes, the Hatch-Waxman Act did not specify whether separate 180-day exclusivities would be accorded to independent ANDA applicants who may first make Paragraph IV Certifications for different dosage forms of the same listed drug or to those independent Paragraph IV filers who may be the first to certify as to different listed patents for the same listed drug (149). The FDA thus fashioned individual regulatory policies as to each of these situations. Initially, the agency awarded separate 180-day exclusivity periods to different ANDA filers based upon the priority of their Paragraph IV Certifications respecting different strengths of the same listed drug. That policy was challenged and upheld as a reasonable exercise of the agencys discretion under the Administrative Procedures Act (APA) (150).
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Similarly, neither the statute nor the FDA regulations specifically provided for single or multiple exclusivities based upon priority of Paragraph IV Certifications as to multiple listed patents relating to a single drug. In one case the agency interpreted its regulations to warrant separate exclusivity awards to two different generic applicants based on the priority of their Paragraph IV Certifications respecting two different listed patents (151). In a subsequent proceeding involving 12 listed patents, the FDA decided that the award of independent exclusivity periods to either of two Paragraph IV filers would result in a blocking situation where neither party could be given approval until the other partys exclusivity as to certain patents had run. The agency decided that any 180-day exclusivity award would be shared between the two applicants (152). In yet another more recent case, FDA refused to provide any shared exclusivity where there was no possibility of blocking exclusivities (153). The 2003 Statutory Changes eliminate the possibility of independent exclusivity periods for different generic applicants, different dosage forms of the listed drug, or different listed patents. Only one 180-day exclusivity period may be obtained for a listed drug, and that period is based on patents for which a Paragraph IV Certification is first made by any generic applicant (13). Under the amendments to the statute, multiple first applicants who submit substantially complete ANDAs with Paragraph IV Certifications on the same day and subsequently obtain approval of their applications are eligible for 180-day exclusivity (154). These first applicants obtain shared exclusivity during the one 180-day exclusivity period. 9.1.5. Commercial Marketing of the Generic Drug by a First Applicant Triggers 180-Day Exclusivity Prior to enactment of the 2003 Statutory Changes, HatchWaxman provided that the 180-day exclusivity provision would be triggered, inter alia, on the date the FDA received notice of the first commercial marketing by any first ANDA applicant (155). This could occur (a) in the relatively rare instance in
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which an ANDA applicant commenced marketing after the 30month stay and prior to a court decision in an infringement action predicated on its filing (156), (b) where the owner of the listed patent had not sued for infringement, or (c) where the ANDA applicant had agreed not to market the listed drug pursuant to a settlement of infringement litigation. In one case relating to the last-mentioned situation, FDA had interpreted the statutory reference to commercial marketing of the drug under the previous application as embracing marketing by the ANDA applicant under license from the NDA holder after settlement of its litigation. Since more than 180 days had passed after commencement of such use, the agency concluded that the 180-day period had run and that other generic manufacturers could commence marketing. Upon attack under the Administrative Procedures Act, the court held that FDAs interpretation of the statutory language was reasonable and denied a preliminary injunction to the first filer (157). Under the 2003 Statutory Changes, the 180-day exclusivity period is only triggered by commercial marketing of the listed drug by any first ANDA applicant(s) (158). As pointed out in Section 9.1.6, the decision of a court (on either the district court or appellate court level) does not directly trigger the 180-day exclusivity period, but may be the precursor of a forfeiture event for which the exclusivity period may be forfeited by the first applicant. 9.1.6. The Effect of a Court Decision on Approval of an ANDA and Triggering of 180-Day Exclusivity Prior to enactment of the 2003 Statutory Changes, the 180-day exclusivity could be effective, inter alia, on the date of a decision of a court in an infringement action based a Paragraph IV Certification (159). FDA initially interpreted the date of the court decision as the date on which the court . . . enters final judgment from which no appeal can be or has been taken (160). Subsequently, in response to a number of adverse court decisions the agency amended its rules to provide that with
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respect to ANDAs containing Paragraph IV Certifications filed after March 2000, a decision of a trial court would trigger the 180-day exclusivity (161). In later litigation in which a trial court held a patent invalid and the patent owner and generic applicant had subsequently entered into a settlement agreement, it was held that the 180-day exclusivity period was triggered by the trial court decision (162). In yet another case, a court held that the 180-day exclusivity period would commence as of the date of a decision dismissing a declaratory judgment action for lack of subject matter jurisdiction where the plaintiff generic company lacked reasonable apprehension of a patent infringement suit (163). Such holding was inconsistent with a previously proposed FDA rule and caused the agency to withdraw the prior regulation (164). In its subsequently published notice FDA was constrained to indicate that it would continue to make 180-day exclusivity decisions on an issue-by-issue basis . . . [and] will also carefully evaluate possible options for future rule making addressing 180-day exclusivity and the timing of ANDA approvals (165). Under the 2003 Statutory Changes, approval of an ANDA or 505(b)(2) application may be made effective on the date on which a district court enters a judgment holding the listed patent invalid or not infringed, permitting (but not requiring) subsequent commercial marketing and based thereon, commencement of the 180-day exclusivity period (166).
9.1.7. The First ANDA Applicant(s) Making a Paragraph IV Certification is Awarded Exclusivity Prior to enactment of the 2003 Statutory Changes, FDA regarded only the first applicant making a Paragraph IV Certification to be entitled to the 180-day exclusivity. In the event of an adverse decision in an infringement suit against the Paragraph IV applicant, FDA regulations provide that it must amend its certification to a Paragraph III Certification indicating that it will not seek approval to market the generic product until
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the expiration of the listed patent (167). In its subsequently withdrawn August 1999 proposed rule, FDA had proposed that only the first Paragraph IV filer could be eligible for the 180-day exclusivity and would lose such award if it amended its certification to a Paragraph III certification for any reason (168). In one case in which the first filer amended its certification to a Paragraph III Certification after settlement with the patent holder, FDA asserted that the first filer retained its exclusivity, but the court found this best of all worlds interpretation in favor of the first filer to be inconsistent with [the] purpose of Hatch-Waxman and that the first filers 180-day exclusivity period had already run (169). In a subsequent case the first Paragraph IV filer settled its litigation with the patent holder, but did not amend its certification to a Paragraph III Certification. FDA concluded it should treat the Paragraph IV Certification as though it had been changed to a Paragraph III Certification, but the court disagreed, finding such construction unreasonable under the Administrative Procedures Act. The court did not reach the rights of the later filer because it found that the exclusivity period had run after the first filer had settled with the patent owner and commenced commercial marketing under the NDA. In a further example of a disputed interpretation of the 180-day exclusivity provisions, the FDA initially concluded that exclusivity could only be awarded to a Paragraph IV filer that had successfully prevailed in its litigation with the patent owner (170). Following multiple adverse court decisions, the agency issued a Guidance indicating that it would no longer enforce this successful defense requirement (171) and thereafter issued an interim rule removing the requirement (172). Further, it has been held that the first Paragraph IV filer may obtain exclusivity even when it is not sued based on the certification (173). Under the 2003 Statutory Changes, the amendment by a first applicant of the Paragraph IV Certification for all of the patents for which it has submitted such a certification is a forfeiture event for which the first applicant will forfeit its 180-day exclusivity period (174).
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9.1.8. Transfer or Waiver of Exclusivity Prior to the 2003 Statutory Changes, the Hatch-Waxman Act did not provide that the 180-day exclusivity may be transferred from one Paragraph IV filer to another or waived in favor of a subsequent filer. Nevertheless, the FDA permitted transfer or waiver in particular, complex factual contexts. Thus, the agency permitted a first Paragraph IV filer to waive its marketing exclusivity in favor of a subsequent filer where the exclusivity period had commenced and the first filer had not yet obtained agency approval and thus could not obtain the benefit of exclusivity (175). More recently, FDA interpreted the statute to permit sharing the potential 180-day exclusivity where two Paragraph IV filers had differing priorities with respect to the multiple listed patents asserted by the prior NDA holder/patent owner (176). Subsequently, when the trial court held that the sharing applicants infringed various of the listed patents, the FDA permitted waiver of the exclusivity in favor of a third filer whose generic product was held not to infringe the patents in question (177). As indicated above, the 2003 Statutory Changes expressly provide that 180-day exclusivity may be forfeited based upon any of a number of distinct forfeiture event(s) and that in the event of such forfeiture no subsequent filer will be eligible for a 180-day exclusivity period (178). 9.1.9. Forfeiture of Exclusivity The events defined in the 2003 Statutory Changes for which the first applicant may forfeit the 180-day exclusivity period include: 1. The later of (a) its failure to market the drug 75 days after approval of its application or 30 months after filing of the application whichever is earlier or (b) as to the first applicant or any other applicant that has received tentative approval of its application, at least one of the following has occurred: (i) 75 days after a final decision or order in an infringement or
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2.
3. 4. 5.
6.
declaratory judgment action holding the patent invalid or not infringed, (ii) a court has signed a settlement order or consent decree entering a final judgment that the patent is invalid or not infringed, or (iii) the patent has been withdrawn from listing by the NDA holder (179). Its withdrawal of the application, or if the FDA considers the application to have been withdrawn as a result of an administrative determination that the application did not meet the requirements for approval (180). It amends or withdraws its Paragraph IV Certification (181). It fails to obtain tentative approval of its application within 30 months after filing (182). It enters into an agreement with another ANDA applicant, the NDA holder, or the patent owner, which has been held in a final decision in an action brought by the Federal Trade Commission or Attorney General to violate the antitrust laws (183). All of the patents as to which the ANDA filer had filed a Paragraph IV Certification have expired (184).
As provided in, event 1, forfeiture of the 180-day exclusivity period cannot be promised on the failure of the first applicant to market the drug within the 75-day period after its effective approval date or after 30 months of its application date unless there has previously been, inter alia, so a final decision that the patent is invalid or not infringed. As noted above, in the event of any such forfeiture, no subsequent ANDA filer will be eligible for the 180-day exclusivity (177). 9.2. Delays in ANDA or 505(b)(2) Approvals Based on Other Marketing Exclusivities Hatch-Waxman contains several other exclusivity provisions that delay approval of ANDAs and 505(b)(2) applications. Of principal interest is the 5-year marketing exclusivity for new chemical entities (NCEs) (14), the 3-year marketing exclusivity
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for new or supplemental NDAs supported by new clinical investigations (15), and the 6-month exclusivity for pediatric studies. With the exception of the pediatric exclusivity provisions, each of these marketing exclusivities was added to HatchWaxman in 1984 in last-minute negotiations with a group of brand-name drug companies that objected to the terms originally negotiated prior to enactment of the legislation. These provisions were thus added to provide additional protection for the brand-name companies in the form of additional delays in the approval of generic drugs. 9.2.1. Five-Year Exclusivity for New Chemical Entities The 5-year NCE exclusivity applies to drugs that do not contain any active ingredient, including any ester or salt thereof, which has been approved in any prior NDA after the 1984 enactment of Hatch-Waxman. The NCE exclusivity differs from the other marketing exclusivities in that it prohibits the submission of an ANDA or 505(b)(2) applicationnot merely its approvalprior to expiration of the exclusivity period (14). In view of the period required to obtain approval of the ANDA or 505(b)(2) application, this provision effectively extends NCE exclusivity beyond 5 years. Moreover, an ANDA or 505(b)(2) application incorporating a Paragraph IV Certification may be submitted 4 years after approval of an NDA entitled to NCE exclusivity. However, if an infringement action is commenced within the fifth year of the NCE exclusivity, the statute provides that the 30-month stay pending the patent infringement proceeding will be extended, if necessary, so that the period after approval of the application entitled to NCE exclusivity totals 71 years, equal to the 2 sum of the 5-year marketing exclusivity plus the 30-month stay (14). Thus, an ANDA or 505(b)(2) application incorporating a Paragraph IV Certification may be filed within the fifth year of an NCE marketing exclusivity, but may not be approved until 71 years after the grant of the application entitled to NCE 2
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exclusivity if the brand-name patent holder initiates an infringement suit as discussed above. 9.2.2. Three-Year Exclusivities for NDAs or Supplemental NDAs Based on New Clinical Investigations The 3-year exclusivity provisions prohibit approvalnot submissionof an ANDA or a 505(b)(2) application for 3 years after approval of an NDA or supplemental NDA approved on the basis of reports of new clinical investigations (other than bioavailability studies) essential to the approval . . . and conducted or sponsored by the person submitting the NDA or supplemental NDA (15). 9.2.3. Pediatric Exclusivity In 1997, and again in 2002, the FDCA was amended to provide a new form of exclusivity, a 6-month period for conducting pediatric studies of listed drugs (185). The pediatric exclusivity delays the approval of ANDAs and 505(b)(2) applications for an additional 6 months after expiration of any pertinent listed patents and extends the 5-year and 3-year marketing exclusivities for 6 months (186). The pediatric exclusivity was originally effective as to NDAs filed before January 1, 2002, and as of this writing has been extended to NDAs submitted prior to October 1, 2007 (187). Pediatric exclusivity applies both to previously approved drugs and drugs that are the subject of pending NDAs. The procedures for obtaining pediatric exclusivity are described elsewhere in this text. If a 6 month pediatric exclusivity has been accorded a particular drug, an additional 6 month exclusivity may be added to the 3-year exclusivity for a supplemental NDA (188). A second 6-month pediatric exclusivity may not, however, further delay ANDA approvals subject to patent certifications (189). The 2002 amendment to the pediatric exclusivity provisions further specifies that the omission of any approved pediatric indication from the labeling for an ANDA will not further delay approval of the generic drug (190).
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10. WITHDRAWAL OF APPROVAL OF AN ANDA As indicated in Section 3.5, the FDA may withdraw or suspend approval of an ANDA when the approval of the listed drug on which the ANDA relies is either withdrawn or suspended. Further, approval of an ANDA or a 505(b)(2) application may be withdrawn on the basis of evidence showing that the drug is unsafe for use or ineffective or that the ANDA or 505(b)(2) application contains any untrue statement of material fact (68). A further provision sanctioning the withdrawal of approval of ANDAs was added by the Generic Drug Enforcement Act of 1992. That amendment specifically provides that the FDA must withdraw approval of an ANDA if it finds that the approval was obtained, expedited, or otherwise facilitated through bribery, payment of an illegal gratuity, or fraud or material false statement (191) or may withdraw approval of an ANDA if it finds that the applicant has repeatedly demonstrated a lack of ability to produce the drug . . . and has introduced, or attempted to introduce, such adulterated or misbranded drug into commerce (192).
11. CITIZEN PETITIONS FDA states that the appropriate procedure for challenging any of its actions is the filing of a citizen petition, a written request that the FDA take specific action (193), in accordance with its regulations (194). Citizen petitions are commonly employed to challenge the agencys actions in connection with exclusivity claims or other matters pertinent to the approval of ANDAs or 505(b)(2) applications. FDA regulations provide the agency with 180 days to respond to a citizen petition (195). Such a response permits the agency to provide an explanation of its position in advance of litigation. Where, however, a petitioner fears that agency action will not be stayed and it will be irreparably harmed, it generally seeks judicial intervention without further delay.
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A party dissatisfied with FDAs action on a citizen petition may seek judicial review in district court. FDA contends that the petitioner must first obtain a final decision on a citizen petition before it seeks judicial relief and will raise the exhaustion of administrative remedies defense in any law suit not preceded by the determination of a citizen petition (196).
12. REFORM AND FUTURE CONTROVERSY The 2003 Rule Changes and 2003 Statutory Changes have effected a number of modifications of the Hatch-Waxman regulatory scheme designed to facilitate more rapid introduction of generic drugs into the marketplace. Such changes include the elimination of the listing of metabolite patents and the restrictions on the listing of polymorph patents in the Orange Book and the limitation to a single 30-month stay of ANDA or 505(b)(2) application approvals. Further, the addition of the multiple grounds for forfeiture of the 180-day exclusivity period were designed to increase the penalties for collusive settlements and, again, hasten market entry. In addition, the changes in the litigation scheme to permit counterclaims for improper Orange Book listings and declaratory judgment proceedings seeking determinations of noninfringement or invalidity of listed patents that have not been asserted on the basis of a Paragraph IV certification are designed to decrease further bars to generic entry. On the other hand, as frequently occurs in the law, change begets further dispute. Hence, future litigation may ensue, for example, on the priority of adjudicating Paragraph IV infringement claims and delisting counterclaims and the propriety of declaratory judgment actions even when constitutionally permissible. It is clear that these and other issues will be the subject of future litigation, and that the Hatch-Waxman statutory/ regulatory scheme will be under further review and subject to additional modification in the foreseeable future because of the continuing competition between brand-name and generic
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marketers, political pressures brought about by upwardly spiraling drug prices, and the ongoing efforts to balance the influence of brand name and generic drugs on the national health care system.
REFERENCES
1. Pub. L. No. 98-417, 98 Stat. 1585, Federal Food, Drug, and Cosmetic Act (FDCA), Human Drug Approval Provisions, FDCA Section 505, 21 U.S.C. x355. Provisions similar to those discussed herein have been enacted for the approval of animal drugs in the Generic Animal Drug and Patent Term Restoration Act of 1988, Pub. L. 100-670, 102 Stat. 3971 (1988). The animal drug approval provisions are outside the scope of this discussion. Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1568 (Fed. Cir. 1997) (quoting H. R. Rep. No. 98-857 (I), at 14-15 (1984), reprinted in 1984 U.S.C.C.A.N. 2647, 264748). July 2002 U.S. Federal Trade Commission (FTC) Report, Generic Drug Entry Prior to Patent Expiration: An FTC Study (the July 2002 FTC Report), pp i and 9 (citing How Increased Competition from Generic Drugs Has Affected Prices and Returns in the Pharmaceutical Industry, Congressional Budget Office (July 1998) at 31). FDCA Section 505( j), codified at 21 U.S.C. Section 355( j). For convenience, 21 U.S.C. Section 355, et seq. are referred to herein by the appropriate FDCA sections, namely Sections 505 et seq. A generic drug is bioequivalent to a previously approved drug if the extent and rate of absorption of the respective drugs do not differ significantly from one another. FDCA Section 505( j)(8)(B). FDCA Section 505(b)(2). Pub. L. 98417, Title II (1984), and Pub. L. 100670, Title II (1988) (creating 35 U.S.C. x156, and amending 35 U.S.C. xx271 and 282). Pub. L. 103465, 108 Stat. 4809 (1994), the Uruguay Round Agreements Act (URAA).
2.
3.
4.
5.
6. 7.
8.
147
9.
35 U.S.C. x 271(e)(1). In its latest interpretation of the scope of the exemption, the Federal Circuit has held that x 271(e)(1) does not preclude patent infringement by drug development activities far beyond those necessary to acquire information for FDA approval of a patented pioneer drug already on the market. Integra Life Sciences I, Ltd. v. Merck KGaA, 331 F.3d 860, 867 (Fed. Cir. June 6, 2003). FDCA Section 505( j)(2)(A)(vii), (viii), [ANDAs]; and Section 505(b)(2)(A)(iv) [Section 505(b)(2) applications]. The Orange Book was so named because it was published by the FDA with orange covers. FDCA Section 505( j)(2)(A)(vii)(IV) [ANDAs]; 21 Code of Federal Regulations (CFR) 314.94(a)(12)(i)(A)(4), [ANDAs]; and FDCA Section 505(b)(2)(A)(iv) [Section 505(b)(2) applications]. Under the FDAs 2003 modified regulations (the 2003 Rule Changes herein) discussed below, the notice requirements were not required for all Paragraph IV Certifications in order to provide only a single 30-month stay per listed drug product (see Sec. 9.1.2). The regulatory changes were nullified in this respect in the 2003 statutory amendment to 21 U.S.C. Section 355 under the Medicare Prescription Drug Improvement and Modernization Act of 2003 (MPDIMA), Title XI Access to Affordable Pharmaceuticals (the 2003 Statutory Changes herein). The amended statute requires the notice with all Paragraph IV Certifications, whether made in generic drug applications or in amendments or supplements to such applications. For convenience, the amended statutory sections, 21 U.S.C. Section 355, et. seq., are referred to herein by the appropriate FDCA Sections, namely Sections 505, et. seq., and by their proposed MPDIMA Sections. FDCA Section 505( j)(5)(B)(iii); amended by MPDIMA Section 1101(a)(2)(A) [ANDAs]; and Section 505(c)(3)(C) amended by MPDIMA Section 1101(b)(2)(B) [Section 505(b)(2) applications]. FDCA Section 505( j)(5)(B)(iv) [ANDAs] amended by MPDIMA Section 1102(a) (1)(iv)(I); there is no comparable exclusivity period for the first filer of a Section 505(b)(2) application. FDCA Section 505( j)(5)(D)(ii) amended by MPDIMA Section 1101(a)(2)(B) [ANDAs]; and Section 505(c)(3)(D)(ii) amended
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13.
14.
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by MPDIMA Section 1101(b)(2)(C) [Section 505(b)(2) applications]. 15. FDCA Section 505( j)(5)(D)(iii) and (iv) amended by MPDIMA Section 1101(a)(2)(B) [ANDAs]; and Section 505(c)(3)(D)(iii) amended by MPDIMA Section 1101(b)(2)(C) [Section 505(b)(2) applications]. July 2002 FTC Report, pp. 6, 8. Amendments to 21 CFR Part 314, 68 Fed Reg 36676 (June 18, 2003). 68 Fed Reg 36676, 366956 (June 18, 2003); 69 Fed Reg 11309 (Mar. 10, 2004). MPDIMA, Title XIAccess to Affordable Pharmaceuticals, amendments to 21 U.S.C. Section 355. FDCA Section 505(b)(1) and (c)(2). FDCA Sections 505(b)(1) and (c)(2); and 21 CFR 314.94(a) (12)(B)(vi). FDCA Section 505( j)(2)(A)(vii) [ANDAs]; and Section 505(b) (2)(A) [505(b)(2) applications]. 21 CFR 314.94(a)(12)(B)(vi) [ANDAs]; and 21 CFR 314.52(d) [505(b)(2) applications]. Under the 2003 Statutory Changes an ANDA or 505(b)(2) applicant must give notice to the patent holder within 20 days from the date the FDA acknowledges filing of the ANDA or 505(b)(2) application, or at the time at which the applicant submits an amendment or supplement to the application. FDCA Section 505( j)(2)(B)(ii) amended by Section 1101(a)(1)(A)[ANDAs]; and FDCA Section 505(b)(3) (B) amended by MPDIMA Section 1101(b)(1)(A) [505(b)(2) applications]. 21 CFR 314.94(a)(12)(B)(vi); Abbott Labs., Inc. v. Zenith Labs., Inc., 35 USPQ2d 1161 (N.D. Ill. 1995) (dismissing claim for patent infringement where plaintiff failed to list patent within 30-day period after issuance of patent). 21 CFR 314.53(b). 21 CFR 314.53(e) and 314.3(b). See October 24, 2002, proposed FDA rulemaking, Applications for FDA Approval to Market a New Drug: Patent Listing
16. 17. 18. 19. 20. 21. 22. 23.
24.
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Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug Is Invalid or Will Not Be Infringed, 21 CFR Part 314 [Docket No. 02N-0417], RIN 0910-AC48 Section II A. 28. 59 Fed Reg 50338, 50343 (Oct. 3, 1994) (The agency believes that its scarce resources would be better utilized in reviewing applications rather than reviewing patent claims.). 21 CFR 314.53(f ); Abbreviated New Drug Application Regulations, 54 Fed Reg 28872, 28910 (July 10, 1989) (In deciding whether a claim of patent infringement could reasonably be asserted . . . the agency will defer to the information submitted by the NDA applicant.); see also AaiPharma v. Thompson, 296 F.3d 227 (4th Cir. 2000); and Watson Pharms., Inc. v. Henney, 194 F. Supp. 2d 442, 445 (D. Md. 2001). 21 CFR 314.53(b) (2003). As used in the rule, polymorphs include chemicals with different crystalline structures, different waters of hydration, solvates, and amorphous forms. 68 Fed Reg 36676, 36678 (June 18, 2003). 68 Fed. Reg. 36676, 36678 (June 18, 2003). 21 CFR 314.53(b), (c) (2003). The categories include: (i) a full description of the polymorphic form, including its physical and chemical characteristics and stability; its synthesis; the process controls used during manufacture and packaging; and such specifications and analytical methods as necessary to assure its identity, strength, quality, and purity; (ii) the executed batch record for a drug product containing the polymorph and documentation that the batch was manufactured under GMP conditions; (iii) demonstration of bioequivalence between the executed batch of the drug product containing the polymorph and the drug product described in the NDA; (iv) a list of all components used in the manufacture of the polymorphcontaining drug product and a statement of the composition of the drug product; a statement of the specifications and analytical methods for each component as are necessary to demonstrate pharmaceutical equivalence and comparable product stability; and (v) comparative in vitro dissolution testing on 12 dosage units, the executed test batch and NDA product. 68 Fed Reg 36676, 36679 (June 18, 2003).
29.
30.
31. 32.
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33.
As used in the rules, a product-by-process patent is one that claims a product by describing or listing process steps to wholly or partially define the claimed product. 68 Fed Reg 36676, 36679 (June 18, 2003). Under U.S. patent law a product by process patent claim is directed to the product, i.e., is a product claim but defines the product by reference to the steps used to make the product. 68 Fed Reg 36676, 36680 (June 18, 2003). 21 CFR 314.53(b) (2003). FDA lists current dosage forms which may be listed as including metered aerosols, capsules, metered sprays, gels, and pre-filled drug delivery systems. 68 Fed Reg 36676, 36680 (June 18, 2003). See Mylan Pharms., Inc. v. Thompson, 268 F.3d 1323 (Fed. Cir. 2001), cert. denied, 123 S. Ct. 340 (2002); and Andrx v. Biovail Corp., 276 F.3d 1368 (Fed. Cir. 2002). See Mylan, 268 F.3d at 1329 and 1333, n.3; and Andrx, 276 F.3d at 1379, n.8. Subsequently, in AaiPharma v. Thompson, 296 F.3d at 235-43, the Court of Appeals for the Fourth Circuit held that the FDAs purely ministerial approach to Orange Book listing was not arbitrary and capricious under the Administrative Procedure Act (APA), but approved of antitrust actions brought against NDA holders who use improper Orange Book listings to extend monopoly power. 296 F.3d at 243. 68 Fed Reg 36676, 36684 (June 18, 2003). 68 Fed Reg 36676 (June 18, 2003). MPDIMA Section 1101(a)(2)(C)(ii)[ANDAs]; and MPDIMA Section 1101(b)(2)(D)(ii)[505(b)(2) applications]. MPDIMA Section 1101(c)(i). FDCA Section 505( j)(2) and (4). FDCA Section 505( j)(7). FDCA Section 505( j)(7)(A)(ii). 54 Fed. Reg. 28872 (July 10, 1989). FDCA Section 505( j)(2)(A).
34. 35. 36.
37.
38.
39. 40. 41. 42. 43. 44. 45. 46. 47.
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48. 49. 50. 51.
FDCA Section 505( j)(2)(A)(i). FDCA Section 505( j)(2)(A)(v). 21 C.F.R. 314.70. 21 C.F.R. 314.94(a)(8)(iv). See Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493, 1496 (D.C. Cir. 1996). (Bristol-Myers Squibbs complaint seeking to enjoin FDA from approving an ANDA for captopril, which omitted an approved indication for treating diabetic nephropathy, was remanded to the trial court with instructions to dismiss.) FDCA Section 505( j)(2)(A)(ii)(I). FDCA Section 505( j)(2)(A)(ii)(I), (II), and (III). FDCA Section 505( j)(2)(A)(iv). FDCA Section 505( j)(8)(B). FDCA Section 505( j)(8)(A)(ii) amended by MPDIMA Section 1103(a)(1); FDCA Section 505( j)(8)(c) amended by MPDIMA Section 1103(a)(2); Schering Corp. v. Sullivan, 782 F. Supp. 645 (D.D.C. 1992), vacated for mootness, 995 F.2d 1103 (D.C. Cir. 1993); Schering Corp. v. FDA, 51 F.3d 390 (3rd Cir. 1995); and Fisons Corp. v. Shalala, 860 F. Supp. 859 (D.D.C. 1994). In Fisons, 860 F. Supp. at 866, the court approved an FDA regulation permitting the waiver of a specific type of in vivo testing for categories of drugs where in vivo bioequivalence was self-evident based on other bioequivalence data in the application. FDCA Section 505( j)(4)(H). 21 CFR 314.127(a)(8)(ii)(A)(1)-(7) (1997). FDCA Section 505( j)(2)(C). FDCA Section 505( j)(2)(A)(iii). FDCA Section 505( j)(2)(A)(ii)(III). FDCA Section 505( j)(2)(C)(i) and (ii). 21 CFR 314.93. FDCA Section 505( j)(2)(C); and 21 CFR 314.93(e). FDCA Section 505( j)(7)(C).
52. 53. 54. 55. 56.
57.
58. 59. 60. 61. 62. 63. 64. 65. 66.
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67. 68. 69. 70. 71. 72.
FDCA Section 505( j)(4)(I); and 21 CFR 314.127(a)(9) and (a)(11) (1997). FDCA Section 505(e). 21 CFR 314.151(b)(2). 21 CFR 314.151(c)(7); and 21 CFR 314.150(a)(1). 21 CFR 314.150(c)(7). FDCA Section 505(b)(2); the Right of Reference or Use simply refers to approval by the prior party, generally the NDA holder, to the generic applicant to refer to or use its prior safety or efficacy investigations. 21 CFR 314.3(b). When such a Right of Reference or Use is relied upon by a 505(b)(2) applicant, it is required to provide in its application a written statement by the owner of the data from each such investigation that the applicant may rely on such data in support of the application and that it will provide the FDA access to the underlying raw data supporting the report of the investigation. 21 CFR 314.50(g)(3). Draft Guidance For Industry Applications Covered by x505(b) (2), Center for Drug Evaluation and Research, October 1999. For example, 505(b)(2) Application No. 021-435 filed by Dr. Reddys Laboratories for approval of amlodipine maleate, relying on data submitted by Pfizer in its NDA for amlodipine besylate (NORVASC ). Citizen Petition by Pfizer Inc. and Pharmacia Corporation, No. 01P-0323 (filed July 27, 2001), and Amendment to Citizen Petition (Apr. 4, 2002); and Pfizer Inc. Citizen Petition dated October 11, 2002. FDCA Section 505(b)(2)(A) and (3). 21 CFR 314.101(d)(9). 21 CFR 314.3. FDCA Section 505( j)(4)(C)(i). See Ref. 14, supra; and 21 CFR 314.108(b)(2). 21 CFR 314.108(a).
73.
74.
75.
76. 77. 78. 79. 80. 81.
153
82. 83. 84. 85.
21 CFR 314.108(b)(2). FDCA Section 505( j)(4)(A) [ANDAs]; and Section 505(d)(1) [505(b)(2) applications]. FDCA Section 505( j)(5)(A) [ANDAs]; and Section 505(c)(1) [505(b)(2) applications]. 21 CFR 314.127 [ANDAs]; and 21 CFR 314.125 [505(b)(2) applications]. Notwithstanding the theoretical opportunity for a hearing, the FDA may deny a hearing if it concludes there are no material factual issues to be determined. FDCA Section 505( j)(5)(C) amended by MPDIMA Section 1101(a)(2)(B) [ANDAs]; and Section 505(c)(1) [505(b)(2) applications]. See Merck Co., Inc. v. Danbury Pharmacal, Inc., 694 F. Supp. 1 (D. Del. 1988), affd, 873 F.2d 1418 (Fed. Cir. 1989). 21 CFR 314.94 (a)(12)(i)(A)(4). 21 CFR 314.94(a)(12)(ii); the regulations specify that this certification be in the following form: In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the listed drug referred to in this application or that claim a use of the listed drug. A certification to substantially the same effect is required with respect to 505(b)(2) applications. 21 CFR 314.50(i)(1)(i)(B)(ii). FDCA Section 505( j)(2)(B)(i) amended by MPDIMA Section 1101(a)(1)(A) [ANDAs]; and Section 505(b)(3) amended by MPDIMA Section 1101(b)(1)(A) [505(b)(2) applications]; 21 CFR 314.95(a)(1). FDCA Section 505( j)(2)(B)(ii) amended by MPDIMA Section 1101(a)(1)(A) [ANDAs]; FDCA Section 505(b)(3)(B) amended by MPDIMA Section 1101(b)(1)(A) [505(b)(2) applications]. 21 CFR 314.95(c)(6) and 21 CFR 314.94 (a)(12) (i)(A)(4). 21 CFR 314.95(c)(2)-(5). 21 CFR 314.95(a)(3); 69 Fed Reg 11309 (Mar. 10, 2004). FDCA Section 505( j)(2)(B), amended by MPDIMA, Section 1101(a)(1)(A) [ANDAs], and FDCA Section 505(b)(3)(B) amended by MPDIMA Section 1101(b)(1)(A) [505(b)(2) applications].
86.
87.
88.
89.
90.
91. 92. 93. 94.
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95.
FDCA Section 505( j)(2)(B)(ii) amended by MPDIMA Section 1101 (a)(1)(A) [ANDAs], and FDCA Section 505(b)(3)(B), amended by MPDIMA Section 1101 (b)(1)(A)[505(b)(2) applications]. The prior law had no time limit. This raised issues as to the effective filing date of an ANDA, Paragraph IV, and who was the first to file for the purpose of awarding 180 days of market exclusivity. In a suit filed by Purepac against FDA on October 29, 2003 in the District of Columbia, Purepac alleged that it was entitled to first-to-file status because a Paragraph IV Certification in an original ANDA is deemed effectively submitted on the date it is received by FDA and that the date of notification to the patent holder is irrelevant. The Pink Sheet, Vol. 65, No. 46, p.12 (November 17, 2003). In this instance FDA awarded first-to-file status to Ivax based upon its original ANDA with a Paragraph IV Certification, submitted one day prior to Purepacs notice to the NDA holder of its amended ANDA with a Paragraph IV Certification. The Pink Sheet, Vol. 65, No. 46, p.12 (November 17, 2003). Purepac later withdrew its action against the FDA and agreed to share 180-day exclusivity with Ivax. The Pink Sheet, Vol. 65, No. 48, p.17 (December 1, 2003). 21 CFR 314.95(f ); and Section 505( j)(5)(B)(iii). FDA requires the ANDA applicant to provide it with a return receipt or other evidence of the date of receipt of the notice by the patent owner and NDA holder. 21 CFR 314.95(e). In AstraZeneca AB v. Mutual Pharm. Co., 221 F. Supp. 2d 528 (E.D. Pa. 2002), the court denied such relief, holding that the ANDA applicants notice was sufficient in that it alerted the patent owner to the applicants claim of noninfringement. However, in two other cases courts have held that insufficient notices could ultimately be relied upon in litigation in support of an award of attorneys fees for willful infringement. Yamanouchi Pharm. Co. Ltd. v. Danbury Pharmacal, Inc., 231 F.3d 1339, 1347-48 (Fed. Cir. 2000); Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., 2001 WL 1397304, at *25-26 (S.D. Ind. Oct. 29, 2001). Section 505( j)(2)(A)(viii) [ANDAs]; Section 505(b)(2)(B) [505(b)(2) applications]; and 21 CFR 314.94(a)(12)(iii). See Patent Provisions Rulemaking, 59 Fed Reg 50338, 50345 (Oct. 3, 1994) (FDA does not have the resources to review
96.
97.
98. 99.
155
patent information for its accuracy and relevance to an NDA.); Proposed ANDA Rules, 54 Fed Reg 28872, 28909 (July 10, 1989) (because the FDA has no experience in the field of patents, the agency has no basis for determining whether a use patent covers the use sought by the generic applicant). 100. See Proposed ANDA Rules, 54 Fed Reg 28872, 28909 (July 10, 1989) (The agency believes that [this] approach more fairly implements Congress intent that patent owners receive preapproval notice of potentially infringing patents.) See AaiPharm, Inc. v. Thompson, 296 F.3d 227, 241 (4th Cir. 2002) ([T]he whole point of the Acts [P]aragraph IV [C]ertification scheme is to let private parties sort out their respective intellectual property rights through patent infringement suits while the FDA focuses on its primary task of ensuring the drugs are safe and effective. This division of labor is appropriate because the FDA has no expertise in making patent law judgment.); Watson Pharm., Inc. v. Henney, 194 F. Supp. 2d 442, 445 (D. Md. 2001) ([the FDA] has no expertisemuch less any statutory franchise to determine matters of substantive patent law. In making its decision to list a patent, therefore it is entirely appropriate and reasonable for the FDA to rely on the patentees declaration as to coverage, and to let the patent infringement issues play out in other, proper arenas . . . ). Purepac Pharm. Co. v. Thompson, 238 F. Supp. 2d 191 (D.D.C. 2002). Purepac, 238 F. Supp. 2d at 205. Warner-Lambert, the patent owner, had consistently represented to FDA that the patent in question claimed the use of the drug gabapentin to treat neurodegenerative diseasesnot epilepsythe only approved indication for the drug, the prior patent for the epilepsy use having expired. Purepac sought only approval for the epilepsy indication. Based upon the specific record, the court ordered FDA to vacate its decision not to approve Purepacs ANDA because it did not include a Paragraph IV Certification respecting the indication for the treatment of neurodegenerative disease for which Purepac did not seek approval (and which had not been previously approved by the agency.) In view of the courts decision, FDA subsequently delisted the patent and required that the applicants with
101.
102.
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pending ANDAs for gabapentin products withdraw any prior certifications or Section viii Statements as to that patent. See January 28, 2003 letter from Gary Buehler, Director Office of Generic Drugs, FDA to ANDA Applicant for Gabapentin (January 28, 2003 Buehler letter) (available at http:// www.fda.gov/cder/ogd/75350.479pat.pdf ). In a subsequent decision, the court found that FDA had acted within its discretion in precluding another generic applicant (Torpharm) from maintaining a Paragraph IV Certification as to the patent in question and asserting 180day exclusivity based on that patent. Torpharm v. Thompson, 260 F. Supp. 2d 69 (D.D.C. Apr. 25, 2003). 103. 104. 68 Fed Reg 36676, 36682 (June 18, 2003). 21 CFR 314.95(d); In the Torpharm case, the court held that it was within the discretion of FDA to hold that the operative date (assuming proper notice) for the filing of an amended Paragraph IV Certification was the date of receipt of the certification (260 F. Supp. 2d at 81-82) and that the penalty for an applicants failure to provide notice at the same time as its amended certification was postponement of the effective date of the certification to the date of transmission of the notice of the amendment (260 F. Supp. 2d at 78-79). 21 C.F.R. 314.94(a)(12)(vi); 68 Fed Reg 36676, 36684 (June 18, 2003). 21 CFR 314.52(a)(3); 314.95(a)(3) (2003). 68 Fed Reg 36676, 36688 (June 18, 2003). 35 U.S.C. x271(e)(1). 35 U.S.C. x271(e)(2); Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 678 (1990). 35 U.S.C. x271(e)(2). 21 CFR 314.107(f )(2). See July 2002 FTC Report, p. 14 [The data revealed 75 drug products, out of a total of 104 NDAs (72 percent), in which the brand-name company sued the first generic applicant.]. Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir. 2003). [In another case involving the drug gabapentin (see
105. 106. 107. 108. 109. 110. 111. 112.
113.
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Ref. 101 and 102 above) the court held that Warner-Lambert could not assert infringement of the patent directed to the unapproved use for treating neurodegenerative diseases, where both the patent on the listed products and the approved indication (the treatment of epilepsy) had previously expired. Though Apotex had submitted a Paragraph IV Certification, the court noted that it was effectively a Section viii Statement of a nonapplicable use patent.] See also Allergan, Inc. v. Alcon Labs, 324 F.3d 1322 (Fed. Cir. 2003); cert. denied, 2003 U.S. Lexis 8602 (December 1, 2003). 114. See Mylan Pharms., 268 F.3d at 1331 (Fed. Cir. 2001) (A review of the amendments shows no explicit provisions allowing an accused infringer to defend against infringement by challenging the propriety of the Orange Book listing of the patent.). See In re Buspirone Anti-Trust Litig., 185 F. Supp. 2d 363 (S.D.N.Y. 2002), in which the District Court held that the brand name defendant was not entitled to NoerrPennington immunity against claims arising out of its allegedly fraudulent listing of an Orange Book patent. As of this writing, this case is on appeal. FDCA Section 505( j)(5)(C)(i)(I)(aa) amended by MPDIMA Section 1101 (a)(2)(C) [ANDA]; FDCA Section 505(c)(3)(D) (i)(I)(aa) amended by MPDIMA Section 1101(b)(2)(D) [505 (b)(2) applications]. Kos Pharmaceuticals, Inc. v. Barr Laboratories, Inc., 242 F. Supp. 2d 311 (S.D.N.Y. 2003). FDCA Section 505( j)(5)(C)(i)(I)(bb) amended by MPDIMA Section 1101(a)(2)(C) [ANDAs}; FDCA Section 505(c)(3)(D) (i)(I)(bb) amended by MPDIMA Section 1101(b)(2)(D) [505 (b)(2) applications]. FDCA Section ( j)(5)(C)(i)(I)(cc) amended by MPDIMA Section 1101(a)(2)(c) [ANDAs]; FDCA Section 355(c)(3)(D)(i)(cc) amended by MPDIMA Section 1101(b)(2)(D) [505(b)(2) applications]. 35 U.S.C. 271(e)(5), created by MPDIMA Section 1101(d). FDCA Section 505( j)(5)(C)(i)(II) amended by MPDIMA Section 1101(a)(2)(C) [ANDAs]; FDCA Section 505 (c)(3)(D)(i)(II) amended by MPDIMA Section 1101(b)(2)(D).
115.
116.
117. 118.
119.
120. 121.
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122.
MPDIMA Conference Agreement at 386. See Dr. Reddys Laboratories, Ltd. v. Pfizer Inc., 2003 WL 21638254 (D.N.J., July 8, 2003; and Teva Pharmaceuticals USA, Inc. v. Pfizer Inc., 2003 U.S. Dist.LEXIS 21940 (D. Mass., December 8, 2003). 35 U.S.C. x 156(a)(1). 35 U.S.C. x 156(a)(2). 35 U.S.C. x 156(a)(3). 35 U.S.C. x 156(a)(4). 35 U.S.C. x 156(a)(5). 35 U.S.C. x 156(b)(1)(A)(i). 35 U.S.C. x 156(b)(1)(B). 35 U.S.C. x 156(g)(6)(A). 37 CFR 1.775. 35 U.S.C. x 156(c). 35 U.S.C. x 156(c)(3). 35 U.S.C. x 156(b)(1). Pfizer Inc. v. Dr. Reddys Laboratories, Inc., Civil Action No. 02-CV-2829, 2002 WL 31833744 (D.N.J. filed June 12, 2002). (The trial court granted Dr. Reddys motion to dismiss the complaint where Pfizer had obtained approval of an NDA for amlodipine besylate and Dr. Reddy sought approval of a 505(b)(2) application for amlodipine maleate.) Pfizer Inc. v. Dr. Reddys Laboratories, Inc., 359 F.3d 1361 (Fed. Cir. 2004). 35 U.S.C. x 154(a)(2). Under a transitional provision, patents in force on June 8, 1995 (without prior term adjustment) are entitled to a term of 20 years from their effective filing dates or 17 years from their issue dates, whichever is greater. FDCA Section 505( j)(5)(B)(i) [ANDAs]; and Section 505(c)(3) (A) [505(b)(2) applications]. FDCA Section 505( j)(5)(B)(ii) [ANDAs]; and Section 505(c)(3) (B) [505(b)(2) applications].
123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135.
136. 137.
138. 139.
159
140.
By way of example, a 30-month stay had been reduced for lack of reasonable cooperation by the brand name company in Andrx Pharms., Inc. v. Biovail Corp., 175 F. Supp. 2d 1362, 1375 (S.D. Fla. 2001), revd, 276 F.3d 1368, 1376 (Fed. Cir. 2002), and extended because of failure of a generic company to reasonably cooperate in Eli Lilly Co. v. ZenithGoldline Pharms., Inc., 2001 WL 238090 (S.D. Ind. Mar. 8, 2001). An extension of the 30-month stay was denied in Zeneca Ltd. v. Pharmachemie B.V., 16 F. Supp. 2d 112 (D. Mass. 1998). GlaxoSmithKline obtained five overlapping 30-month stays, commencing in 1998 and extending to September 2003, by the multiple listing of several patents related to the drug paroxetine, followed by sequential infringement suits against Apotex, one of several generic ANDA applicants. July FTC Report, pp. 5152 and 3334. See also FDA Proposed Rule on Patent Listing Requirements and 30-Month Stays on ANDAs, 67 Fed Reg 65448, 65454-56 (Oct. 24, 2002). July 2002 FTC Report, p. 44. It has been reported that drug costs increased almost 16% in 2001, more than either the cost of hospitals or doctors services. Wall Street Journal, January 30, 2003, p.1, Presidents Plans for Medicare Hit Republican Flack. July 2002 FTC Report, p. ii. Senate Bill entitled Greater Access to Affordable Pharmaceuticals Act of 2001 (GAAP), S. 812, H.R. 1862. White House October 21, 2002 Press Release, entitled President Takes Action to Lower Prescription Drug Prices by Improving Access to Generic Drugs. 67 Fed Reg 65448, et seq. (Oct. 24, 2002). 68 Fed Reg 36676, 36688-90 (June 18, 2003). The statute and FDA regulations required that ANDAs may be separately filed for individual dosage forms of the same listed drug. 21 CFR 314.92(a)(1). Apotex, Inc. v. Shalala, 53 F. Supp. 2d 454 (D.D.C. 1999), affd, 1999 WL 956686 (D.C. Cir. Oct. 8, 1999). Subsequently,
141.
142. 143.
144. 145. 146.
147. 148. 149.
150.
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separate 180-day marketing exclusivities were accorded to Barr Laboratories as the first to make a Paragraph IV Certification as to the 10 mg and 20 mg dosage forms of fluoxetine hydrochloride (Eli Lillys Prozac ), and Dr. Reddys Laboratories as the first to make such a certification as to the 40 mg dosage form of the same drug, following the court decision holding the last-to-expire of Lillys listed patents invalid. 151. 152. August 2, 1999 Response to Citizens Petitions re: cisplatin, Docket No. 99P-1271/PSA 1 and PSA 2. November 16, 2001, letter from Gary Buehler, Director Office of Generic Drugs, FDA, to Andrx Pharmaceuticals and GenPharm, Inc. Re: Omeprazole Delayed-Release Capsules (available at www.fda.gov/cder/ogd/shared_exclusivity.htm). Neither Andrx nor GenPharm was subsequently accorded exclusivity, the District Court having held that the listed patents in question are valid and infringed by their respective dosage forms. In re Omeprazole Patent Litig., 222 F. Supp. 2d 423 (S.D.N.Y. 2002). January 28, 2003, Buehler letter regarding gabapentin. FDCA Section 505( j)(5)(B)(iv)(II)(bb) amended by MPDIMA Section 1101(a)(1). FDCA Section 505( j)(5)(B)(iv)(I) (prior to the 2003 Statutory Changes) Generally, ANDA applicants are reluctant to so proceed because of the magnitude of potential damages in the event of an adverse determination in infringement litigation. Mylan Pharms., Inc. v. Thompson, 2001 WL 1654781 (N.D. W.Va. 2001). FDCA Section 505( j)(5)(B)(iv)(I) amended by MPDIMA Section 1102(a)(1). FDCA Section 505( j)(5)(B)(iv)(II) (prior to the 2003 Statutory Changes). 64 Fed Reg 42873 (Aug. 6, 1999). 65 Fed Reg 43233 (July 13, 2002); Guidance for Industry, Court Decisions, ANDA Approvals, and 180-Day Exclusivity
153. 154. 155. 156.
157. 158. 159. 160. 161.
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Under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act (March 2000), published at 65 Fed Reg 16922 (Mar. 30, 2000), citing TorPharm, Inc. v. Shalala, 1997 U.S. Dist. LEXIS 21983 (D.D.C. Sept. 15, 1997), appeal withdrawn and remanded, 1998 U.S. App. LEXIS 4681 (D.C. Cir. Feb. 5, 1998), vacated No. 971925 (D.D.C. Apr. 9, 1998); Mova Pharm. Corp. v. Shalala, 140 F.3d 1060 (D.C. Cir. 1998); Granutec, Inc. v. Shalala, 46 U.S.P.Q. 2d 1398 (4th Cir. 1998); and Mylan Pharms., Inc. v. Shalala, 81 F. Supp. 2d 30 (D.D.C. 2000). 162. Mylan Pharms., Inc. v. Henney, 94 F. Supp. 2d 36, 58 (D.D.C. 2000), vacated as moot sub nom; and Pharmachemie B.V. v. Barr Labs., Inc., 276 F.3d 627, 632 (D.C. Cir. 2002). Teva Pharms., USA, Inc. v. FDA, 182 F.3d 1003 (D.C. Cir. 1999). 67 Fed Reg 66593 (Nov. 1, 2002), 180-Day Generic Drug Exclusivity For Abbreviated New Drug Applications, withdrawing proposed rule published in 64 Fed Reg 42873 (Aug. 6, 1999). 67 Fed Reg 66594 (Nov. 1, 2002). FDCA Section 505( j)(5)(B)(iii)(I) amended by MPDIMA Section 1102(a)(1). 21 CFR 314.94(a)(12)(viii)(A). 64 Fed Reg 42873 (Aug. 6, 1999). Mylan Pharms., Inc. v. Henney, 94 F. Supp. 2d 36, 41, 57-58 (D.D.C. 2000), vacated as moot sub nom. 21 CFR 314.107(c)(1) (1997), revoked in 63 Fed Reg 59712 (Nov. 5, 1998). FDA, Guidance for Industry: 180 Day Generic Drug Exclusivity Under the Hatch-Waxman Amendments to Federal Food, Drug and Cosmetic Act, 63 Fed Reg 37890 (July 14, 1998), citing Mova Pharm. Corp. v. Shalala, 955 F. Supp. 128 (D.D.C. 1997), affd, 140 F.3d 1060 (D.C. Cir. 1998); and Genentech, Inc. v. Shalala, 1998 WL 153410 (4th Cir. 1998); see also Andrx Pharms., Inc. v. Friedman, No. 980099 (D.D.C. Mar. 30, 1998).
163. 164.
165. 166. 167. 168. 169. 170. 171.
162
Gross et al.
172. 173. 174. 175.
63 Fed Reg 59710 (Nov. 5, 1998). Purepac Pharm. Co. v. Friedman, 162 F.3d 1201 (D.C. Cir. 1998). FDCA Section 505( j)(5)(D)(i)(III) amended by MPDIMA Section 1101(a)(2). In Boehringer Ingleheim Corp. v Shalala, 993 F. Supp. 1 (D.D.C. 1997), the court denied a temporary restraining order seeking to preclude approval of a waiver by GenPharm Inc. of an exclusive period to market ranitidine hydrochloride in favor of Granutec, Inc., a later filer. The court concluded that FDAs interpretation of the statute, approving the waiver agreement between GenPharm and Granutec, was not arbitrary and capricious, and an abuse of discretion or otherwise in violation of the APA. November 16, 2001, letter from Gary Buehler, Director Office of Generic Drugs, FDA, to Andrx Pharmaceuticals and GenPharm, Inc. re. Omeprazole Delayed-Release Capsules (available at www.fda.gov/cder/ogd/shared_exclusivity.htm). Andrx and GenPharm were thus able to waive exclusivity in favor of Kremers Urban Development Co. (Kudco) and Schwarz Pharma, Inc. which the trial court had held not to infringe the various omeprazole dosage form patents held valid by the trial court. See Astra Aktiebolag v. Andrx Pharms., Inc., 222 F. Supp. 2d 423 (S.D.N.Y. 2002). MPDIMA Section 1102(a)(2)(D). MPDIMA Section 1102(a)(2)(D)(i)(I). MPDIMA Section 1102(a)(2)(D)(i)(II). MPDIMA Section 1102(a)(2)(D)(i)(III). MPDIMA Section 1102(a)(2)(D)(i)(IV). MPDIMA Section 1102(a)(2)(D)(i)(V). MPDIMA Section 1102(a)(2)(D)(i)(VI). The Food and Drug Administration Modernization Act of 1997, Public Law 105-115 (1997), Section 111; and Best Pharmaceuticals for Children Act, Public Law 107-109 (2002), Section 505a(b)(2)(B).
176.
177.
178. 179. 180. 181. 182. 183. 184. 185.
163
186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196.
FDCA Section 505a(b)(1) [ANDAs] and FDCA Section 505a(c)(1) [505 (b)(2) applications]. FDCA Section 505a(a)(n). FDCA Section 505a(b)(1)(ii) [ANDAs] and (c)(1)(ii) [505(b)(2) applications]. FDCA Section 505a(g). FDCA Section 505a(l). FDCA Section 335c(a)(1). FDCA Section 335c(a)(2). 21 CFR 10.30. 21 CFR 10.25(a), 10.30. 21 CFR 10.30(e)(2). 21 CFR 10.45(b), (c).
6
Food and Drug Administration Modernization Act
ARTHUR Y. TSIEN and PATRICIA E. PAHL Olsson, Frank & Weeda, P.C. Washington, D.C., U.S.A.
1. INTRODUCTION The Food and Drug Administration Modernization Act (FDAMA), Public Law No. 105115, was enacted on November 21, 1997. This Act made numerous changes to the Federal Food, Drug and Cosmetic Act and the regulation of food, drugs, devices, and biological products. This chapter summarizes FDAMAs effects upon the regulation of drugs and biologicals. FDAMA was major and complex legislation. The U.S. Food and Drug Administration (FDA) has had to promulgate numerous guidances, policies, and regulations to implement
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FDAMAs provisions. Some parts of FDAMA have been tested in litigation; courts have held some FDAMA provisions to be in violation of the law. Important provisions of FDAMA include the following: Modernizing the regulation of biological products Eliminating the batch certification and monograph requirements for insulin and antibiotics Streamlining the approval processes for drug and biological manufacturing changes Reducing the need for environmental assessment as part of a product application Codifying FDA regulations and practice to increase patient access to experimental drugs and to accelerate review of important new medications Creating a database on clinical trials patients can access Requiring advance notice when a manufacturer plans to discontinue certain drugs Permitting manufacturers to disseminate information about unapproved uses of drugs under certain limited circumstances Allowing a firm to disseminate peer-reviewed journal articles about an off-label indication of its product under certain circumstances Allowing drug companies to provide economic information about their products to formulary committees, managed care organizations, and similar large-scale buyers of health-care products Creating exemptions for compounded drug products Otherwise reducing or simplifying many regulatory obligations of manufacturers This chapter is subdivided into six topical areas: Pediatric Studies Clinical Investigations Drug Applications and Approvals Drug Manufacturing and Compounding Information Dissemination and Labeling FDA Management and Policies
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Each topical area is further divided into sections that correspond to applicable sections of FDAMA, such as Data Requirements for Drugs and Biologics, Pilot and Small-Scale Manufacture, and Dissemination of Information on New Uses. Each section discusses the FDAMA requirements, and any implementing guidances, regulations, and policies, as well as any litigation that has altered the applicability and enforcement of that section of FDAMA.
2. PEDIATRIC STUDIES AND EXCLUSIVITY 2.1. Pediatric Studies of Drugs Section 111 of the Food and Drug Administration Modernization Act (FDAMA), pediatric studies of drugs, provides the Food and Drug Administration (FDA) with authority to request pediatric studies for a drug and to grant 6 months of extra market exclusivity to the sponsor or manufacturer (1). FDA has the authority to make this request if, prior to approval of an application that is submitted under 21 U.S.C. 355(b)(1), FDA determines that data regarding the use of the new drug in pediatric populations may produce health benefits in that population. This provision also allows FDA to request pediatric studies for drugs that are already marketed. The provision was scheduled to expire on January 1, 2002. In a revised guidance document issued in September 1999, FDA provided industry with guidance in interpreting the new provision until superseded by regulations or new guidance (2). The guidance focuses on how studies may qualify for pediatric exclusivity under the new section. A pediatric study is defined as at least one clinical investigation (that, at FDAs discretion, may include pharmacokinetic studies) in the pediatric age groups in which a drug is anticipated to be used. Generally, an application filed under section 505(b)(1) of the Food, Drug and Cosmetic Act (FDC Act) (21 U.S.C. 355(b)(1)) will qualify for pediatric exclusivity if all of the
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following have occurred (3): 1. FDA issued a Written Request for pediatric studies: a. before the approval of the new drug application (NDA), or b. for an active moiety approved for adults and/or part of the pediatric population for an approved indication that occurs in the pediatric population and appears on the List of Approved Drugs for Which Additional Pediatric Information May Produce Health Benefits in the Pediatric Population (the List) 2. 3. 4. The sponsor submitted reports of the requested studies after FDA made the Written Request The sponsor submitted studies that responded completely to the Written Request The sponsor submitted reports of the studies in accordance with a written agreement or, if there was no written agreement, in accordance with commonly accepted scientific principles The sponsor submitted reports of the studies in accordance with FDAs requirements for filing FDA accepted the reports of the studies
5. 6.
While a sponsor cannot submit studies for pediatric exclusivity prior to receiving a Written Request from FDA, a sponsor may obtain a Written Request by submitting proposed pediatric study requests addressing the pediatric studies necessary to use the active moiety appropriately in pediatric subpopulations. The guidance also details how over-the-counter (OTC) drugs approved under section 505(b) may qualify for pediatric exclusivity (4). Products that contain an antibiotic, where the antibiotic was the subject of any application for marketing received before November 21, 1997 (an old antibiotic), are not eligible to receive pediatric exclusivity unless (a) the antibiotic has or obtains orphan drug exclusivity under section 527
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of the Act and (b) the requirements for pediatric exclusivity are met. On May 20, 1998, FDA published the list of drugs approved for use in adults for indications that occur in the pediatric population (5). The list is updated annually, as required by law. In January 2001, FDA submitted a status report to Congress on the pediatric exclusivity provision (6). Three days after the provision was scheduled to sunset, Congress passed and the President signed into law an extension of the pediatric study provision, the Best Pharmaceuticals for Children Act (7). The new law includes some additional provisions, which include applying studies to neonates, requiring adequate representation of racial and ethnic groups, establishing an Office of Pediatric Therapeutics, requiring certain label changes in exchange for the grant of exclusivity, and mandating public dissemination of pediatric information. 2.2. FDAs Pediatric Rule and Subsequent Court Challenge FDA proposed what is known as the Pediatric Rule in 1997; it became effective April 1, 1999 (8). The regulations required that manufacturers of certain new and marketed drugs and biological products conduct studies to provide adequate labeling for the use of these products in children. The regulation authorized FDA to require pediatric studies for certain drugs and new indications if the drug product under investigation would likely be used in a substantial number of pediatric patients or would provide a meaningful therapeutic benefit to pediatric patients over existing treatments (9). Under the Pediatric Rule, FDA could also require pediatric studies of marketed drugs if either of these conditions applied and inadequate labeling could pose significant risks. While the FDAMA pediatric studies provision provided sponsors with the incentives to conduct the studies that sponsors said were necessary, the Pediatric Rule, according to FDA, was necessary to address some of the gaps left by the pediatric exclusivity provision (10).
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FDAs Pediatric Rule was challenged in court. On October 17, 2002, the U.S. District Court for the District of Columbia ruled that FDA did not have the authority to issue the Pediatric Rule and barred FDA from enforcing it. Although the government decided not to pursue an appeal in the courts, FDA has stated its intention to work with Congress in an effort to enact legislation requiring pharmaceutical manufacturers to conduct appropriate pediatric clinical trials (11).
3. CLINICAL INVESTIGATIONS 3.1. Information Programs on Clinical Trials for Serious or Life-Threatening Diseases Section 113 of FDAMA, Information Programs on Clinical Trials for Serious or Life-Threatening Diseases (12), directs the Secretary of Health and Human Services (DHHS) to establish, maintain, and operate a data bank of information on clinical trials for drugs to treat serious or life-threatening diseases and conditions. It thus creates a public resource for information on studies being conducted under FDAs investigational new drug (IND) regulations (21 C.F.R. Part 312). Section 113 of FDAMA requires that information provided through the Clinical Trials Data Bank be in a form that can be readily understood by the public (13). In response, the National Institutes of Health (NIH), through its National Library of Medicine (NLM) and with input from FDA and others, developed the Clinical Trials Data Bank. The Clinical Trials Data Bank contains (a) information about federally and privately funded clinical trials for experimental drug and biological products for treating patients with serious or life-threatening diseases or conditions, (b) a description of the purpose of each experimental drug, (c) patient eligibility criteria, (d) a description of the location of clinical trial sites, and (e) a point of contact for patients wanting to enroll in the trial (14). FDA has issued a guidance document for clinical investigators and sponsors that (a) provides recommendations for
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industry on the submission of protocol information to the Clinical Trials Data Bank (including information about the types of clinical trials for which submissions are required under section 113 of the Modernization Act, as well as the content of those submissions) and (b) addresses procedural issues, including how to submit required and voluntary protocol information to the Clinical Trials Data Bank (15). The guidance also addresses issues related to submitting certification to HHS that disclosure of information for a particular protocol would substantially interfere with the timely enrollment of subjects in the clinical investigation. 3.2. Clinical Investigations The 1962 Drug Amendments to the FDC Act (16), passed unanimously by Congress, for the first time in history required that pharmaceutical companies establish by substantial evidence the effectiveness of a drug prior to marketing it. The term substantial evidence was defined as evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed (17). Because the FDC Act uses the plural investigations, FDA had, since the Amendments were enacted, required drug manufacturers to submit at least two adequate and well-controlled studies showing the effectiveness of the drug (18). Section 115 of FDAMA amended the definition of substantial evidence in section 505(d) of the FDC Act to clarify that FDA, at its discretion, may make exception to the general requirement that there be more than one adequate and wellcontrolled investigation to support an effectiveness determination (19). As a practical matter, however, FDAs general view is that, in most cases, two studies will still be required to establish safety and efficacy adequately (20).
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Section 115 also amended section 505(b)(1) of the FDC Act to direct FDA to review and develop guidance, as appropriate, on the inclusion of women and minorities in clinical trials . . . (21). To meet this requirement, the Center for Drug Evaluation and Research (CDER) established an ad hoc working group, FDAMA Women and Minorities Working Group, with representation from the agency and the National Institutes of Health. In 1998, the Working Group issued a report, after consulting with industry. There was a consensus that no additional guidance is needed at this time, and the Group offered to confer with the agency if this situation should change in the future (22). 3.3. Streamlining Clinical Research on Drugs Section 117 of FDAMA, Streamlining Clinical Research, amended section 505(i) of the FDC Act by codifying some of FDAs procedures for handling applications for INDs, including the clinical hold procedure. As amended by FDAMA, section 505(i)(2) now provides that an initial IND application must include information on study design, adequate reports of basic information, certified by the applicant to be accurate, necessary to assess safety, adequate chemistry, manufacturing and controls information, and primary data tabulations from animal or human studies (23). A clinical investigation may begin 30 days after FDA receives an IND submission meeting these requirements. This provision, in fact, built on an FDA guidance that had already significantly reduced the size of IND submissions. Section 117 of FDAMA also establishes procedural and substantive requirements for clinical holds (24). FDA may at any time prohibit a clinical investigation from starting or continuing by issuing a clinical hold, but FDA must specify the basis for a clinical hold and confirm its determination in writing. This document must include the specific information available to the Secretary which served as the basis for such clinical hold (25). In December 1998, FDA published a final rule implementing this provision (26). The rule amended the IND clinical hold requirements, set forth in 21 C.F.R. 312.42,
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to state that the agency will respond in writing to a sponsors request that a clinical hold be removed from an investigation within 30 calendar days of the agencys receipt of the request and the sponsors complete response to the issue(s) that led to the clinical hold. FDAMA also amended the statute to specify the standard for issuing a clinical hold, which is that the drug represents an unreasonable risk to the safety of the subjects of the investigation or other reasons established by FDA through regulation (27). The IND regulations issued by FDA are required to provide that investigators will inform subjects that drugs are being used for investigational purposes and will obtain consent except where it is not feasible or it is contrary to the best interests of the subjects (28). 3.4. Expanded Access to Investigational Therapies and Diagnostics Section 402 of FDAMA, Expanded Access to Investigational Therapies and Diagnostics, added section 561 to the FDC Act (29). The new section was intended to authorize expanded access to drugs and devices that are still undergoing investigation. In many ways, the statutory provision simply codified existing agency practices. Section 561 applies to drugs and devices intended for use in serious diseases and conditions in emerging situations. The term serious was intended by Congress to be construed broadly, to include diseases that, while not life-threatening, could be devastating to patients and their families. FDA may authorize shipments of investigational drugs and devices under these circumstances. This provision merely codified existing FDA drug regulations (30). Section 561(b) allows physicians to request that a manufacturer provide an investigational drug or device for a particular patient if (a) the physician determines that there is no comparable or satisfactory therapy and the probable risk from the drug is not greater than the probable risk from the disease; (b) FDA determines there is sufficient evidence of safety and effectiveness to support use in the particular case; (c) FDA
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determines that providing the drug or device will not interfere with initiation, conduct, or completion of clinical trials; and (d) the sponsor or clinical investigator submits a protocol consistent with the IND or investigational device exemption (IDE) regulations for treatment use in small numbers of patients (31). Section 561(c) authorizes expanded access to investigational drugs and devices under treatment protocols. Again, this provision largely codified FDAs treatment IND regulations. The statute also authorized the agency to disseminate information about the availability of drugs and devices under these expanded access protocols. Section 561(d) authorizes FDA to terminate expanded access at any time if the requirements of this section are no longer being met. While FDAs Center for Devices and Radiological Health (CDRH) has issued a guidance document describing that Centers activities to implement section 402 of FDAMA, CDER has not. 3.5. Reports of Postmarketing Approval Studies Section 130 of FDAMA, Reports of Postmarketing Approval Studies, added section 506B to the FDC Act (32). This section provides FDA with additional authority for monitoring the progress of postmarketing studies that drug and biologics applicants have agreed to conduct. Under section 506B(a), applicants who are required by FDA, or who have entered into an agreement with FDA, to conduct a postmarketing study are now required to provide the agency with an annual report on the status of the study until it is completed or terminated. These annual reports must address the progress of the study or the reasons for the failure of the applicant to conduct the study (33). Section 506B also requires FDA to keep the public and medical community informed about the postmarketing obligations and activities of applicants. More specifically, under section 506B(c), FDA is required to develop and publish annually in the Federal Register a report on the status of postmarketing
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studies that applicants have agreed to conduct and for which status reports have been submitted (34). For these purposes, section 506B(b) indicates that any information necessary to identify the sponsor of a study and establish the status of a study and the reasons, if any, for any failure to carry out the study, shall be considered public information (35). On December 1, 1999, the agency published in the Federal Register a proposed rule to implement section 506B (36). On October 30, 2000, the agency published the final rule (37), and by Federal Register notice published on February 20, 2001 (38), FDA delayed the effective date of the rule until April 30, 2001. The final rule makes several changes to the existing regulations for approved human drugs and licensed biological products, to incorporate the statutory provisions described above (39). In addition, on April 3, 2001, FDAs Center for Biologics Evaluation and Research (CBER) issued a draft guidance to complement [ . . . ] the rule by describing in greater detail the content, format, and timing of the postmarketing study reports required by section 506B (40). The guidance also describes (a) FDAs timeframes for reviewing the status reports it receives; (b) how FDA will make information about postmarketing studies public; and (c) what that information will be (41). Section 130(b) of FDAMA directed FDA to submit a special postmarketing study report to Congress by October 1, 2001 (42). In this report, FDA is required to: (a) summarize the status reports that have been submitted under section 506B; (b) evaluate the performance of applicants in fulfilling their postmarketing study commitments; (c) evaluate the agencys timeliness in reviewing the postmarketing studies it has received; and (d) make any necessary legislative recommendations concerning postmarketing studies. On March 12, 2002, FDA issued its report to Congress (43). The report discussed the need for postmarketing studies, including accelerated approval clinical benefit studies, and deferred pediatric studies, the agencys experience with postmarketing studies, and FDAs steps to implement the provisions of Section 130 of FDAMA on postmarketing studies. FDA also noted the need for more
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resources to optimize its efforts in surveillance of applicant compliance with postmarketing commitments and to conduct timely review of information resulting from completed postmarketing studies (44).
4. DRUG APPLICATIONS AND APPROVALS 4.1. Fast Track DrugsExpedited Study and Approval Section 112 of FDAMA, Expedited Study and Approval, added section 506 to the FDC Act (45). Section 506 was added to expedite the development and approval of new drugs that address unmet medical needs relating to serious or life-threatening conditions. The section did not actually represent any radical or innovative thinking but rather essentially codified FDAs existing accelerated approval regulations (46) under which drugs for serious or life-threatening conditions could be approved based on surrogate endpoints. The statute did, however, expand that fast track system to include clinical endpoints as well. Section 506(a) provides that sponsors may request fast track designation concurrently with filing of the IND or at any time thereafter (47). FDA must act on requests within 30 days. Section 506(b) includes the various standards for approval, limitations, and conditions, taken from FDAs existing accelerated approval regulations, with the addition of clinical endpoints (48). Section 506(c) provides for submission and review of a rolling NDA for a fast track drug. To expedite the review process, FDA may begin reviewing portions of the NDA as they are ready rather than waiting for the complete application to be submitted and filed (49). On November 18, 1998, FDA announced a guidance for industry regarding Policies and Procedures for Fast Track Products (50). In the guidance, FDA explained that Section 506 authorizes it to take actions appropriate to facilitate the development and expedite the review of an application for such
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a product, and that these actions are not limited to those specified in the fast track provision but also encompass existing FDA programs to facilitate development and review of products for serious and life-threatening conditions, which include both FDAs regulations on accelerated review, and the priority review designation procedures used by both the CDER and CBER (51). In the guidance, FDA discusses the regulations, policies, and procedures related to facilitating development and expediting review of promising therapies for serious and life-threatening conditions for which there is an unmet medical need. The intent of the guidance is to clarify the criteria and processes for designation of fast track products and to present a coherent, integrated description of the diverse activities and policies that can facilitate development and expedite review of drugs that demonstrate the potential to advance the treatment of serious and life-threatening illnesses (52). The guidance elaborates upon the criteria for qualification in the fast track drug development programthe drug must be for treatment of a serious or life-threatening condition; and the drug must demonstrate the potential to address an unmet medical need for that condition. 4.1.1. Definition of Serious or Life-Threatening Condition The seriousness of a condition generally is based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one. Acquired immunodeficiency syndrome (AIDS), all other stages of human immunodeficiency virus (HIV) infection, Alzheimers dementia, heart failure, cancer, and many other diseases are serious. Many chronic illnesses that are generally well managed by available therapy can have serious outcomes, such as asthma, rheumatoid arthritis, diabetes mellitus, systemic lupus erythematosus, depression, and many other diseases. For a condition to be serious, the condition should be associated with morbidity that has substantial impact on day-to-day functioning. Shortlived and self-limiting morbidity will usually not be sufficient,
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but the morbidity need not be irreversible if it is persistent or recurrent (53). For a product to be in a fast track drug development program, it must not only be used in patients with a serious condition, it must be intended to treat a serious aspect of that condition. For example, a therapeutic product would be considered to treat a serious condition if it is being evaluated for effects on a serious symptom of the condition. A preventive product would be considered to treat a serious condition if it is being evaluated for its ability to prevent the condition. A product that is intended to treat a condition while avoiding the side effects of currently accepted treatments might be considered to treat a serious condition if the side effects avoided are serious. FDA may designate the development of such a therapy as a fast track drug development program when (a) currently accepted therapy is widely used despite an unavoidable serious risk; (b) serious outcomes are a significant public health issue; and (c) the new therapy shows significant potential to have a substantially improved overall safety profile with at least similar efficacy (54). 4.1.2. Demonstrating the Potential to Address Unmet Medical Needs Section 506(a) of the FDC Act further requires that the drug demonstrate the potential to address unmet medical needs. An unmet medical need is a medical need that is not addressed adequately by an existing therapy. If no therapy exists for a serious condition, there is an obvious unmet medical need, and a new treatment effective in that condition would meet this aspect of the criteria for fast track designation (55). Where there is available therapy for the condition, the developmental program for the new agent would address unmet medical needs if it evaluated any of the following (56): Improved effect on serious outcomes of the condition that are affected by alternate therapies. Effect on serious outcomes of the condition not known to be affected by the alternatives.
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Ability to provide benefits in patients who are unable to tolerate or are unresponsive to alternative agents. Ability to provide benefit similar to those of alternatives while avoiding serious toxicity that is present in existing therapies. Ability to provide benefit(s) similar to those of alternatives but with improvement in some factor, such as compliance or convenience, that is shown to lead to improved effects on serious outcomes. The type of information needed to demonstrate the potential of a drug to address unmet medical needs would depend on the stage of drug development. FDA will rely on summaries of available data to determine whether the potential to address unmet medical needs has been demonstrated (57). 4.1.3. Process for the Designation of a Drug as a Product in a Fast Track Drug Development Program A sponsor may submit a request for fast track designation at the time of original submission of its IND, or at any time thereafter prior to receiving marketing approval of its BLA or NDA. A request for fast track designation should be submitted as an amendment to the sponsors IND (58). In general, the submission to support a request for fast track designation should establish that the criteria necessary for designation are met, i.e., (a) that the drug is intended to treat a serious or life threatening condition, and (b) that the drug has the potential to address unmet medical needs. A submission for fast track designation should contain all discussion and supporting documentation needed to permit a reviewer to assess whether the criteria for fast track designation are met. Any data or published reports that support assertions made in the discussion section of the fast track submission and that have not
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previously been submitted to the sponsors IND should be included in the submission. FDA will respond to a request for fast track designation within 60 calendar days of receipt of the request (59). It is foreseeable that, for certain products in fast track drug development programs, it will become apparent that the development programs do not continue to meet the criteria for fast track designation. If the sponsor recognizes that the fast track drug development program will no longer be pursued, the sponsor should inform FDA. Additionally, FDA may choose to send a letter notifying the sponsor that the program is no longer classified as a fast track drug development program (60). 4.1.4. Programs for Expediting Development and Review The guidance further sets out other specific programs that are available to a sponsor in a fast track drug development program. With the exception of the submission of portions of a BLA/NDA before submission of the entire application, these other programs described in the guidance been established in regulations under authority separate from FDAMA. Therefore, products that are not in drug development programs that have been designated as fast track may also be able to take advantage of these programs. The guidance provides more information on these regulatory programs (61). If an applicant seeks approval of a product in a fast track drug development program based on evidence of an effect on a less than well-established surrogate endpoint, FDA may grant accelerated approval based on a determination that the effect on the surrogate endpoint is reasonably likely to predict clinical benefit. Drug approval under the accelerated approval regulations may also be based on demonstrated clinical effects that are reasonably likely to predict such benefit (62). Section 506(b) essentially codifies these accelerated approval regulations (63).
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4.2. Data Requirements for Drugs and Biologics Section 118 of FDAMA, data requirements for drugs and biologics, required FDA, within 12 months of the statutes enactment, to issue a guidance describing when abbreviated reports may be submitted in lieu of the full reports for clinical and non-clinical studies that are required to be included in an NDA or biologics license application (BLA). This provision responded to the regulated industrys concern that drug development and approval times had increased in the United States (beyond the time required in Europe and Japan) in part because of the increasing demands of NDA reviewers for individual case report forms and other detailed supporting data, whereas reviewers in other countries rely to a much greater extent on summary or abbreviated study reports. In August 1999, FDA issued the mandated guidance, which was intended to advise sponsors of the circumstances when full study reports, abbreviated reports, and synopses can be used to submit data concerning the effectiveness of new drugs and biological products (64). Generally, as set out in the Guidance, full study reports should be submitted for all clinical and human pharmacology investigations that contribute to the evaluation of effectiveness for the proposed indication or that otherwise support information included in labeling. Abbreviated reports should be submitted for studies that are not intended to contribute to the evaluation of product effectiveness or provide definitive information on clinical pharmacology, but about which the reviewer needs sufficient information to determine that the study results do not cast doubt on the drugs effectiveness claims or the description of the clinical pharmacology. Synopses should be submitted for studies that are not relevant to the evaluation of product effectiveness or clinical pharmacology, but that provide information the reviewer needs to evaluate the safety data from the study (65). For clinical efficacy and safety studies, FDA describes the following scheme for the submission of reports or
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synopses: 1. Studies for which full reports should be submitted: Full study reports should ordinarily be submitted for all studies from clinical investigations of drugs or biological products that are the subject of very limited clinical development programs (i.e., programs with a total of fewer than six clinical trials from any phase of drug development). Full study reports should also be submitted for clinical effectiveness studies that (a) evaluate a dose, regimen, patient population, and indication for which marketing approval is sought, and (b) are capable by design, conduct, and enrollment of assessing the effectiveness of the product. Examples include: Studies providing the basis for dose recommendations (e.g., dose-comparison studies). Controlled studies identified by the applicant as contributing directly to substantial evidence of effectiveness. Controlled studies that support an intended comparative claim. Controlled studies of different indications (e.g., stages of disease, different study populations) or dosage forms or regimens if they are intended to provide support for approval (66).

2. Studies for which abbreviated reports should be submitted: Abbreviated reports should be submitted for studies that do not meet the above criteria, and that meet the following conditions: (a) the studies are not intended to contribute to the evaluation of product effectiveness, and (b) the reviewer needs sufficient information about the studies to determine that their results do not, in fact, cast doubt on the effectiveness claims for the product. Abbreviated reports should contain full safety reports.
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Examples of studies that should be submitted as abbreviated reports include: Studies with active controls that do not provide the primary or substantiating evidence of effectiveness. Studies of related indications for which marketing approval is not being sought. Studies not designed as efficacy studies or designed as efficacy studies for different indications that contribute significant information about product safety. Studies of doses or dosage forms not intended for marketing (unless they are intended to provide significant substantiating evidence of effectiveness) (67). 3. Studies for which synopses should be submitted: Some studies are generally only examined in sufficient depth to assess if they cast doubt on the safety of the product for the proposed indication. For these studies, complete safety information should be included in the Integrated Summary of Safety part of the NDA. Examples of studies that should be submitted as synopses include: Studies of unrelated indications for which marketing approval is not being sought. Studies evaluating routes of administration for which marketing approval is not being sought. Incomplete studiesthose that enroll fewer than one third of intended patients, unless stopped for safety reasons or for inability to show efficacy. Early general phase 1 safety-tolerance studies (68). For pharmacokinetic, bioavailability, and clinical pharmacology studies, FDA describes the following scheme for the submission of reports or synopses: 1. Studies for which full reports should be submitted: Clinical pharmacology and biopharmaceutics studies that support labeling statements.
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The most relevant (e.g., best designed) in a series of similar studies. When studies in a series are not in agreement, all studies of that type should be submitted as full reports. Dose ranging studies for phase 2 and 3 studies. Bioavailability and bioequivalence studies that compare performance of the formulation or dosage form used in clinical trials to that intended for marketing. One representative assay validation study for each analytical method at each analytical site (69).
2. Studies for which abbreviated reports should be submitted: Less relevant studies in a series of similar studies (see above). Bioavailability/bioequivalence studies not assessing performance of material used in clinical trials relative to dosage forms intended for marketing (70). Studies have been shown to have defects, such as in design, that render them incapable of supporting a useful and/or relevant conclusion. Bioavailability/bioequivalence studies not assessing performance of material used in clinical trials relative to dosage forms intended for marketing. Discontinued studies. Studies from abandoned indications (71).
3. Studies for which synopses should be submitted:

The guidance describes in great detail the precise content of abbreviated clinical reports and synopses. Generally, FDA instructs the applicant to look to the requirements for the submission of data set out in the International Conference on Harmonisation (ICH) Guidance (72). For clinical efficacy studies, an abbreviated report should contain a full report of information related to safety and enough information to allow the reviewers to fully assess whether the efficacy results, if any, cast doubt on the effectiveness of the product for the proposed indication. The abbreviated study
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report should contain only selected sections from the ICH guidance. The Abbreviated Studies Guidance explains which sections from the ICH guidance the applicant may omit (73). An abbreviated report should include all safety information included in a full report, whereas efficacy information should be concise and not as comprehensive as in a full report. An abbreviated clinical pharmacology and biopharmaceutics study report should include generally the same elements as an efficacy study report, and also include: Summary tables of mean values, standard deviations or coefficients of variation, confidence intervals and observed ranges, along with sample size. For assay validation studies, assay performance should be summarized in enough detail for the reviewer to assess the adequacy of the assay performance. Formulation information including batch or lot numbers and qualitative and quantitative composition (74). A synopsis should contain sufficient information to allow the reviewer to assess whether the results cast doubt on the safety of the product for the proposed indication. The synopsis should summarize the study, including sufficient data to illustrate results. An example of the structure and content of a synopsis is described in the ICH guidance. A synopsis should contain, among other things, the study protocol and protocol amendments and a complete discussion of the safety data from these studies (75). 4.3. Content and Review of Applications Section 119 of FDAMA, Content and Review of Applications, amended section 505(b) of the FDC Act to improve the process for FDA review of NDAs and BLAs (76). Parallel amendments were made in section 505( j) for abbreviated NDAs (77). Section 505(b)(4)(A) now provides that FDA must issue guidance for reviewers relating to promptness in conducting the review, technical excellence, lack of bias and conflict of interest, and knowledge of regulatory and scientific standards (78). These standards must apply equally to all individuals who review
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applications. As of April 27, 1999, FDA determined that its existing guidance documents were sufficient to satisfy this statutory requirement (79). Section 505(b)(4)(B) requires FDA to meet with a sponsor upon receiving reasonable written request for the purpose of reaching agreement on the design of pivotal trials. Agency minutes must be prepared and made available to the sponsor (80). Sections 505(b)(4)(C) and (D) state that any agreement on study design at such a meeting must be put in writing (81). After testing begins, the agreement cannot be changed unilaterally by FDA unless the director of the reviewing division issues a written decision that a substantial scientific issue essential to determining the safety or effectiveness of the drug has been identified after the testing has begun (82). Upon request, the director must meet with the sponsor to document the scientific issue on which this decision is based. In February 2000, FDA issued a guidance for industry entitled Formal Meetings with Sponsors and Applicants for PDUFA Products (83). The guidance sets out the procedures of CDER and CBER for formal meetings between FDA and sponsors regarding the development and review of products in human drug applications as defined in section 735(1) of the FDC Act, i.e., products covered by the Prescription Drug User Fee Act (PDUFA) (84). This guidance document describes procedures for requesting, scheduling, conducting, and documenting such formal meetings for PDUFA drug products. There are three categories of meetings between sponsors or applicants for PDUFA products and CDER or CBER staff: Type A, Type B, and Type C. Each type of meeting is subject to different procedures: Type A Meetingone that is immediately necessary for an otherwise stalled drug development program to proceed (i.e., a critical path meeting). Type A meetings generally are reserved for dispute resolution, clinical holds, and special protocol assessments (discussed further below). Type A meetings should be scheduled to occur within 30 days of FDAs receipt of a written request from the sponsor for a meeting.
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Type B Meetingincludes (a) pre-IND meetings; (b) certain end of phase 1 meetings; (c) end of phase 2/ pre-phase 3 meetings; and (d) pre-NDA/BLA meetings. FDA will honor sponsor requests for Type B meetings except under very unusual circumstances. Type B meetings should be scheduled to occur within 60 days of the Agencys receipt of the sponsors written request. FDA expects to grant only one of each of the Type B meetings for each potential application. Type C Meetingany meeting other than a Type A or Type B meeting between FDA and a sponsor or applicant regarding the development and review of a PDUFA drug products application. Type C meetings should be scheduled to occur within 75 days of the Agencys receipt of the sponsors written request (85). The sponsor should make the meeting request in writing to the appropriate division director within the applicable office within FDA. The request should be submitted as an amendment to an application, unless the request is made prior to the submission of an IND. The sponsor should contact the appropriate review division to determine to whom it should send the meeting request. Any meeting request should include adequate information, including the following: 1. 2. 3. 4. 5. 6. 7. Product name and application number (if applicable). Chemical name and structure. Proposed indication(s). The type of meeting being requested (i.e., Type A, Type B, or Type C). A brief statement of the purpose of the meeting. A list of the specific objectives/outcomes expected from the meeting. A preliminary proposed agenda, including estimated amounts of time needed for each agenda item and designated speaker(s). A draft list of specific questions, grouped by discipline.
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A list of all individuals (including titles) who will attend the proposed meeting from the sponsors organization and consultants. A list of FDA staff (or particular disciplines) the sponsor requests participate in the proposed meeting. The approximate date on which the sponsor will send supporting documentation to the review division. Suggested dates and times for the meeting (86).
The review division should respond to the sponsor within 14 days of receipt of the meeting request (87). The sponsor must submit an information package to FDA in advance of the meetingat least 2 weeks prior to a Type A meeting, 4 weeks prior to a Type B meeting, and 2 weeks prior to a Type C meeting. The information package should be paginated with a table of contents, appropriate indices, appendices, cross-references, and tabs differentiating sections. Hard copies of the information package should be provided for each FDA participant, with an extra five copies for consultation (88). The cover letter should clearly identify the date, time, and subject of the meeting. Generally, the package should include items 18 discussed above (updated as appropriate) and the following (89): A list of specific questions grouped by discipline Clinical data summary (as appropriate) Preclinical data summary (as appropriate) Chemistry, manufacturing, and controls information (as appropriate) An FDA recorder will prepare minutes of any formal meeting with a sponsor for a PDUFA product. Sponsors may provide a draft of the firms minutes in writing or may identify at the end of the meeting the critical outcomes they believe should be included in the meeting documentation. The sponsor should submit draft minutes promptly for FDA to consider them (90). Sponsors and applicants may notify FDA of significant differences in understanding regarding the content of the official
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minutes of a meeting and, eventually, seek an appeal of FDAs response (91). In addition, in May 2002, FDA issued another guidance entitled Special Protocols Assessment (92). The Special Protocols Assessment Guidance provides the CDER and CBER procedures for evaluating issues related to the adequacy (e.g., design, conduct, and analysis) of certain proposed studies conducted under section 735(1) of the FDC Act (93) and PDUFA. The PDUFA goals for special protocol assessment and agreement provide that, upon request of the product sponsor of a PDUFA drug product, FDA will evaluate within 45 days a sponsors proposed protocol to assess whether the protocol meets scientific standards and regulatory requirements. As the PDUFA goals for protocol assessment are broader and more specific than those required by FDAMA, the Special Protocols Assessment Guidance focuses on procedures to achieve the PDUFA goals. The FDAMA protocol assessment requirements will also be fulfilled by achieving the PDUFA goals. The Special Protocols Assessment Guidance sets out the procedures applicants would use for requesting special protocol assessment. Protocols supporting NDAs, BLAs, and efficacy supplements to approved NDAs and BLAs may all be eligible for review under this guidance. Three types of protocols related to PDUFA products are eligible for the special protocol assessment procedures: (a) animal carcinogenicity protocols; (b) final product stability protocols, and (c) clinical protocols for phase 3 trials, where the data will form the primary basis for an efficacy claim (94). The following procedures apply (95): CDER and CBER generally recommend that a sponsor submit a protocol intended for special protocol assessment to the Agency at least 90 days prior to the anticipated start of the study. FDA will not provide an assessment if the study has already begun. A sponsor interested in an assessment on a carcinogenicity protocol should notify FDA at an end-of-phase-2 meeting or send a letter stating an intent to request
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special protocol assessment at least 30 days prior to submitting the request. The sponsor should submit relevant background information so FDA can review reference material related to carcinogenicity protocol design prior to receiving the carcinogenicity protocol. Generally, a standard stability protocol will be based on the principles described in applicable agency stability guidance documents. For special protocol assessment of a protocol for a clinical trial that will form the primary basis of an efficacy claim in an NDA or BLA, the sponsor should have had a meeting with the review division. However, if FDA is already familiar with the proposed clinical trial and has an understanding of the questions that will be raised regarding the protocol (for instance with efficacy supplements), FDA can provide a special protocol without requiring a meeting. The sponsor should submit each protocol for assessment as a separate amendment to the sponsors IND. The cover letter should clearly identify the submission as a Request for Special Protocol Assessment. The request should be submitted to the appropriate review division in CDER or applications division in CBER (96). The Special Protocols Assessment Guidance sets out in detail those who should receive a copy of the cover letter requesting an assessment (97). In the request for special protocol assessment, the sponsor should pose focused questions concerning specific issues regarding, among other things, the protocol and protocol design and/or data analysis for the proposed investigation. The sponsor should also describe, in a separate document, information, data, and assumptions that will assist the agency in evaluating the protocol. This discussion might include the following (98): Information to assess the role of the study in the overall development of the drug. Information supporting the proposed trial, including power calculations, the choice of study endpoints, and other critical design features.
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Description of any anticipated regulatory outcomes, such as approval of a claim and proposed labeling. Information on product characterization, manufacturing, specifications, strengths, container closure, and other information, if the sponsor seeks FDA assessment of a stability protocol. If the information is contained in the IND, it can be submitted by cross-reference. As stated in the PDUFA goals, the applicable team within FDA reviewing the protocol will send comments within 45 calendar days of receipt of the sponsors request for the special protocol assessment. If a sponsor submits a revised protocol, for any reason, while FDA is still reviewing the previous submission, the new submission has the effect of restarting the 45-calendar-day review clock (99). FDA can ask an advisory committee, members of a committee, or others such as special government employees and consultants to review protocols (100). If a sponsor requests a meeting with FDA after receiving a special protocol assessment letter, FDA will handle the matter as a request for a Type A meeting under the PDUFA goals for meeting management (101). The guidance emphasizes that all agreements and disagreements between FDA, and the sponsor regarding special protocol assessments should be clearly documented in writing (102). A special protocol assessment can document FDAs agreement that the design and planned analysis of a study adequately address objectives in support of a regulatory submission. Having agreed to the design, execution, and analyses proposed in a protocol reviewed under this process, FDA is generally bound to that determination and may not later change its views, unless public health concerns become evident that were unrecognized at the time of protocol assessment under this process (103). Documented special protocol assessments are binding on the agency and should not be changed at any time, except under the following circumstances (104): Failure of a sponsor to follow a protocol that was agreed upon
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If the relevant data, assumptions, or information provided by the sponsor are found to be false or omit relevant facts. Changes in personnel, whether at the sponsor or at FDA, should not affect any documented special protocol assessment (105).
4.4. Requirements for Radiopharmaceuticals Section 122 of FDAMA, Requirements for Radiopharmaceuticals, required FDA to promulgate regulations governing the approval of radiopharmaceuticals (106). Proposed regulations were required to be issued within 180 days of enactment of FDAMA, with final regulations due within 18 months of enactment. Accordingly, on May 22, 1998, FDA proposed to amend its drug and biologics regulations by adding provisions that would clarify the evaluation and approval of in vivo radiopharmaceuticals used in the diagnosis or monitoring of diseases (107). The proposed regulations describe certain types of indications for which FDA may approve diagnostic radiopharmaceuticals and also set forth criteria that the agency would use to evaluate the safety and effectiveness of a diagnostic radiopharmaceutical under the FDC Act and the Public Health Service (PHS) Act. A final rule was issued May 17, 1999, and became effective July 16, 1999 (108). In accordance with the requirements of FDAMA, the final rule added new regulations pertaining to the review and approval of in vivo radiopharmaceuticals used for diagnosis and monitoring. The new regulations are set forth in 21 C.F.R. Parts 315 and 601 and are intended to complement and clarify existing regulations on the approval of drugs and biologics in 21 C.F.R. Parts 314 and 601. The regulations define a diagnostic radiopharmaceutical as one of (109): An article that is intended for use in the diagnosis or monitoring of a disease or a manifestation of a disease
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in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons Any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such article FDAs determination of the safety and effectiveness of a diagnostic radiopharmaceutical includes consideration of the following (110): The proposed use of the diagnostic radiopharmaceutical in the practice of medicine The pharmacological and toxicological activity of the diagnostic radiopharmaceutical The estimated absorbed radiation dose of the diagnostic radiopharmaceutical A diagnostic radiopharmaceutical may be indicated for the following uses, among others (111): Structure delineation Functional, physiological, or biochemical assessment Disease or pathology detection or assessment Diagnostic or therapeutic patient management Where a diagnostic radiopharmaceutical is not intended to provide disease-specific information, the proposed indication may refer to a biochemical, physiological, anatomical, or pathological process or to more than one disease or condition (112). FDA will assess the effectiveness of a diagnostic radiopharmaceutical by evaluating its ability to provide useful clinical information for its proposed indications for use. This evaluation may depend upon one or more of the following criteria established in a defined clinical setting (113): The claim of structure delineation is established by demonstrating the ability to locate anatomical structures and to characterize their anatomy. The claim of functional, physiological, or biochemical assessment is established by demonstrating reliable
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measurement of function(s) or physiological, biochemical, or molecular process(es). The claim of disease or pathology detection or assessment is established by demonstrating that the diagnostic radiopharmaceutical has sufficient accuracy in identifying or characterizing the disease or pathology. The claim of diagnostic or therapeutic patient management is established by demonstrating that the test is useful in diagnostic or therapeutic patient management. Factors to be considered in the safety assessment of a diagnostic radiopharmaceutical include the following (114): The radiation dose The pharmacology and toxicology of the radiopharmaceutical The risks of an incorrect diagnostic determination The adverse reaction profile of the drug Results of human experience with the radiopharmaceutical for other uses Results of any previous human experience with the carrier or ligand of the radiopharmaceutical when the same chemical entity as the carrier or ligand has been used in a previously studied product To establish the safety of a diagnostic radiopharmaceutical, FDA may require, among other information, the following types of data (115): Pharmacology data Toxicology data Clinical adverse event data Radiation safety assessment. The radiation safety assessment must establish the radiation dose by radiation dosimetry evaluations in humans and appropriate animal models. The maximum tolerated dose need not be established (116).
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4.5. Insulin and Antibiotics Section 125 of FDAMA, Insulin and Antibiotics, eliminated the approval and batch certification requirements for insulin and antibiotics in sections 506 and 507, respectively, of the FDC Act and made them subject instead to the NDA requirements of section 505 that apply generally to new drugs. On May 13, 1998, FDA issued a direct-to-final rule implementing these provisions (117). The rule repealed the agencys regulations governing certification of drugs containing insulin and made conforming amendments to other sections of its regulations. The agency used a direct final rulemaking for this action because it expected that there would be no significant adverse comment on the rule, given that most of the amendments in the rule are a direct result of the repeal of the statutory certification provision and the remainder, in the agencys view, repealed or updated out-of-date, noncontroversial regulations dealing with insulin. The rule became effective September 25, 1998 (118). Under section 125, the nonpatent market exclusivity provisions applicable to other products covered by an NDA would henceforth also apply for any antibiotic NDA submitted to FDA after November 1997. Section 125 further specified that antibiotics approved by FDA under section 507 of the FDC Act prior to the enactment of FDAMA will be deemed to be subject to approved NDAs and abbreviated NDAs (depending on whether they were approved through the full or abbreviated process under section 507) (119). The market exclusivity provisions of the FDC Act were not, however, made applicable to such applications. On January 24, 2000, FDA issued a proposed rule to implement the market exclusivity provisions of section 125 (120), but this rule has not yet been finalized. Notwithstanding the repeal of sections 506 and 507 of the FDCA and FDAs implementing regulations, section 125 left existing law in place with respect to exports, so that unapproved insulin and antibiotic products would continue to be exportable under section 801(e) of the FDC Act, without regard to the more restrictive requirements of section 802 for other unapproved new drugs (121).
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4.6. Approval of Supplemental Applications for Approved Products Section 403 of FDAMA, Approval of Supplemental Applications for Approved Products, set forth requirements relating to FDAs approval of supplemental applications (122). The provisions were added out of a congressional recognition that many drugs and biologics are used off-label because NDA or BLA holders have no incentive to submit a supplemental application for new conditions of use. Congress therefore wanted the agency to reduce the disincentives to the submissions of these applications by reducing the cost and increasing the efficiency of handling them within the agency (123). Subsection (a) required FDA to publish in the Federal Register by May 1998, standards for the prompt review of supplemental applications for approved articles. Subsection (b) required FDA to issue final guidance that would (1) clarify the circumstances in which published materials may be the basis for approval of a supplemental application; (2) specify data requirements, in order to avoid duplicating data that has been submitted previously; and (3) define supplemental applications that are eligible for priority review (124). On May 15, 1998, FDA issued a guidance implementing section 403 (125). In the guidance, FDA set out its performance goals for reviews of efficacy supplements. The guidance defines which supplements are eligible for priority review. Under CDERs policy, an application or supplement for a drug product will receive a priority review when the product, if approved, would be a significant improvement compared to marketed products, including nondrug products/therapies in the treatment, diagnosis, or prevention of a disease (126). CBERs standard operating procedures specify that a biological product original or supplemental application will receive priority review where the product, if approved, would be a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious or life-threatening disease (127). FDA will use these same criteria to determine whether an efficacy supplement is eligible for priority review (128).
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Subsection (c) required FDA to designate an individual who would be responsible for encouraging the prompt review of supplemental applications and working with applicants to facilitate submissions. Finally, subsection (d) required the Secretary of HHS to develop programs and policies that will foster collaboration between FDA, NIH, professional medical and scientific societies, and others, to identify any studies that may support supplemental applications and to encourage sponsors to make supplemental applications or conduct further research in support of a supplemental application based on such studies. 4.7. Product Classification Section 416 of FDAMA added a new section 563 to the FDC Act to provide for classification of products (129). New section 563(a) provides that a person submitting an application for approval of a product under the FDC Act may request that FDA classify the product as a drug, biologic, device, or combination product. FDA must respond within 60 days, giving the classification of the product and the reasons for the determination. If FDA fails to respond in 60 days, the submitters recommendation for a classification will be deemed to be a final decision by FDA. In either case, FDA may not modify the classification unless the submitter consents to the reclassification in writing, or there is a public health reason for the reclassification that is based on scientific evidence. FDA has yet to issue a proposed rule implementing this provision (130).
5. DRUG MANUFACTURING AND COMPOUNDING 5.1. Manufacturing Changes for Drugs Section 116 of FDAMA, Manufacturing Changes, established requirements for making and reporting manufacturing changes to an approved NDA or ANDA (131). For any major
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manufacturing change, prior to distributing the changed drug, the sponsor must (132): Validate the effects of the change on the identity, strength, quality, purity, and potency of the drug as those characteristics may relate to the safety or effectiveness of the drug Submit to FDA a supplemental application for such change and receive FDA approval for the supplement. The supplement must include the information that validates the change. A major change is one that has substantial potential to affect adversely the identity, strength, quality, purity, or potency of the drug with respect to the safety or effectiveness of a drug. Such a change fulfills one of the following (133): Is made in the qualitative or quantitative formulation of the drug Is determined by FDA, by regulation or guidance, to require completion of an appropriate clinical study demonstrating equivalence of the drug to the drug as manufactured without the change Is another type of change determined by the Secretary by regulation or guidance to have a substantial potential to adversely affect the safety or effectiveness of the drug For any manufacturing change that is not major, prior to distributing the changed drug, the sponsor, as with major changes, must validate the effects of the change on the identity, strength, quality, purity, and potency of the drug as those characteristics may relate to the safety or effectiveness of the drug (134). Section 116 sets out how FDA may regulate drugs subject to manufacturing changes that are not deemed major. FDA may authorize the sponsor to distribute such drugs without submitting a supplemental application for such changes and may distinguish categories of changes that must be subject to a supplement prior to distribution from those that need not be subject to a supplement (135). For any changes not requiring a supplemental application, the sponsor must submit a report to FDA, as the agency
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specifies. FDA may permit the sponsor to submit only one cumulative report for the year (136). For changes that do require supplemental applications (but are not major changes, requiring prior approval), the sponsor may commence distribution of the changed drug 30 days after FDA receives the supplemental application (137). If FDA disapproves the supplemental application, FDA may order the sponsor to cease the distribution of the drugs that have been made with the manufacturing change (138). In November 1999, FDA published a guideline implementing section 116, Guidance for IndustryChanges to an Approved NDA or ANDA (139). As the guidance explains, section 116 provides the following reporting categories (140): A major change has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product. A major change requires the submission of a supplement and approval by FDA prior to distribution of the product made using the change (506A(c)(1)). This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement. An applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. This type of supplement is called, and should be clearly labeled, a Prior Approval SupplementExpedited Review Requested. A moderate change is a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. One type of moderate change requires the submission of a supplement to FDA at least 30 days before the distribution of the product made using the change. This type of supplement is called, and should be
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clearly labeled, a SupplementChanges Being Effected in 30 Days. FDA may identify certain moderate changes for which distribution can occur when FDA receives the supplement. This type of supplement is called, and should be clearly labeled, a SupplementChanges Being Effected. A minor change is a change that has minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. The applicant must describe minor changes in its next Annual Report. 5.1.1. Assessing the Effect of Manufacturing Changes A drug to which the sponsor has made a manufacturing change must validate the effects of the change on the identity, strength, quality, purity, and potency of the product as these factors may relate to the safety or effectiveness of the product. The validation should include a determination that the drug substance intermediates, drug substance, inprocess materials, and/or drug product affected by the change conform to the specifications set out in the approved application. The assessment should also include, as appropriate, evaluation of any changes in the chemical, physical, microbiological, biological, bioavailability, and/or stability profiles of the drug. The type of additional testing that an applicant should perform would depend on the type of manufacturing change, the type of drug substance and/or drug product, and the effect of the change on the quality of the product (141). An important component of this validation of changes is establishing equivalency. The sponsor should usually assess the extent to which the manufacturing change has altered the drug by comparing test results from pre- and postchange material and determining if the test results are equivalent. An exception to this general approach is that when bioequivalence is redocumented for certain ANDA postapproval changes, the
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comparator should be the reference listed drug. If a manufacturing change adversely affects the identity, strength, quality, purity, or potency of the drug product, the change must be filed in a prior approval supplement (142). 5.1.2. Changes in Components and Composition
Changes in the qualitative or quantitative formulation, including inactive ingredients, are considered major changes and should be filed in a prior approval supplement, unless exempted by regulation or guidance (506A(c)(2)(A)). The deletion or reduction of an ingredient intended to affect only the color of a product may be reported in an annual report. 5.1.3. Changes to Manufacturing Sites
CDER should be notified about a change to a different site to (a) manufacture or process drug products, in-process materials, drug substances, or drug substance intermediates; (b) package drug products; (c) label drug products; and (d) test components, drug product containers, closures, packaging materials, in-process materials, or drug products. A move to a different manufacturing site, when it is a type of site routinely subject to FDA inspection, should be filed as a prior approval supplement if the site does not have a satisfactory CGMP inspection for the type of operation (143). The guidance provides detailed descriptions of what types of site changes should be reported to FDA and how they should be reported. For example (144): Moving to a different manufacturing site when FDA has never inspected the new site typically is major change that must be subject to a prior approval supplement. Moving to a different manufacturing site for the primary packaging of a modified-release solid oral dosage form products is a moderate change that is subject to a SupplementChanges Being Effected in 30 Days. Moving to a different manufacturing site for the manufacture for processing of the final intermediate is a
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moderate change that is subject to a Supplement Changes Being Effected. A move to a different manufacturing site for labeling is a minor change that may be reported in the annual report. 5.1.4. Changes to Manufacturing Processes The guidance provides detailed descriptions of what types of changes to manufacturing processes should be reported to FDA, and how they should be reported. For example (145): Any fundamental change in the manufacturing process or technology, such as changing the drug product manufacture from dry to wet granulation is a major change that must be subject to a prior approval supplement. For drug products and drug substances, most changes in the process, process parameters, and/or equipment are moderate changes subject to a SupplementChanges Being Effected in 30 Days. A change in methods or controls that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, purity, or potency that it purports or is represented to possess is a moderate change that is subject to a Supplement Changes Being Effected. A minor change in an existing code imprint for a dosage form such as changing from a numeric to alphanumeric code is a minor change that may be reported in the annual report. 5.1.5. Changes to Specifications All changes in specifications from those in the approved application must be submitted in a prior approval supplement unless otherwise exempted by regulation or guidance. The guidance provides detailed descriptions of what types of changes to specifications should be reported to FDA and how they
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should be reported. For example (146): Establishing a new regulatory analytical procedure (such as are used to define a characteristic of the drug substance or drug product) is a major change that must be subject to a prior approval supplement. Relaxing an in-process acceptance criterion associated with microbiological monitoring of the production environment, materials, and components that are included in NDA and ANDA submissions is a moderate change that is subject to a SupplementChanges Being Effected in 30 Days. An addition to a specification that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, purity, or potency that it purports to possess is a moderate change that is subject to a SupplementChanges Being Effected. Any change in a specification made to comply with an official compendium is a minor change that may be reported in the annual report. 5.1.6. Changes to Packaging The guidance provides detailed descriptions of what types of changes to packaging should be reported to FDA and how they should be reported. For example (147): A change in the primary packaging components for any product when the primary packaging components control the dose delivered to the patient (e.g., the valve or actuator of a metered-dose inhaler) is a major change that must be subject to a prior approval supplement. Most changes to a container closure system are moderate changes that are subject to a SupplementChanges Being Effected in 30 Days. A change in or addition or deletion of a desiccant is a moderate change that is subject to a Supplement Changes Being Effected.
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A change in the size and/or shape of a container containing the same number of dose units for a nonsterile solid dosage form is a minor change that may be reported in the annual report. 5.1.7. Changes to Labeling The guidance provides detailed descriptions of what types of changes to labeling should be reported to FDA, and how they should be reported. For example (148): Changes based on postmarketing study results, including, but not limited to, labeling changes associated with new indications and usage are major changes that must be subject to a prior approval supplement. Most changes to a container closure system are moderate changes that are subject to a SupplementChanges Being Effected in 30 Days. A SupplementChanges Being Effected should be submitted for any labeling change that (a) adds or strengthens a contraindication, warning, precaution, or adverse reaction; (b) adds or strengthens a statement about drug abuse, dependence, psychological effect, or overdosage; (c) adds or strengthens an instruction about dosage and administration that is intended to increase the safe use of the product; (d) deletes false, misleading, or unsupported indications for use or claims for effectiveness; or (e) is specifically requested by FDA. Editorial changes and changes made to comply with an official compendium are minor changes that may be reported in the annual report. 5.2. Pilot and Small-Scale Manufacture Section 124 of FDAMA, Pilot and Small-Scale Manufacture, amends section 505(c) of the FDC Act (149). The new language of section 505(c) provides that a drug manufactured in a pilot or other small facility may be used to demonstrate the safety and effectiveness of the drug and to obtain approval for the
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drug prior to manufacture of the drug in a larger facility, unless FDA makes a determination that a full-scale production facility is necessary to ensure the safety or effectiveness of the drug (150). The same provision was added to the part of the FDC Act governing approval of animal drugs (151). 5.3. Registration of Foreign Establishments Section 417 of FDAMA, Registration of Foreign Establishments, amended 510(i) of the FDC Act (152). Prior to FDAMA, foreign establishments could, but were not required to, register with the FDA. FDA, by regulation, did require foreign establishments to list their drug products regardless of whether the foreign establishment was registered. Pursuant to 417 of FDAMA, any foreign company engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or a device that is imported or offered for import into the United States must register with the Secretary the name and place of business of the establishment (153). The establishment must also provide the information required by the FDC Act for drug listing (154). Based upon regulations promulgated under FDAMA, an owner or operator of an establishment is required to register a drug with FDA before beginning manufacture or processing if the drug is subject to an NDA, ANDA, BLA, new animal drug application, abbreviated new animal drug application, or a medicated feed mill license application (155). FDAMA also authorized FDA to enter into cooperative arrangements with officials of foreign countries (156). The purpose of these cooperative agreements is to ensure that adequate means are available for determining whether the drugs manufactured or otherwise prepared by a foreign establishment should be refused admission into United States when they are imported or offered for import. No drug may be imported or offered for import into the United States unless it is listed and manufactured or otherwise prepared at a registered foreign drug establishment. This restriction does not apply to a drug imported or offered for import for
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investigational use. Regulations implementing this section provide that foreign establishments must submit all listing information, including labels and labeling and registration information in English (157). The establishment must also have a United States agent and identify the name and other business information for that agent (158). United States agent means a person residing or maintaining a place of business in the United States whom a foreign establishment designates as its agent. This definition excludes mailboxes, answering machines or services, or other places where an individual acting as the foreign establishments agent is not physically present (159). The owner or operator of an establishment entering into the manufacture or processing of a drug or drugs shall register the establishment within 5 days after the beginning of the operation and shall submit a list of every drug in commercial distribution at that time. If the owner or operator of the establishment has not previously entered into such an operation, the owner or operator shall register within 5 days after submitting a new drug application (such as an NDA, ANDA, etc.). Owners or operators must renew their registration information annually (160). Foreign drug establishments whose drugs are imported or offered for import into the United States must comply with the establishment registration and drug listing requirements unless the drugs enter a foreign trade zone and are reexported from that foreign trade zone (161). 5.4. Mutual Recognition Agreements and Global Harmonization Section 410 of FDAMA, Mutual Recognition Agreements and Global Harmonization, amends section 803 of the FDC Act (162). Section 410 directs FDA to take certain steps in support of the Office of the United States Trade Representative and the Secretary of Commerce in furtherance of global harmonization. Section 410 requests that FDA (163): Meet with representatives of other countries to discuss methods to reduce the burden of regulation and
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harmonize regulatory requirements, consistent with consumer protection. Engage in efforts to move toward acceptance of Mutual Recognition Agreements (MRAs) relating to the regulation of devices and Good Manufacturing Practices (GMPs) between the European Union and the United States. FDA shall participate regularly in meetings with representatives of other foreign governments to discuss and reach agreement on methods and approaches to harmonize regulatory requirements (164). FDAMA required FDA to make public a plan that establishes a framework for achieving mutual recognition of good manufacturing practices inspections (165). FDA issued that framework on May 20, 1998, in FDA Framework for Achieving Mutual Recognition of Good Manufacturing Practices InspectionsA Plan That Establishes a Framework For Achieving Mutual Recognition of Good Manufacturing Practices Inspections (166). This guidance establishes that any foreign country must have in place regulatory requirements for GMPs that are at least equivalent to FDA requirements in order for FDA to recognize that countrys GMP standards. 5.5. Pharmacy Compounding On March 16, 1992, FDA issued a CPG, section 7132.16 (later renumbered as 460.200) to delineate FDAs enforcement policy on pharmacy compounding. In section 127 of FDAMA, Congress essentially codified that CPG and added section 503A to the FDC Act to clarify the status of pharmacy compounding under federal law (167). Under section 503A, drug products that were compounded by a pharmacist or physician on a customized basis for an individual patient were entitled to exemptions from three key provisions of the FDC Act: (a) the adulteration provision of section 501(a)(2)(B) (concerning the good manufacturing practice requirements); (b) the misbranding provision of section 502(f )(l) (concerning the labeling of drugs with adequate directions for use); and (c) the new drug
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provision of section 505 (concerning the approval of drugs under new drug or abbreviated new drug applications). To qualify for these statutory exemptions, a compounded drug product was required to satisfy several requirements, some of which were to be the subject of FDA rulemaking or other actions. Among the restrictions set forth in section 127 of FDAMA were certain prohibitions upon the advertising of compounded drugs. Several compounding pharmacies challenged these restrictions. On February 6, 2001, the Ninth Circuit Court of Appeals declared section 503A invalid in its entirety (168). The U.S. Supreme Court affirmed the 9th Circuit Court of Appeals decision that found section 503A of the Act invalid in its entirety because it contained unconstitutional restrictions on commercial speech (i.e., prohibitions on soliciting prescriptions for and advertising specific compounded drugs) (169). The Court did not rule on, and therefore left in place, the 9th Circuits holding that the unconstitutional restrictions on commercial speech could not be severed from the rest of section 503A. Accordingly, all of section 503A of FDAMA regarding pharmacy compounding is invalid. On June 7, 2002, FDA reissued its CPG 460.200 to eliminate what it deemed the unconstitutional requirements and to provide regulatory guidance on pharmacy compounding practice (170). FDA recognizes that pharmacists traditionally have compounded reasonable quantities of human drugs with a valid prescription for an individual patient from a licensed practitioner. This activity is within the traditional practice of pharmacy and not a matter of regulatory concern to FDA (171). However, FDA also believes that some retail pharmacies are engaged in manufacturing and distributing unapproved new drugs for human use in a manner that is clearly outside the bounds of this traditional pharmacy practice and that these pharmacies are violating the FDC Act. The practices of many of these entities are more consistent with those of drug manufacturers and wholesalers than with those of retail pharmacies. Pharmacies engaged in activities analogous to manufacturing and distributing drugs for
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human use may be held to the same standards as drug manufacturers. When the scope and nature of a pharmacys activities are like those normally associated with a drug manufacturer, FDA states that it will seriously consider enforcement action. In determining whether to initiate such an action, FDA will consider whether the pharmacy engages in any of the following acts: Compounding of drugs in anticipation of receiving prescriptions, except in very limited quantities. Compounding drugs that were withdrawn or removed from the market for safety reasons. [FDA has published a list of such drugs (172).] Compounding finished drugs from bulk active ingredients that are not components of FDA-approved drugs without an FDA-sanctioned IND in accordance with 21 U.S.C. 355(i) and 21 CFR 312. Receiving, storing, or using drug substances without first obtaining written assurance from the supplier that each lot of the drug substance has been made in an FDAregistered facility. Receiving, storing, or using drug components not guaranteed or otherwise determined to meet official compendia requirements. Using commercial-scale manufacturing or testing equipment for compounding drug products. Compounding drugs for third parties who resell to individual patients or offering compounded drug products at wholesale to other state-licensed persons or commercial entities for resale. Compounding drug products that are commercially available in the marketplace or that are essentially copies of commercially available FDA-approved drug products. In certain circumstances, it may be appropriate for a pharmacist to compound a small quantity of a drug that is only slightly different from an FDAapproved drug that is commercially available. In these circumstances, FDA will consider whether there is
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documentation of the medical need for the particular variation of the compound for the particular patient. Failing to operate in conformance with applicable state law regulating the practice of pharmacy (173).
6. INFORMATION DISSEMINATION AND LABELING 6.1. Health Care Economic Information Section 114 of FDAMA, health care economic information, amended section 502(a) of the FDC Act (174). Section 114 added the following (175):
Health care economic information provided to a formulary committee, or other similar entity, in the course of the committee or the entity carrying out its responsibilities for the selection of drugs for managed care or other similar organizations, shall not be considered to be false or misleading under this paragraph if the health care economic information directly relates to an indication approved under section 505 or under section 351(a) of the Public Health Service Act for such drug and is based on competent and reliable scientific evidence.
Information that is relevant to the substantiation of the health care economic information presented pursuant to this section must be made available to FDA upon request (176). The statute defines health care economic information as any analysis that identifies, measures, or compares the economic consequences, including the costs of the represented health outcomes, of the use of a drug to the use of another drug, to another health care intervention, or to no intervention (177). 6.2. Elimination of Certain Labeling Requirements Section 126 of FDAMA eliminated certain labeling requirements for prescription drugs. Prior to the enactment of FDAMA, the FDC Act stated that a prescription drug product
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would be deemed to be misbranded if, at any time prior to dispensing, its label fails to bear the statement, Caution: Federal law prohibits dispensing without prescription. Section 126 of FDAMA eliminated this requirement. Prior to dispensing, the label of prescription products must contain the symbol Rx only (178). The Rx only statement should be prominent and conspicuous. FDA prefers that the statement appear on the main panel of container labels and carton labeling. The Rx only statement is not required for package insert labeling. However, if a manufacturer chooses to include the statement, the agency prefers that it be placed in the Title section of the package insert. Manufacturers may exercise discretion as to whether to include the quotation marks and whether the word only appears in upper or lower case letters (179). Prior to FDAMA, section 502(d) of the FDC Act required the labels of certain habit-forming drugs to bear the statement WarningMay be habit forming. FDAMA eliminated this requirement as well. In implementing regulations, FDA added new 21 C.F.R. 290.1 and 290.2. Section 290.1 was added to make clear that a drug that is a controlled substance listed in schedule II, III, IV, or V of the Federal Controlled Substances Act (CSA) or implementing regulations must, unless FDA otherwise determines, be dispensed by prescription only (180). Section 290.2 retains the exemption from the prescription-dispensing requirement for small amounts of codeine in combination with other nonnarcotic active medicinal ingredientsthese products may continue to be dispensed over the counter, without a prescription (181). 6.3. Notification of Discontinuance of a Lifesaving Product Section 131 of FDAMA, Notification of Discontinuance of a Lifesaving Product, added a new section to the FDC Act (182). Section 131 provides that the sole manufacturer of a drug shall notify FDA of its intent to discontinue manufacture of the drug at least 6 months prior to the date of the
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discontinuance (183). This 6-month notification requirement only applies if the drug is life supporting, life sustaining, or intended for use in the prevention of a debilitating disease or condition. The notice prior to discontinuance only applies if the drug is subject to an application approved under section 505(b) of the FDC Act (an NDA) or 505( j) of the FDC Act (an ANDA). This means that the notification prior to discontinuance does not apply to drugs licensed under the PHS Act, such as biologics, including blood products, sera, toxins, and vaccines. The notification prior to discontinuance requirement does not apply to a product that was originally derived from human tissue and was replaced by a recombinant product. FDA may reduce the 6-month notification period if the manufacturer certifies that good cause exists for the reduction (184). Examples of situations where good cause exist include (185): A public health problem may result from continuation of manufacturing for the 6-month period A biomaterials shortage prevents the continuation of manufacturing for the 6-month period A liability problem may exist for the manufacturer if the manufacturing is continued for the 6-month period Continuation of the manufacturing for the 6-month period may cause substantial economic hardship for the manufacturer The manufacturer has filed for bankruptcy The manufacturer can stop making the product but still distribute it to satisfy existing market need for 6 months. A manufacturer may also be able to show on some other basis that good cause exists for a reduction in the 6-month notification period. To the maximum extent practicable, FDA must distribute information on the discontinuation of the drugs described above to appropriate physician and patient organizations. FDA proposed a regulation implementing section 131 on November 7, 2000 (186). That regulation is not yet final. It also proposes additional procedures. The proposed 21 C.F.R.
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314.91 would set out how a manufacturer would apply to the agency for a shortening of the 6-month notification period (187): The applicant must certify in a written request that, in its opinion and to the best of its knowledge, good cause exists for the reduction. The applicant must submit the following certification: The undersigned certifies that good cause exists for a reduction in the 6-month notification period required in Sec. 314.81(b)(3)(iii)(a) for discontinuing the manufacture of (name of the drug product). The following circumstances establish good cause (one or more of the circumstances described above). The certification must be signed by the applicant or the applicants attorney, agents (representative), or other authorized official. For drugs regulated by CDER, the certification must be submitted to the director of the division that is responsible for the drug application. One copy of the certification must be sent to the Drug Shortage Coordinator, at the address of the Director of CDER, and one copy of the certification must be sent to the Drug Listing Branch. For drugs regulated by CBER, the certification must be submitted to the Director of CBER. 6.4. Dissemination of Information on New Uses Prior to passage of FDAMA, FDA essentially had limited the dissemination of information on unapproved uses of medical devices, drugs, and biologics to responses to unsolicited requests for the information (188). Outside this narrow exception, if a manufacturer disseminated information on an unapproved use, FDA would consider the product adulterated or misbranded. For years there had been heated debate among various interest groups as to whether the restrictions on the dissemination of information on off-label uses should be loosened. Section 401 of FDAMA represented Congresss attempts
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to legislate a compromise of sorts among these competing interests. Section 401 added a new subchapter D to the FDC Act, consisting of new sections 551557 authorizing manufacturers to disseminate information about unapproved (offlabel) uses of approved drugs, biological products, and devices (189). New section 551 permits a manufacturer to distribute written information concerning a use not described in the approved labeling under certain conditions described in the statute (190). The information can be distributed to practitioners, pharmacy benefit managers, insurers, group health plans, and governmental agencies. It cannot be distributed directly to patients. Section 551(b) sets forth requirements for distributing information under this section; these requirements are quite restrictive and include requirements that the product be approved, that the information to be disseminated not be derived from research conducted by another manufacturer, except with its permission, and that the manufacturer submit the information to FDA 60 days before beginning distribution, together with safety and effectiveness information from clinical trials and safety information from reports of clinical experience. Further, the only information that a manufacturer may distribute is (a) an unabridged reprint of a peerreviewed article published in a scientific or medical journal about a clinical investigation, which would be considered scientifically sound, or (b) a reference publication containing similar information (191). Under new section 553, a manufacturer must submit to FDA on a biannual basis a list of articles and reference publications distributed under section 551 and a list identifying the categories of persons that received them (192). Under new section 554, a manufacturer may disseminate information about an off-label use only if it has submitted to FDA a supplemental application covering the new use, the manufacturer certifies that it will submit such a supplement, or it has an exemption from the supplement requirement (193). A manufacturer may request an exemption from the supplement requirement from FDA if it would be economically
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prohibitive or unethical to conduct the studies and submit the supplement. Under new section 555, FDA may, if it receives new information indicating that the new use may not be effective or may present a significant risk to public health, take appropriate action, including ordering the manufacturer to cease dissemination (194). FDA may also order a manufacturer to cease dissemination if there has been a failure to comply with the statutory requirements. FDA may also order a manufacturer to correct information that has been disseminated. In July 1999, Judge Royce C. Lamberth of the United States District Court for the District of Columbia struck down much of this provision (and the prior guidance document) as violative of the First Amendment free speech rights of drug manufacturers (195). The court enjoined FDA from interfering where a manufacturer wishes to disseminate to a healthcare professional a reprint of an article published in a bona fide peer-reviewed journal or an excerpt from a reference textbook, if it (a) is published by a bona fide independent publisher and (b) is otherwise generally available for sale in bookstores or other distribution channels, where similar books are normally available (196). The courts injunction was based on a finding that the FDAMA provisions on the dissemination of information about off-label uses were flawed because they failed to advance the governments asserted interest in encouraging drug manufacturers to obtain approval for on-label indications for off-label use. Instead, the court found that almost all of the requirements were designed to force a balanced presentation of information to physicians in order to prevent them from potentially being misled. Potentially misleading speech, however, is not proscribable under the First Amendment. The First Amendment could be overcome only where speech is more likely than not to mislead. Moreover, the court found that the fact that physicians can freely exchange articles amongst themselves, and the fact that FDA permitted manufacturers to distribute the same information in response to a physician inquiry, cast doubt on the
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validity of FDAs professed concern over the ability of article reprints to mislead physicians. On February 11, 2000, the U.S. Court of Appeals for the District of Columbia, ruling basically on procedural grounds, vacated the district courts injunction as it related to FDAMA (197). The ruling was based on FDAs position, enunciated for the first time during the appeal, that it did not claim authority to regulate the dissemination of information based on FDAMA. According to FDA, FDAMA merely created safe harbors that could be followed without fear of government action. Moreover, while companies were free to try other mechanisms, FDA stated that if the safe harbors were not followed, a company ran the risk that reprints could be used as evidence in an enforcement action brought against the company for shipping an unapproved drug. The Court of Appeals ruled, in effect, that the First Amendment issue on which the district court had based its decision was not ripe for decision. Noteworthy, however, was the courts comment in footnote 7 of the opinion that we certainly do not criticize the reasoning or conclusions of the district court (198). The end result is that a pharmaceutical, biological product, or medical device company has two options with regard to dissemination of off-label information. The more conservative approach is simply to refrain from disseminating offlabel information except in the rare instances where it can be done in accordance with the safe harbor set forth in section 401 and FDAs implementing regulations. Second, a company may consider continuing to disseminate, to healthcare professionals, certain types of off-label information in accordance with the district court opinion in the Washington Legal Foundation case. As noted, the Court of Appeals did not question the substance of Judge Lamberths First Amendment analysis, and presumably it remains good law. Importantly, however, if a company chooses to continue disseminating information in accordance with the vacated injunction, FDA may consider the dissemination of off-label information as evidence of a new intended use in a traditional misbranding or distribution of an unapproved product
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enforcement action. Legal counsel should be consulted when such activity is planned.
7. FDA MANAGEMENT AND POLICIES 7.1. Scientific Advisory Panels Section 120 of FDAMA, Scientific Advisory Panels, authorizes FDA to establish panels of experts to provide advice and recommendations regarding a drugs clinical investigation and subsequent approval for marketing (199). FDA may both establish new panels of experts and continue to use its existing advisory committees. In a guidance document implementing section 120, FDA stated that its existing advisory committee regulations at 21 C.F.R. Part 14 do not need to be amended to comply with FDAMA (200). As to membership requirements, FDA stated that existing advisory committees need not amend their membership to comply with the new FDAMA provisions. However, in the interest of furthering the goals of the statutory amendments, CDER and CBER intend generally to modify current advisory committee membership on a meeting-by-meeting basis and to recharter committees, as needed, to reflect the representation described in 21 U.S.C. 355(n)(3) (201). Under the new provision, a new advisory committee is comprised of core members of the panel and other individuals who may be called upon to participate in a given meeting on an ad hoc basis. The core members of the advisory committee are appointed by the Commissioner or his/her designee based on their scientific or technical expertise and serve for the duration of the committee or until their terms of appointment expire, they resign, or the Commissioner or his/her designee removes them. The core membership of a committee may be supplemented on an ad hoc basis to include (a) representation of consumer/patient interests; (b) representation from the interests of the drug manufacturing industry; and (c) at least two members who are specialists with expertise in the particular disease or
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condition for which the drug under consideration is proposed to be indicated (202). Each panel member must disclose all conflicts of interest and may not vote on any matter where the member or the immediate family of such member could gain financially from the matter. While the Commissioner (or his or her designee) may grant a waiver of any conflict of interest requirement if the waiver is necessary to the panels work, there are no waivers where the panel is considering the members own scientific work (203). Ad hoc committee members who are representatives of consumer or patient interests, or who have expertise in the particular disease or condition for which the drug under consideration is proposed to be indicated, may vote if (a) the member has the requisite scientific or technical expertise and (b) participation is not prevented by conflict of interest laws and regulations. Because of inherent conflict-of-interest concerns, representatives of the drug manufacturing industry will not be voting members of the committee. No regular, full-time employee of the United States government who is engaged in the administration of the FDC Act may be a voting member of an advisory committee (204). Within 90 days after a scientific advisory panel makes recommendations on any matter under its review, the FDA official responsible for the matter must review the conclusions and recommendations of the panel and notify the affected persons of the final decision on the matter or of the reasons why no such decision has been reached (205). 7.2. Modernization of Regulation Section 123 of FDAMA was intended to modernize certain aspects of FDA regulation of drugs and biological products. Section 123 codified numerous practices that CBER had already required of biologics manufacturers. Section 123 also sought to minimize the differences between FDAs regulation of drugs approved under section 505(b)(1) of the FDC Act (206) and section 351 of the PHS Act (207).
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Prior to FDAMA, the PHS Act did not require specific FDAapproval or licensure of a biological drug product. FDAMA amended the PHS Act to clarify what FDA has long required. No person may introduce a biological product into commerce unless (208): The product is covered by a biologics license Each package of the biological product is plainly marked with (a) the proper name of the biological product contained in the package; (b) the name, address, and applicable license number of the manufacturer of the biological product; and (c) the expiration date of the biological product. At one time, FDA had required two separate licenses for the lawful marketing of a biological productthe Establishment License Application (ELA) and the Product License Application (PLA). In the regulation implementing section 123, FDA eliminated the distinction and created a single application, the Biologics License Application (BLA), which is intended to be analogous to the NDA for drugs (209). Section 123 of FDAMA also charges FDA with approving BLAs only for biological products that are safe, pure, and potent and that are manufactured, processed, packed, and held to standards that assure the biological product continues to be safe, pure, and potent. The applicant must agree to an inspection of any facility that is the subject of the BLA (210). In regulations implementing FDAMA, FDA explicitly extended the current good manufacturing practices (CGMP) requirements applicable to drug products to biological products as well (211). FDAMA also explicitly extends the FDC Act to cover all biological products licensed under the PHS Act, but does not require that such products also have approved drug applications (212). FDA regulations implementing FDAMA clarify procedures for submitting an application for marketing approval for a radioactive biological product in order to help ensure consistency with CBER and CDER policies. The regulation clarifies that when the biological component of a radioactive coupled
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antibody determines the site of action, the sponsor should submit a BLA to CBER (213). 7.3. Dispute Resolution Section 404 of FDAMA, dispute resolution, added a new section 562 to the FDC Act (214). If there is a scientific controversy under the FDC Act or section 351 of the PHS Act, and no specific provision of the Act or a regulation provides a right to agency review of the matter, the sponsor, applicant, or manufacturer may request review under procedures established by FDA. In the Federal Register of November 18, 1998, FDA amended 21 C.F.R. 10.75 to state explicitly that a sponsor, applicant, or manufacturer of a drug or device may request review of a scientific controversy by an appropriate advisory committee (215). Should FDA deny such a request, FDA must set forth the reasons for the denial request in writing to the requester (216). Persons who receive a CDER or CBER denial of their request for a 404 review by an advisory panel may submit a request for review of that denial to FDAs Chief Mediator and Ombudsman (217). Each Center within FDA is responsible for developing and administering its own processes for handling requests for section 404 reviews (218). CDER and CBER issued a joint guidance concerning dispute resolution in February 2000 (219). Generally, a drug sponsor should rely upon FDAs existing regulations (220) and seek resolution of any scientific or procedural dispute at the Division level using formal or informal mechanisms, as appropriate. The following is the path of an appeal through CDER or CBER (221): Initial appeal to Division Office Director Deputy Center Director Center Director Because all FDA decisions on a particular scientific matter must be based on information in the matters administrative file, the sponsor may not submit new information as part of an appeal. If the sponsor has new information, it should
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submit that information first to the reviewing Division for consideration (222). At any point in the formal dispute resolution process, a sponsor may request that an appropriate advisory committee review the scientific dispute. The sponsor may make the request as part of the original formal appeal or as an amendment to the formal appeal. FDA encourages sponsors to make the request as early in the dispute resolution process as is feasible (223). A sponsor interested in requesting formal dispute resolution by an Office or Center should do so only if an attempt for resolution at the previous supervisory level was unsuccessful. The sponsor should submit a written request and supporting documentation to the appropriate CDER or CBER office. The sponsor should also submit a copy of the appeal, as an amendment to the application, to the appropriate Division document room (224). The request for dispute resolution should include the following information (225): Cover sheet that clearly identifies the submission as FORMAL DISPUTE RESOLUTION REQUEST in bold, uppercase letters. Application number (IND, NDA, BLA, ANDA), if applicable Proprietary name and established name for a product in CDER; proper name and trade name for a product in CBER Division or Office where the application is filed Proposed indication(s), if applicable Brief, but comprehensive statement of each issue to be resolved, including: Clearly describe the issue to be resolved Identify the issue as scientific, procedural, or both State the steps that have been taken to resolve the issue, including informal dispute resolution Identify possible solutions, including, for scientific issues, whether an advisory committee review is requested. State expected outcome
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Statement identifying the division that issued the original decision on the matter and, if applicable, the last agency official who attempted to formally resolve the matter List of documents previously submitted to the agency that is deemed necessary for resolution of the issue(s) (If a sponsor prefers, copies of such documents may be resubmitted to the agency.) Statement that the previous supervisory level has received and had the opportunity to review all of the material relied on for dispute resolution Name, title, and telephone and fax numbers of company contact for the appeal On receiving the dispute resolution request, the Dispute Resolution Project Manager (DRPM) will forward the request to the appropriate CDER or CBER official (the Official). The Official, on behalf of FDA, will generally provide a written response to a sponsor who requested formal dispute resolution. The written response will specifically agree or disagree with the outcome desired by the sponsor, agree or disagree with parts of the proposed outcome, or indicate a resolution that is different than that proposed by the sponsor. The response will include reasons for any disagreement and any actions that the sponsor can take to address issues FDA has raised (226). If a PDUFA product is at issue in the dispute, the Official should complete the review and respond in writing or by telephone within 30 calendar days from the DRPMs receipt of the formal request. The Official is required to follow a telephone response with a written one within 14 days. If FDA is unable to complete the review and respond within 30 days, the Official will notify the sponsor, explain the reasons for the delay, and discuss the time frame for completing the review. Where additional data or input from others are needed to reach a decision on the appeal, the 30-day response should be a description of the plan for obtaining the information (e.g., requesting further information from the sponsor, deciding to schedule a meeting with the sponsor, bringing the issue for discussion at an advisory committee). In such cases, once FDA receives the required information, the Official will again have 30 days to respond
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(227). For non-PDUFA products, the Official will make all reasonable efforts to resolve the dispute as expeditiously as possible (228). If a sponsor seeking resolution of a scientific dispute requests advisory committee review of the matter, the Official will determine whether such review is appropriate and would be helpful to the agency at that time in the formal appeal process. The Official will communicate this determination to the sponsor following the procedures described above. Generally, in FDAs view, an issue is appropriate for advisory committee review if it is related to matters of technical expertise that require some specialized education, training, or experience to understand and resolve. Issues that generally are not appropriate for advisory committee review include those that involve (a) potential criminal activity (e.g., submission of false information); (b) allegations of intellectual or regulatory bias; (c) questions of inter-Center authority, such as which FDA Center will have lead regulatory responsibility for a particular matter and other matters in which regulatory policy or procedures are dominant; and (d) matters for which the Center Director has not been delegated authority (229). If FDA agrees to the request and refers the matter to an advisory committee, the matter will be brought to the next scheduled advisory committee meeting for which there is time available on the agenda for adequate discussion of the issue. It may not be feasible to raise the matter at the next scheduled meeting. The advice and recommendations of an advisory committee concerning a scientific dispute will not bind the agency to a particular action or policy (230). After receiving the committees advice, FDA will notify the sponsor of its determination on the matter within 30 days. Unless otherwise provided by law, an FDA decision based on an advisory committee recommendation is not final agency action subject to judicial review (231). If the reviewing Official does not grant advisory committee review, the Official will notify the sponsor in writing of such decision, including the reason(s) for the denial. This notification may be included in the written response to the formal dispute resolution. The sponsor may appeal this denial up the
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chain of command in the Center as part of any subsequent request for dispute resolution of the underlying matter. After exhausting the Centers mechanisms for appealing a decision denying advisory committee review, a sponsor may request review of the Centers decision through FDAs supervisory chain of command to the Commissioner of Food and Drugs. Requests for such review should be submitted to the agencys Chief Mediator and Ombudsman (232). 7.4. Agency Guidances Section 405 of FDAMA, Agency Guidances, codified certain parts of the agencys current Good Guidance Practices (GGPs) and directed the agency to issue a regulation consistent with the FDC Act that specifies FDAs policies and procedures for the development, issuance, and use of guidance documents (233). The rule implementing this change, 21 C.F.R. 10.115, became effective October 19, 2000. Section 405 and the regulation are intended to make the agencys procedures for development, issuance, and use of guidance documents clear to the public. The regulation defines a guidance document as a document prepared for FDA staff, applicants/sponsors, and the public that describes the agencys interpretation of, or policy on, a regulatory issue. Guidances include, but are not limited to, documents that relate to the design, production, labeling, promotion, manufacturing, and testing of regulated products; the processing, content, and evaluation or approval of submissions; and inspection and enforcement policies (234). Guidance documents do not include documents relating to internal FDA procedures, agency reports, general information documents provided to consumers or health professionals, speeches, journal articles and editorials media interviews, press materials, warning letters, memoranda of understanding, or other communications directed to individual persons or firms (235). FDA is required to develop guidance documents with public participation and ensure that information identifying the existence of the guidances, and the guidances themselves,
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are publicly available in written and, if feasible, electronic format (236). Section 405 provides that guidances do not create or confer any legally enforceable rights for or on any person. A regulated entity may choose an approach other than the one set forth in a guidance document. However, the alternative approach must comply with the relevant statutes and regulations (237). Section 405 also provides that guidances do not legally bind FDA (238). However, guidances do present the current views of the agency on a subject or issue, and the agency must ensure that its employees do not deviate from such guidances without appropriate justification and supervisory concurrence (239). To ensure that employees comply with guidances, FDA will train all new and current employees to follow the guidances. Additionally, FDA Centers and Offices will monitor the development and issuance of guidances to assure that GGPs are followed (240). There is to be a period for public participation and comment prior to implementation of a guidance if the guidance (a) sets forth initial interpretations of a statute or regulation, (b) changes an interpretation or policy that is of more than a minor nature, or (c) involves complex scientific or highly controversial issues (241). Guidances meeting one of these three criteria are known as Level 1 guidance documents; all other guidances are known as Level 2 guidance documents (242). The public may comment upon Level 2 guidances, which set forth existing practices or minor changes in policy, upon implementation (243). An interested party may participate in the development and issuance of guidance documents by suggesting areas of guidance development to FDA and by commenting upon proposed guidance documents (244). According to the guidance procedure, if FDA wishes to communicate new or different regulatory expectations to a broad public audience for the first time, it must use a guidance document and comply with FDAMA and the implementing regulations. FDA must follow the GGPs set out in the regulations whenever regulatory expectations that are not readily apparent from the statute or regulations are first communicated to a broad public audience (245).
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A standard guidance document (246): Includes the term guidance Identifies the center(s) or office(s) issuing the document Identifies the activity to which and the people to whom the document applies Prominently displays a statement of the documents nonbinding effect Includes the date of issuance Notes if it is a revision to a previously issued guidance, and identifies the document that it replaces Contains the word draft if the document is a draft guidance Must not include mandatory language such as shall, must, required, or requirement, unless FDA is using these words to describe a statutory or regulatory requirement. Section 405 included other housekeeping matters with regard to guidance practice within FDA (247): In developing guidance documents, FDA shall ensure uniform nomenclature and uniform internal procedures for approval of such documents. Guidance documents and revisions should be properly dated and should indicate the nonbinding nature of the documents. FDA must periodically review all guidance documents and, where appropriate, revise such documents. FDA must maintain electronically and update and publish periodically in the Federal Register a list of guidance documents. Section 405 established that an effective appeals mechanism must be in place to address complaints that FDA is not developing and using guidance documents in accordance with FDAMA (248). FDAs implementing regulation created such a process (249). Any aggrieved party is directed to follow the FDA chain of command pursuant to 21 C.F.R. 10.115(o) to address any issue concerning guidance documents.
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7.5. Environmental Impact Review Section 411 of FDAMA, Environmental Impact Review, is a housekeeping provision relating to the environmental impact of FDA actions and FDA-regulated activities. The National Environmental Policy Act of 1969 (NEPA) requires that the laws, policies, and regulations of the United States be in accordance with NEPA policies. To comply with NEPA, many submissions that regulated entities and interested parties make to FDA must be accompanied by an environmental assessment (250). The environmental assessment must provide sufficient information to enable FDA to determine whether a particular proposed action (such as the manufacture of a new drug) may significantly affect the quality of the human environment. As an example, NDA applicants must address how their drug-manufacturing processes will affect solid waste disposal, effluent discharges into waterways, and air emissions. If FDA determines, based upon the applicants submitted environmental assessment, that the proposed action may significantly affect the quality of the human environment, FDA may prepare an environmental impact statement (251). Section 411 provides that any FDA-prepared environmental impact statement conducted in accordance with FDAs regulations also will be deemed to satisfy the detailed statement requirements set out in NEPA (252). 7.6. National Uniformity for Nonprescription Drugs and Cosmetics Section 412 of FDAMA, national uniformity for nonprescription drugs and cosmetics, established national uniformity for nonprescription drugs (and cosmetics as well) (253). Under section 412, a state or other political subdivision may not establish or continue in effect any requirement for a nonprescription drug that is different from or in addition to, or that is otherwise not identical with a requirement under the FDC Act, the Poison Prevention Packaging Act of 1970, or the Fair Packaging and Labeling Act (254). Preemption of differing state and local requirements applies to any requirement
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relating to public information or any other form of public communication relating to a warning of any kind for a drug (255). There are some exemptions to the uniformity requirement. A state or political subdivision may make an application to FDA for an exemption by regulation. FDA must issue a public notice of the application and provide an opportunity for written and oral presentation of views. For FDA to issue an exemption from the requirement of national uniformity for nonprescription drugs, it must find that the proposed exemption (a) would protect an important public interest that would otherwise be unprotected, including the health and safety of children; (b) would not cause any drug to be in violation of any applicable requirement or prohibition under federal law; and (c) would not unduly burden interstate commerce (256). FDA must make a decision on a requested exemption within 120 days (257). The national uniformity requirements do not apply to any state or political subdivision requirement that relates to the practice of pharmacy or that requires that a drug be dispensed only by prescription (258). Additionally, the national uniformity provisions are to have no effect upon State product liability law (259). Further, section 412 mandated that all nonprescription drug labels include the identification of all inactive ingredients, in alphabetical order, and the established name and quantity of all active ingredients (260).
REFERENCES
1. 2. 21 U.S.C. 355a. Guidance for Industry, Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act, (September 1999), available at http://www.fda.gov/cder/ guidance/2891fnl.pdf. Pediatric Exclusivity Guidance at 23. Pediatric Exclusivity Guidance at 3.
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See Update of List of Approved Drugs for Which Additional Pediatric Information May Product Health Benefits in the Pediatric Population, available at http://www.fda.gov/cder/ pediatric/peddrugsfinal.htm. See The Pediatric Exclusivity Provision: January 2001 Status Report to Congress, available at http://www.fda.gov/cder/ pediatric/reportcong01.pdf (hereinafter Status Report). P.L.No. 107109, January 4, 2002. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, 62 Fed. Reg. 43, 900 (proposed Aug 15, 1997); 63 Fed Reg 66,632 (Dec. 2, 1998). 21 C.F.R. 314.55(c). Status Report at ii. See FDAs website at http://www.fda.gov/cder/pediatric. 42 U.S.C. 282(j). See 42 U.S.C. 282(j)(3)(A). Guidance for Industry, Information Program on Clinical Trials for Serious or Life Threatening Diseases or Conditions (March 2002), available at http://www.clinicaltrials.gov. http://www.fda.gov/cder/guidance/4856fnl.htm. 21 U.S.C. 355. 21 U.S.C. 355(d). Guidance for Industry, Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products, (May 1998), at 3, available at http://www.fda.gov/cder/ guidance/1397fnl.pdf. 21 U.S.C. 355(d). See note 16, supra. 21 U.S.C. 355(b)(1). Memorandum from Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research, to Michael A. Friedman, M.D., Acting Commissioner, (July 20, 1998), and accompanying
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FDAMA Women and Minorities Working Group Report, available at http://www.fda.gov/cder/guidance/women.pdf. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 21 U.S.C. 355(i)(2). 21 U.S.C. 355(i)(3). 21 U.S.C. 355(i)(3). Investigational New Drug Applications: Clinical Holds, 63 Fed. Reg. 68,676 (Dec. 14, 1998). 21 U.S.C. 355 (i)(3)(B). 21 U.S.C. 355(i)(4); 21 C.F.R. 50.20, 50.23, 50.25. 21 U.S.C. 360bbb. 21 C.F.R. 312.36. 21 C.F.R. 312.35(b). 21 U.S.C. 356b. 21 U.S.C. 356b(a). 21 U.S.C. 356b(c). 21 U.S.C. 356b(b). 62 Fed. Reg. 67,207 (Dec. 1, 1999). 65 Fed. Reg. 64,607 (Oct. 30, 2000). 66 Fed. Reg. 10,815 (Oct. 30, 2000). 21 C.F.R. 314.81(b)(vii). 66 Fed. Reg. 17,912 (April 4, 2001). Guidance for Industry, Reports on the Status of Postmarketing StudiesImplementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (April 2001), available at http://www.fda.gov/cber/gdlns/ post040401.pdf. 21 U.S.C. 356b(b). CBER, Report to Congress: Reports on Postmarketing Studies [FDAMA 130], available at http://www.fda.gov/cber/fdama/ pstmrktfdama130.htm. Id.
42. 43.
44.
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45. 46. 47. 48. 49. 50. 51.
21 U.S.C. 356. 21 C.F.R. 314.500 et seq. 21 U.S.C. 356(a). 21 U.S.C. 356(b). The user fee deadlines, however, will be calculated based on the date the application is complete. 63 Fed. Reg. 64,094 (Nov. 18, 1998). Guidance for Industry: Fast Track Drug Development Programs, Designation, Development and Application Review (September 1998), available at http://www.fda.gov/cber/gdlns/ fsttrk.pdf (hereinafter Fast Track Guidance). Fast Track Guidance at 3. Fast Track Guidance at 34. Fast Track Guidance at 45. Fast Track Guidance at 6. Fast Track Guidance at 67. Fast Track Guidance at 7. Fast Track Guidance at 7. Fast Track Guidance at 89. Fast Track Guidance at 9. Fast Track Guidance at 10. 21 C.F.R. 314.510; 21 C.F.R. 601.41; Fast Track Approval Guidance at 15. Fast Track Approval Guidance at 15. Guidance for Industry, Submission of Abbreviated Reports and Synopses in Support of Marketing Application (August http://www.fda.gov/cder/guidance/ 1999), available at 2097fnl.pdf (hereinafter Abbreviated Reports Guidance). Abbreviated Reports Guidance at 3. Abbreviated Reports Guidance at 45. Abbreviated Reports Guidance at 56.
52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64.
65. 66. 67.
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68. 69. 70. 71. 72.
Abbreviated Reports Guidance at 6. Abbreviated Reports Guidance at 7. Abbreviated Reports Guidance at 7. Abbreviated Reports Guidance at 78. Guidance for Industry, Structure and Content of Clinical Study Reports (July 1996), available at http://www.fda.gov/ cder/guidance/iche3.pdf. Abbreviated Reports Guidance at 8. Abbreviated Reports Guidance at 9. Abbreviated Reports Guidance at 910. 21 U.S.C. 355(b). 21 U.S.C. 355(j). 21 U.S.C. 355(b)(4)(A). See Implementation of the Food and Drug Administration Modernization Act of 1997: Completed Items, available at http://www.fda.gov/po/modactchart/modact97fini.html. 21 U.S.C. 355(b)(4)(B). 21 U.S.C. 355(b)(4)(C)(D). 21 U.S.C. 355(b)(4)(C)(ii). http://www.fda.gov/cder/guidance/2125fnl.pdf (hereinafter PDUFA Meetings Guidance). 21 U.S.C. 379g(1); PDUFA Meetings Guidance at 1. PDUFA Meetings Guidance at 24. PDUFA Meetings Guidance at 5. PDUFA Meetings Guidance at 5. PDUFA Meetings Guidance at 67. PDUFA Meetings Guidance at 78. PDUFA Meetings Guidance at 9. PDUFA Meetings Guidance at 9.
73. 74. 75. 76. 77. 78. 79.
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http://www.fda.gov/cder/guidance/3764fnl.htm Special Protocol Guidance). 21 U.S.C. 379g(1). Special Protocol Guidance at 2. Special Protocol Guidance at 45. Special Protocol Guidance at 5. Special Protocol Guidance at 5. Special Protocol Guidance at 6. Special Protocol Guidance at 7. Special Protocol Guidance at 8. Special Protocol Guidance at 8.
(hereinafter
21 U.S.C. 355(b)(4)(C); Special Protocol Guidance at 9. Special Protocol Guidance at 9. Special Protocol Guidance at 9. Special Protocol Guidance at 10. 21 U.S.C. 355 note. 63 Fed. Reg. 28,301 (May 22, 1998). 64 Fed. Reg. 26,657 (May 17, 1999). 21 C.F.R. 315.2; 21 C.F.R. 601.31. 21 C.F.R. 315.3; 21 C.F.R. 601.32. 21 C.F.R. 315.4(a); 21 C.F.R. 601.33(a). 21 C.F.R. 315.4(b); 21 C.F.R. 601.33(b). 21 C.F.R. 315.5(a); 21 C.F.R. 601.34(a). 21 C.F.R. 315.6(a); 21 C.F.R. 601.35(a). 21 C.F.R. 315.6(c); 21 C.F.R. 601.35(c). 21 C.F.R. 315.6(d); 21 C.F.R. 601.35(d). 63 Fed. Reg. 26,694 (May 13, 1998). On January 5, 1999, FDA also issued a proposed rule to amend its regulations to remove references to the repealed
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statutory provision certified antibiotic remove references 64 Fed. Reg. 448 been finalized. 119. 120. 121. 122. 123. 124. 125.
of the FDC Act under which the agency drugs. The agency is also proposing to to the repealed antibiotic monograph. (Jan 5, 1999). This proposal has never
21 U.S.C. 355 note. 65 Fed. Reg. 3,623 (Jan 24, 2000). 21 U.S.C. 382(i). 21 U.S.C. 371 note. See H.R. Rep. No. 105310 (1997). 21 U.S.C. 371 note. Guidance for Industry, Standards for the Prompt Review of Efficacy Supplements, Including Priority Efficacy Supplements (May 1998), available at http://www.fda.gov/cder/ guidance/2423fnl.pdf (hereinafter Efficacy Supplements Guidance). Efficacy Supplement Guidance at 1. Efficacy Supplement Guidance at 2. Efficacy Supplement Guidance at 2. 21 U.S.C. 360bbb-2. See, generally, http://www.fda.gov/po/modactchart/modact97 num.html (reviewing FDAMA items remaining for implementation). 21 U.S.C. 356a. 21 U.S.C. 356a(a),(b),(c)(1). 21 U.S.C. 356a(c)(2). 21 U.S.C. 356a(a). 21 U.S.C. 356a(d). 21 U.S.C. 356a(d). 21 U.S.C. 356a(d). 21 U.S.C. 356a(d).
126. 127. 128. 129. 130.
131. 132. 133. 134. 135. 136. 137. 138.
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139.
Guidance for IndustryChanges to an Approved NDA or ANDA (November 1999), available for download at (hereinafter http://www.fda.gov/cder/guidance/2766fnl.pdf) Changes Guidance). Changes Guidance at 23. Changes Guidance at 5. Changes Guidance at 6. Changes Guidance at 8. Changes Guidance at 911. Changes Guidance at 1116. Changes Guidance at 1619. Changes Guidance at 1724. Changes Guidance at 2425. 21 U.S.C. 355(c)(4). 21 U.S.C. 355(c)(4). 21 U.S.C. 360b(c)(4). 21 U.S.C. 360(i). 21 U.S.C. 360(i)(1); 21 C.F.R. 207.20(a). 21 U.S.C. 360(i)(2); 21 C.F.R. 207.20(a). 21 C.F.R. 207.20(c). 21 U.S.C. 360(i)(3). 21 C.F.R. 207.40(b). 21 U.S.C. 360(i)(1); 21 C.F.R. 207.40(c). 21 C.F.R. 207.3(a)(11). 21 C.F.R. 207.21(a). 21 C.F.R. 207.40(a). 21 U.S.C. 383. 21 U.S.C. 383(c)(1)(2). 21 U.S.C. 383(c)(3).
140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164.
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165. 166. 167. 168. 169. 170.
21 U.S.C. 383(c)(4). Available at http://www.fda.gov/oc/fdama/fdamagmp.pdf. 21 U.S.C. 353a. Western States Medical Center v. Shalala, 238 F.3rd 1090 (9th Cir. 2001). Thompson v. Western States Medical Center, 122 S. Ct. 1597 (2002). 67 Fed. Reg. 39,409 (June 7, 2002); CPG 460.200, available at http://www.fda.gov/OHRMS/DOCKETS/98fr/02D-0242_gdl 0001.pdf. CPG 460.200. CPG 460.200, Appendix A. CPG 460.200. 21 U.S.C. 352(a). 21 U.S.C. 352(a). 21 U.S.C. 352(a). 21 U.S.C. 352(a). See 21 U.S.C. 353(b)(4). See also 21 C.F.R. 201.100(b)(1). Guidance for Industry, Implementation of Section 126 of the Food and Drug Administration Modernization Act of 1997 Elimination of Certain Labeling Requirements (July 1998), available at http://www.fda.gov/cder/guidance/2496fnl.pdf. 21 C.F.R. 290.1. 21 C.F.R. 290.2. 21 U.S.C. 346c. 21 U.S.C. 356c(a) (proposed 21 C.F.R. 314.81(b)(3)(iii)(a), 65 Fed. Reg. 66,665, 66,670 (Nov. 7, 2000)). 21 U.S.C. 356c(b). 21 U.S.C. 356c(b) (proposed 21 C.F.R. 314.91(b),(d) 65 Fed. Reg. 66,665, 66,670 (Nov. 7, 2000)). 65 Fed. Reg. 66,665 (Nov. 7, 2000).
171. 172. 173. 174. 175. 176. 177. 178. 179.
180. 181. 182. 183. 184. 185. 186.
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187. 188.
Proposed 21 C.F.R. 314.91(c), 65 Fed. Reg. 66,665, 66,670 (Nov. 7, 2000). 21 U.S.C. 360bbb. See also Guidance for Industry, Dissemination of Reprints of Certain Published Original Data (Oct. 1996), 61 Fed. Reg. 52,800 (Oct. 8, 1996). 21 U.S.C. 360aaa360aaa-6. 21 U.S.C. 360aaa(b). 21 U.S.C. 360aaa(b). 21 U.S.C. 360aaa-2. 21 U.S.C. 360aaa-3. 21 U.S.C. 360aaa-4. Washington Legal Foundation v. Henney, 56 F. Supp. 2d. 81 (D.D.C. 1999). Id. Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C. Cir. 2000). Id. at 337. 21 U.S.C. 355(n)(1). Guidance for Industry, Advisory Committees: Implementing Section 120 of the Food and Drug Administration Modernization Act of 1997, (October 1998), available at http://www.fda.gov/cder/guidance/2117fnl.pdf (hereinafter Advisory Committee Guidance). Advisory Committee Guidance at 2. 21 U.S.C. 355(n)(3); Advisory Committee Guidance at 23. 21 U.S.C. 355(n)(4). 21 U.S.C. 355(n)(3); Advisory Committee Guidance at 23. 21 U.S.C. 355(n)(8). 21 U.S.C. 355(b)(1). 42 U.S.C. 262. 42 U.S.C. 262(a).
189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200.
201. 202. 203. 204. 205. 206. 207. 208.
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209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219.
21 C.F.R. 601.2(a); 64 Fed. Reg. 56,441, 56,450 (Oct. 20, 1999). 42 U.S.C. 262(a)(2)(A). 64 Fed. Reg. at 56,443; 21 C.F.R. 601.2(d). 42 U.S.C. 262(j). 64 Fed. Reg. at 56,443; 21 C.F.R. 601.2(b). 21 USC 360bbb-1. 63 Fed. Reg. 63,978 (Nov. 18, 1998); 21 C.F.R. 10.75(b)(2). Id. 21 C.F.R. 10.75(b)(2). 63 Fed. Reg. at 63,979. Guidance for Industry: Formal Dispute Resolution: Appeals Above The Division Level (Feb. 2000), available at http:// www.fda.gov/cder/guidance/2740fnl.pdf (hereinafter FDR Guidance). 21 CFR 10.75, 312.48, 314.103. FDR Guidance at 3. 21 C.F.R. 10.75(d); FDR Guidance at 3. FDR Guidance at 4. FDR Guidance at 45. FDR Guidance at 5. FDR Guidance at 6. FDR Guidance at 6. FDR Guidance at 7. FDR Guidance at 7. 21 C.F.R. 14.5(b). FDR Guidance at 78. FDR Guidance at 78; 21 C.F.R. 10.75. 21 U.S.C. 371(h).
220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233.
239
234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256. 257. 258. 259. 260.
21 C.F.R. 10.115(b)(1)(2). 21 C.F.R. 10.115(b)(2). 21 U.S.C. 371(h)(1)(A); 21 C.F.R. 10.115. 21 C.F.R. 10.115(d). 21 U.S.C. 371(h)(1)(A); 21 C.F.R. 10.115(d). 21 U.S.C. 371(h)(1)(B); 21 C.F.R. 10.115(d). 21 C.F.R. 10.115(l). 21 U.S.C. 371(h)(1)(C). 21 C.F.R. 10.115(c). 21 U.S.C. 371(h)(1)(D). 21 C.F.R. 10.115(g)(h). 21 C.F.R. 10.115(e). 21 C.F.R. 10.115(i). 21 U.S.C. 371(h)(2)(3). 21 U.S.C. 371(h)(4). 21 C.F.R. 10.115(o). 21 C.F.R. 25.15(a). 21 C.F.R. 25.15(b). 42 U.S.C. 4332(2)(C). 21 U.S.C. 379r. 21 U.S.C. 379r(a). 21 U.S.C. 379r(c)(2). 21 U.S.C. 379r(b)(1). 21 U.S.C. 379r(b)(2). 21 U.S.C. 379r(c)(1). 21 U.S.C. 379r(e). 21 U.S.C. 352(e)(1).
7
FDA Antibiotic Regulatory Scheme: Then and Now
IRVING L. WIESEN Stamford, Connecticut, U.S.A.
1. INTRODUCTION The history of antibiotic* regulation demonstrates the interplay between regulatory schemes, which are artifacts of history, and the scientific/regulatory constraints and marketing conditions in which they operate. Largely an outgrowth of a narrow legislative fix of a scientific and regulatory need, the antibiotic regulatory scheme grew to unwieldy proportions as the market for such drugs increased. Accordingly, the U.S.
*Antibiotic: any drug containing any quantity of any chemical substance produced by a microorganism that has the capacity to inhibit or destroy microorganisms in dilute solution (1). 241
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Food and Drug Administration (FDA), within the statutory mandate, increasingly revised the regulatory requirements governing antibiotic drugs, gradually eliminating them in successively more radical revampings of its drug approval requirements. This window into FDA rule and policymaking finally closed in 1997, when Congress enacted the Food and Drug Administration Modernization Act (FDAMA), which finally and unambiguously put an end to the particularand peculiarrequirements for antibiotic drugs.
2. ANTIBIOTIC REGULATION: A BRIEF HISTORY In 1906 Congress passed the first comprehensive scheme of federal law to regulate the marketing of pharmaceutical products. Lacking an approval requirement, however, the Food and Drugs Act of 1906 merely proscribed the entry into interstate commerce of drugs that were misbranded or adulterated. In 1938 Congress passed the Food, Drug and Cosmetic Act (FDCA), which remains the overall federal drug regulatory scheme to this day. The FDCA introduced for the first time a requirement that all drugs marketed in the United States after enactment of the Act be reviewed prior to marketing. The criterion of such review, however, was merely for safety no requirement of effectiveness existed until passage of the Drug Amendments of 1962. Antibiotics and insulin-containing drugs were added to the regulatory scheme beginning in a series of steps in 1941 and culminating in 1945 (2) and were also contained in the 1962 amendments. However, the procedures for establishing safety and efficacy applicable to other new drug antibiotics were subject to a far different regulatory scheme. This scheme was two-pronged, requiring that antibiotics adhere to a drug monograph published by FDA and that each batch of antibiotic be certified as conforming with established standards of manufacture and conformity with specifications.
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Under the monograph system, FDA issues a set of rules that are given broad applicability to any prospective marketer. Any prospective marketer may market the product in conformity with the rules and specifications contained in the monograph without preclearance of the product per se. In the case of antibiotics, the monographs were developed on the basis of the first product reviewed and approved in the antibiotic class. Thereafter, any prospective marketer merely needed to show that it was bioequivalent to the first product for which the monograph was developed and that it followed the specifications of the monograph. In this way, the antibiotic-approval mechanism paralleled and prefigured the approval mechanism for generic drugs, by which subsequent versions of a drug are approvable based upon standards developed in connection with the first approved product. Like generic drugs prior to 1962, the first-approved applicant owned no proprietary rights in the information used in approval of the product that could bar approval of subsequent applicants who relied on the first approval. Attendant to the monograph system, antibiotics were also subject to a batch certification requirement, which was instituted due to the relative newness of antibiotic manufacturing. Thus, notwithstanding the existence of the monograph, antibiotics were also subject to a requirement that served as a counterpart to the monograph system, which was the requirement for batch certification. This requirement, enshrined in the FDCA statute (3), required that each batch of antibiotic be certified to conform with regulations of identity, strength, quality, and purity. To meet this requirement, the antibiotic marketer provided a sample of each batch of the antibiotic to FDA prior to marketing for laboratory testing and certification that the requirements for marketing set forth by the statute were met. Batches that were found by FDA to meet the required standards were issued an Antibiotic Certificate, which permitted their shipment in interstate commerce, Certified by FDA (4). Unsurprisingly, the batch certification requirement represented a huge burden on both manufacturers and the FDA. As recounted by its Chief, Antibiotic Drug Review Branch of
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the FDA, the mechanism had long become expensive, timeconsuming, and ultimately a bottleneck in drug distribution (5):
The law required the Government to charge fees to those manufacturers requesting the required certification tests. Fees in excess of $5 million dollars were collected annually on a usercost basis to carry on the testing and certification program. The regulated industrys demands on the agencys testing service increased year by year as the market grew larger and larger. The agencys testing services became slower and slower due to personnel and facilities limitations imposed by the Office of Management Budget. As a result, during the late 1970s large quantities of antibiotic products were being held in quarantine for many weeks by industry while waiting for FDAs clearance at a time when interest rates were at an all time high.
As a result, FDA increasingly took advantage of its power under the statute (6) to exempt antibiotic products or manufacturers from the batch certification requirement if the FDA determined that it was not needed to assure the safety and effectiveness of the drug product. FDA took several increasingly significant steps: in October 1980, FDA indicated to the industry that testing of topical antibiotics would no longer be required. As described by the FDA, this small step was not effective, leading to a cascade of events: Such limited deregulation [topical antibiotic exemption] was not sufficient to relieve stock build-up. The Agency then tried selective testing where certain tests were skipped and certifications granted on the basis of the manufacturers test results. With less testing, there was less income to support the laboratories costs and the program headed for a financial deficit (7). Finally, on September 7, 1982, FDA decided to eliminate entirely the batch certification program as unnecessary to assure the safety and effectiveness of antibiotics, whose manufacturing by then had become well understood and whose consistency had proven itself over many years of practice. The new program was made effective on October 1, 1982. Instead of the batch certification procedure, the industry and FDA would be guided by compendial and regulatory specificationsspecifically FDAs monographs setting forth standards of identity,
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strength, quality and purityand by FDAs Good Manufacturing Practices regulations and policies applicable to production (8). In 1986 this exemption was extended to over-the-counter antibiotics that complied with the applicable monograph. As a result of FDAs revamping of its antibiotic-approval process, the way was now cleared for significant new activity by manufacturers and enhanced delivery of antibiotic products to the market. FDA described the effect of this deregulatory effort shortly there after, in 1986 (9):
At the time batch-by-batch testing of antibiotic products was terminated by FDA, a little over two years ago, there were approximately 65 domestic and 52 foregin manufacturers having products tested for marketing. Since that phase of de-regulation 25 additional domestic and 8 foreign companies have submitted one or more Form 5/6 applications to enter the U.S. Antibiotic market for the first time.
The FDA analysis concluded, [a]s deregulation occurs, growth and competition in the industry follows (10). The certification regulations remained in effect as a standard of drug quality by which adulteration and misbranding could be gauged. Nevertheless, FDA retained the power to reimpose the requirement for certification where it determined that a manufacturer or several manufacturers experience a problem that is believed to pose a significant health risk. In such event, the requirement for certification would be reimposed only on the company or companies in which the problem was evident (11). This process remained in effect until the recent repeal of the entire antibiotic application scheme by Congress in the Food and Drug Modernization Act of 1997, discussed below.
3. THE CERTIFICATION PROCESS At the time the antibiotic provisions were enacted in 1945, the only antibiotic product then on the market was penicillin. In subsequent years, well over one hundred additional antibiotic products were developed and approved by FDA. Most of these approvals were under the 1945 regulatory scheme,
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which utilized a monograph system in conjunction with batch certification. To receive permission to market a product, the applicant was required to address a request for certification of a batch of an antibiotic drug to the Commissioner of the FDA. The application was required to contain information describing the batch, including results of testing required by the regulations, and batch composition. Each batch shipped in interstate commerce was required to adhere to stated standards of identity, strength, quality, and purity. Additionally, batches were required to have results for tests and methods of assay, including sterility tests, biological tests, microbiological assays, chemical tests, and tests for certain antibiotic dosage forms. In its application, the manufacturer was required to submit actual samples of each batch of antibiotic which FDA would test in its own laboratories. Upon review and confirmation by FDA that the batch met appropriate requirements, FDA would certify the batch as safe and effective and fit for distribution in interstate commerce. These certifications were contained in an Antibiotic Certificate issued by FDA to the applicant. Batches released prior to such FDA certification were deemed misbranded under Section 502(1) of the FDCA and were subject to seizure and other legal sanctions. Certification was a creature of FDA discretion. FDA was authorized to withhold certification of any batches it deemed required a further demonstration of safety and effectiveness. In this respect, FDA could require any additional testing or other information it deemed appropriate, and it did so in cases where new information or other changed circumstances indicated that the standard certification may no longer have been sufficient (12). Moreover, FDA had the power to suspend certification procedures for any person or company found to have used fraud, misrepresentation, or concealment in the application for certification or to otherwise have falsified records required by the regulations to be maintained by the company. The 1962 Drug Amendments added a requirement that drugs prove efficacy, in addition to safety, prior to distributiona requirement that was equally applicable to antibiotics. Prior to these amendments, FDA had been authorized to certify certain antibioticspenicillin, streptomycin, chlortetracycline,
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chloramphenicol, and bacitracinas safe and effective. Other antibiotics available at the time were either classified as safe and effective or generally recognized as safe (GRAS), and therefore did not require a finding of effectiveness prior to marketing. As a result of the 1962 Amendments, which now required proof of effectiveness, FDA determined that antibiotics marketed under a pre-1962 New Drug Application (NDA) would be certified or released from certification under the pre-1962 regulatory scheme, despite the fact that the pre-1962 regulatory scheme did not review drugs for efficacy. To address the new efficacy requirements, FDA determined to proceed under the rubric of its Drug Efficacy Study Implementation Program (DESI) to provide appropriate regulations for these antibiotics. As a result of the 1962 Amendments, FDA required the submission for several antibiotics of scientific evidence of substantial well-controlled clinical studies demonstrating the effectiveness of the product. Those products that failed to provide such evidence had their certifications revoked, and the regulations under which they were marketed were repealed by FDA. Legal challenges to this action failed (13). In addition, after review of submissions for other antibiotics, FDA withdrew certification and revoked approval of several antibiotic and antibiotic combination products that did not meet FDAs standards of substantial scientific evidence (14).
4. EXEMPTIONS FROM CERTIFICATION REQUIREMENTS Under the FDCA, FDA was permitted to exempt certain products from certification as a requirement for proving safety and efficacy. Accordingly, the FDA exempted antibiotic drugs from the requirements of certification (15). Promulgated by FDA to relieve the bottleneck in antibiotic approvals, this new regulation exempted from the certification requirements of the FDCA all antibiotic drugs provided there was an approved antibiotic application for each product.
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The antibiotic approval process had previously been contained in FDAs Form FD-1675, rather than in a regulation. This form contained the information required to be submitted by the applicant for approval of the antibiotic and was also referred to as a Form 5 and Form 6 application. Form 5 applications were for antibiotics for which no standards had previously been developed as shown in 21 CFR, Parts 440455; Form 6 applications were for products for which such standards already existed and contained in the regulation. In 1985 FDA published new regulations, known as the NDA Rewrite Regulations, which entirely revamped the application procedures for drug products. In these regulations the FDA dispensed with the previous regulatory scheme of Forms 5 and 6 for antibiotics and replaced it with appellations that more closely mirrored those of nonantibiotic drugs. Accordingly, after May 23, 1985, antibiotic applications were classed as either New Antibiotic Drug Applications or Abbreviated Antibiotic Drug Applications (16). Consonant with the new regulatory framework, applicants and manufacturers could now make certain changes in their products without requiring prior FDA approval (17).
5. FDAMA In 1997 President Clinton signed into law the Food and Drug Administration Modernization Act. This act, which was designed in part to introduce legal mechanisms to permit the speedier and broader introduction of pharmaceutical products to consumers, also addressed a number of prevailing historical anomalies in FDAs review and approval process. Among these anomalies was the approval mechanism for antibiotics, whose distinction from the general class of pharmaceuticals had long lost any scientific rationale. Accordingly, Section 125 of Title I of the Act repealed section 507 of the FDCA, which contained the separate application scheme for antibiotics. Essentially, the import of the repeal is that antibiotics would, with certain exceptions, be reviewed and approved on the same basis as any other pharmaceutical product.
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The Act specifically provided, moreover, that any full application (NDA) approved under FDCA Section 597 before the signing into law of FDAMA would be deemed to have been submitted and filed under the general pharmaceutical provisions, section 505(b) of the FDCA, and approved for safety and effectiveness under section 505(c) thereof. In addition, all abbreviated applications (ANDAs) approved under section 507 would be deemed to have been filed and approved under section 505( j) of the Act, applicable to ANDAs for general pharmaceutical products. One consequence of the effective dating of the repeal, however, was that antibiotic applications submitted to FDA before the date of FDAMA were not subject to the patent listing and notification requirements, as well as the exclusivity attendant thereto.* The inevitable result was that post-FDAMA applications for pre-FDAMA (old) antibiotics were not required to include patent information, and were not eligible for the exclusivities of Sections 505(c) or 505( j) of the FD&C Act. This included applications for a new dosage form or new indication for an old antibiotic. 6. FDAS PROPOSED RULE In the Federal Registers of May 12, 1998, (18) and January 5, 1999, (19) FDA issued conforming amendments to its regulations to remove provisions which were made obsolete by FDAMA, specifically the provisions that governed certification of antibiotic drugs (20).
*Under Section 505 of the FDCA, abbreviated new drug applications are required to certify the status of their product in relation to the patents claimed by the listed product in the Orange Book. These certifications indicate whether the product infringes the listed product, whether the applicant claims no patents of the listed product apply to the applicants product, whether listed patents apply, or whether listed patents apply but the patents are invalid. The application itself is deemed a legal infringement of any patents and therefore may precipitate a patent infringement lawsuit by the owner of the listed drug against the applicant who certifies that listed patents apply, but are invalid. The statute provides a period of exclusivity to the first to file such a certification in the event of a patent infringement lawsuit by the listed product owner.
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Under Section 125(d)(1), drugs that had been approved pursuant to Section 507 of the Act were now to be deemed approved under the standard new drug provisions of the Act and would be considered as NDA drugs. These drugs, having been approved under the previous regulatory scheme, had not been subject to the patent and exclusivity provisions of the Act that were enacted under the Drug Price Competition and Patent Restoration Law (Waxman-Hatch), enacted in 1984, which were contained in Section 505 of the Act. Accordingly, FDAMA also exempted antibiotic-related drug applications from the drug exclusivity and patent listing provisions of Waxman-Hatch. As a result, Section 125 of FDAMA exempted from the exclusivity and patent listing requirements all applications that contained an antibiotic drug that was the subject of a marketing application received by FDA under former Section 507 of the Act and received by FDA prior to the enactment of FDAMA on November 21, 1997. This included applications that were withdrawn, not filed, or even refused approval under Section 507. In 2000 FDA published a proposed rulemaking notice in the Federal Register in which it fleshed out its approach to its regulatory stance on marketing exclusivity and patents for antibiotic drugs (21). Notwithstanding the relatively bright-line distinctions contained in FDAMA, an issue remained that was reminiscent of the original enactment of the Waxman-Hatch amendments, i.e., the definition of the type of drug product included in its strictures. In the case of FDAMAs Section 125 exemption, therefore, it remained unclear what constituted an antibiotic exempt from the requirementsand benefitsof drug exclusivities and patent listing.* Accordingly, in the Federal Register of January 24, 2000, FDA proposed regulations governing the exemption of
*The effect of drug listing in the Orange Book, for example, is to grant the owner of the Reference Listed Drug (RLD) an automatic thirty-month stay of approval in the event the RLD owner sued a generic applicant for patent infringement following certification by the generic applicant that its product did not infringe the patent of the RLD.
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antibiotic applications from regulatory provisions governing marketing exclusivity and patents (22). In its Notice, FDA noted that under the former Section 507 of the Act antibiotic drugs were not subject to the patent listing and exclusivity provisions of Section 505. Under Section 125 of the Modernization Act, however, this distinction is preserved with an expansive line (23). Under Section 125, applications are exempted that contain an antibiotic drug that was the subject of a marketing application received by FDA under former Section 507 prior to the enactment of FDAMA on November 21, 1997. Drugs approved and marketed under former Section 507, as well as drugs that were the subject of applications which may have been withdrawn, not filed, or refused approval under section 507 of the act were similarly excluded from the patent listing and exclusivity provisions of Section 505 (24). The term antibiotic drug, the FDA recounted, is defined in Section 125 of FDAMA as:
Any drug (except for drugs for use in animals other than humans) composed wholly or partly of any kind of penicillin, streptomycin, chlortetracycline, chloramphenicol, bacitracin, or any other drug intended for human use containing any quantity of any chemical substance which is produced by a microorganism and which has the capacity to inhibit or destroy microorganisms in dilute solution (including a chemically synthesized equivalent of any such substance) or any derivative thereof.
From this definition, FDA concluded, the term antibiotic drug refers not only to the active chemical substance, but to any derivative of the substance, such as a salt or ester of the substance. Accordingly, FDA determined, Section 125s applicability applied to any drug that is the subject of a marketing application containing an active moiety that could be found in a drug application submitted to the agency prior to the enactment of FDAMA.*
*FDA defined an active moiety as the molecule or ion responsible for physiological or pharmacological action, excluding appended portions that would cause the drug to be an ester, salt, or other noncovalent derivative of the molecule (65 FR at 3625).
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In defending its position, FDA noted that it had previously taken the same position with regard to nonantibiotic drugs with regard to patent listing and exclusivity:
In interpreting the exclusivity provisions in the Hatch-Waxman Amendments, the agency concluded that Congress did not intend to confer significant periods of exclusivity on minor variations of previously approved chemical compounds. . . . Therefore, the agency determined that it is appropriate to assess whether the drug seeking exclusivity is a new chemical entity, that is, a drug that does not contain any previously approved active moiety (25).
Having established that the congressional intent was to exempt from patent listing and exclusivity any applications for the same active moiety of a prerepeal antibiotic drug, FDA went on to propose a mechanism [t]o help interested persons determine which drug products [are] exempt from the marketing exclusivity and patent provisions by maintaining in the Code of Federal Regulations (CFR) a list of the names of each prerepeal active moiety, in Section 314.109(b) of the CFR. This list, FDA indicated, is intended to be comprehensive and to provide interested persons a means of determining whether a marketing application would be for a drug that contains a prerepeal antibiotic.* Included with its proposed rule was a list of these active moieties of pre-repeal antibiotics that the FDA considered exempt from patent listing and exclusivity provisions of Section 505 of the Act (26).
7. FDAS GUIDANCE In implementing the repeal, FDA issued a Guidance document in which it outlined a new numbering system for applications
*Although intended to be comprehensive, FDA notably stressed its use as an aid to interested parties, but without legal effect. Thus, if any products were inadvertently omitted from the list, such omissions would not affect the regulatory status of the application: the application would still be exempt from patent listing and exclusivity, notwithstanding inadvertent omission from the list. 65 FR at 3625
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subject to the old and new regulatory schemes and, in addition, more clearly defined which applications were subject to the respective statutory frameworks (27). The Guidance indicated that the Section 125 exemption contained in the Modernization Act applicable to old antibiotics applied to applications that contained in whole, or in part (i.e., as part of a combination product), an antiobiotic drug, as defined in the Act (28). Moreover, the Guidance made clear, the antibiotic contained in the application would need to have been received by FDA prior to FDAMA, whether or not approved, marketed, marketed and withdrawn by the Sponsor, for any reason, submitted and withdrawn by the Sponsor, and not further submitted. Action letter templates for Section 507 drugs would no longer be used, nor would monographs for antibiotics be published or maintained. With respect to bulk drug applications, prior to FDAMA FDA had required that bulk antibiotic drug substances be either batch certified or exempted from batch certification via an approved antibiotic drug application. FDA had used an approval mechanism for bulk antibiotics that was similar to the approval mechanism for finished antibiotic applications. Under the new scheme, FDA indicated it would treat information regarding bulk drug substances as DMFs, like their nonantibiotic counterparts. Accordingly, this information would no longer require specific approval, but rather, like DMFs, would merely be filed with the Agency and considered as part of the drug application. Like nonantibiotics, antibiotics could also henceforth contain drug substance information in the finished product application itself (29). As a result, all unapproved bulk applications pending at the FDA were converted by FDA into DMFs and assigned DMF reference numbers.
8. CONCLUSION The history and development of antibiotic regulation represents a process of increasing evolution of a particular legislative scheme which had, over time, increasingly outstripped the historical circumstances and needs that were its provenance.
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Revised by FDA to take account of both changing scientific standards and regulatory and marketplace realities, the scheme was finally abandoned entirely by Congress and folded into the standard drug regulations, thereby putting an end to its unique approval mechanism and separate status.
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. FDCA x 507(a); 21 U.S.C. 357(a). Pub. L. No. 77-366, 55 Stat. 851 (1941); Pub. L. No. 79-139, 59 Stat. 463 (1945); codified at 21 U.S.C. x 356. Section 507 of the FDCA; 21 U.S.C. x 357. John D. Harrision, Antibiotic application requirements, Clin Res Practices Drug Reg Affairs 4(4) 265, 267 (1986). Id. at 267. 21 U.S.C. x 357(a). Harrison, id. at 267. See FDA Proposal, 47 FR 19957, May 5, 1982; see also former 21 CFR 314.50, 314.55. Harrison, id. at 269. Id. FDA Order, 47 FR 39155, September 7, 1982. See Barr Laboratories, Inc. v. Harris, 482 F. Supp. 1183 (DDC 1980). See Pfizer, Inc. v. Richardson, 434 F.2d 536 (2d Cir. 1970). See In the Matter of Antibiotic Antifungal Drugs (FDA 1988), 198889n FDC LRept Dev Trans Bind at 38,070. 21 CFR 433.1(a) (repealed). See former 21 CFR 314. See former 21 CFR 314.70. 63 FR 26066.
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19. 20. 21. 22. 23. 24. 25. 26. 27.
64 FR 396; 64 FR 26657 (May 17, 1999). 21 CFR parts 430 to 460. Marketing exclusivity and patent provisions for certain antibiotic drugs, 65 FR 3623 (January 24, 2000). 65 FR 3623 (January 24, 2000). Id. at 3624. Id. Id. 65 FR at 3625. Guidance for industry and reviewers: repeal of Section 507 of the Federal Food, Drug and Cosmetic Act, FDA Center for Drug Evaluation and Research (CDER), May 1998. Section 201( jj) of the FDCA. See Guidance for industry: drug master files for bulk antibiotic drug substances, FDA Center for Drug Evaluation and Research (CDER), November, 1999.
28. 29.
8
Pioneer and Generic Drugs: Balance Between Product Life Cycle Extension and Anticompetitive Behavior
ROBERT G. PINCO and BARBARA A. BINZAK Buchanan Ingersoll Professional Corporation Washington, D.C., U.S.A.
1. INTRODUCTION Consumers, although they may not realize it, live the effects of the Drug Price Competition and Patent Term Restoration Act of 1984, known commonly as the Hatch-Waxman Amendments (also known as the Waxman-Hatch Amendments, or simply the Amendments)(1) every day. The primary effect of the Amendments was to create the abbreviated new drug application (ANDA) process, which established an administrative mechanism for rapid clearance of generic drugs by allowing shortened
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applications to be filed with the U.S. Food and Drug Administration (FDA). In these days of rapidly escalating health care costs, especially medicines, the result has been to give consumers less expensive versions of the medications they need to maintain their health. The passage of the Drug Price Competition and Patent Term Restoration Act of 1984 signified Congresss attempt to strike a balance between the need for pharmaceutical innovation and less expensive drugs. This balance has not always been preserved, however. This chapter builds on the previous discussions of HatchWaxman in this book and explores the ramifications of the Amendments almost 20 years after their enactment. In particular, the chapter examines the sophisticated regulatory strategies that pioneer companies sometimes employ to maximize the value of their products and the issues faced by generic companies as they seek to bring their generic drugs to market. While many of these strategies may be legal within the bounds of Hatch-Waxman, some have raised the interest and subsequent involvement of the Federal Trade Commission (FTC), since such actions not only stretch and bend the contours of Hatch-Waxman, but also raise antitrust concerns. The chapter also addresses some of the reform efforts that have been proposed from both a regulatory and a legislative standpoint. Given the high and ever-increasing cost of pioneer drugs, the publics unyielding desire to have low-cost generic drug options when filling their prescriptions, and the governments need to lower health care costs, debate centered on reform of Hatch-Waxman is unlikely to disappear in the near future.
2. BRIEF OVERVIEW OF HATCH-WAXMAN 2.1. Purpose The Hatch-Waxman Amendments were passed by Congress with two goals in mind: balancing incentives for pioneer drug manufacturers to continue bringing research-based products to market and providing opportunities for generic drug manufacturers to enter the market in a timely manner with lower-cost
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products (hereinafter Study) (2). Since the enactment of the Amendments, generic drugs have moved from relative insignificance to become a major factor in reducing U.S. health care costs. While this figure was only 19% in 1984, the year HatchWaxman became law, it has increased to 47% (3). A Congressional Budget Office (CBO) study has estimated that, for drugs sold by retail pharmacies, consumers saved $8$10 billion by filling their prescriptions with generic drugs during 1994 (4), and it is estimated that these savings have increased dramatically since the CBO study was carried out almost 10 years ago. Generic drugs clearly save the American public money; however, the costs incurred by the pioneer drug manufacturers who engage in the research and development of new pharmaceutical compounds can be huge. The Boston Consulting Group has estimated that it can take more than 14 years and upwards of $880 million to bring a new drug to market. While much of this amount can be attributed to failed research efforts along the way to achieving success with a single compound, such sums must nevertheless be expended in order to bring a single product to market (5). Therefore, while it is important to make less expensive medicines available to the public, it is also important for those companies engaging in research and development to be compensated for their costs and efforts. This is the delicate balance of objectives that Hatch-Waxman sought to both establish and preserve. 2.2. The 30-Month Stay and 180-Day Exclusivity Provisions The Federal Food, Drug, and Cosmetic Act (FFDCA; the Act) is the primary statutory authority for the regulation of drugs in the United States (6). The Hatch-Waxman Amendments amended the FFDCA in part by adding section 505( j) to the Act (codified at 21 U.S.C. x 355( j)), which established the abbreviated new drug application process.* As a result, generic
*FDAs regulations governing the new drug approval process and the abbreviated new drug approval process can be found at 21 C.F.R. Part 314 (applications for FDA approval to market a new drug).
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drug manufacturers can rely on FDAs previous determination that the pioneer drug (also known as the innovator or listed drug) on which the generic is based is safe and effective.* It is the pioneer drug manufacturer that must submit a new drug application (NDA) that contains not only safety and effectiveness data, but patent information on the new drug covered by the NDA as well (7). This patent information from the NDA is listed in an FDA publication, Approved Drug Products with Therapeutic Equivalence Evaluations, known as the Orange Book (8). When a generic drug manufacturer files an ANDA, the application must contain a certification for all of the patents that are found in the Orange Book for the pioneer drug upon which the generic product is based. There are four possible certifications that the ANDA applicant may make (9): 1. 2. 3. 4. Patent information has not been filed (paragraph I). The patent has expired (paragraph II). The patent will expire on a given date (paragraph III). The patent is invalid or will not be infringed by the manufacture, use, or sale of the generic drug for which the ANDA was filed (paragraph IV).
The filing effects of each of these certifications is different; for a paragraph IV certification, which is the provision at issue in this chapter, the key determination that must be made is whether or not the patent(s) on the pioneer drug are infringed by the filing of the ANDA for the generic drug. When a paragraph IV certification is filed, a complex set of events are put into motion.y First, the ANDA applicant must notify the patent holder and the NDA holder for that patent listed in the Orange Book that is referenced in the paragraph IV certification of the ANDA. This notification must indicate that an application has been submitted to obtain approval
*A list of the content requirements for an ANDA can be found at 21 U.S.C. Sect. 355( j)(2)(A). y These procedures are detailed in 21 U.S.C. Sects. 355( j)(2)(B) and ( j)(5)(A)-(B).
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to engage in the commercial manufacture, use, or sale of such drug before the expiration of the patent referred to in the certification (10). Therefore, this filing of the ANDA, if the generic drug is going to be marketed before the pioneer patent expires, constitutes an act of infringement.* As a result, the NDA holder or patent holder of the pioneer drug may choose to file a lawsuit against the ANDA applicant for patent infringement. This action must be taken, however, within 45 days of receiving notice from the ANDA applicant that the ANDA was filed. No declaratory judgment may be sought during the 45-day period. Once the suit is filed, a 30-month stay provision is triggered. In effect, the ANDA may not be approved by FDA for 30 months from the date the NDA holder/patent holder received notice from the ANDA applicant. The 30-month time period may be altered in length, however, if an earlier decision is made by a court in the patent infringement suit or if a court decides on some shorter or longer period than 30 months for the stay to be in effect. It is important to also note that if a pioneer manufacturer later obtains patent(s) on the pioneer drug that is the subject of an earlier-filed ANDA, the ANDA applicant must certify as to the new patent(s) listed after filing the ANDA, if the patent was listed within 30 days of issuance (11). It is this later listing of patents, and the triggering of subsequent 30-month stay periods, that has led to certain abuses, which will be addressed in this chapter. Second, since the first generic drug manufacturer to file an ANDA with a paragraph IV certification takes the risk that it may be sued for patent infringement, the generic company is awarded a 180-day exclusivity period to market its generic drug, which is also provided for in the Amendments. The beginning of this 180-day period is triggered by the first of two possible events to occur. The period may begin on the date
*Note, however, that it is not an infringing act to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products (35 U.S.C. Sect. 271(e)(1)).
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the generic drug is first commercially marketed. Alternatively, the period may begin on the date a court decides the pioneer patent is invalid or not infringed. Only when this 180-day period has expired can FDA approve other ANDAs it receives for the same drug (12). As is apparent, these time periods are considered extremely valuable to drug manufacturers, both pioneer and generic. A pioneer manufacturer will want to invoke the 30month stay provision, when possible, to extend the life of its patents as long as it can before generic competitors can enter the market and begin to compete. On the other hand, a generic drug manufacturer will utilize the 180-day exclusivity period to its advantage, so that other generic competitors are forced to wait to enter the market as long as possible. This tension is illustrated in Sec. 3 which highlights recent consent orders that have been issued by the FTC against various drug manufacturers in response to allegations of anticompetitive behavior.
3. PRACTICES RAISING ANTITRUST CONCERNS The FTC has become involved in enforcement of the HatchWaxman Amendments because of the antitrust implications raised when drug manufacturers, individually or in agreement with each other, attempt to side-step the legal effects of the Amendments. These activities and agreements appear to fall into two general categories: (a) agreements between a pioneer and a generic drug manufacturer or two generic drug manufacturers, and (b) activities solely of pioneer drug manufacturers. Agreements coming within the former category often include payments to a potential generic drug manufacturer to stay off the market and not compete with a product that is already on the market, at times affecting the tolling of the 180-day period of generic drug exclusivity. Actions falling within the latter category include strategies to list additional patents covering a pioneer drug in the Orange Book just prior to patent expiration, in an attempt to generate an additional 30-month stay period. While some of the activities these
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companies have engaged in may be technically legal within the bounds of the Amendments, it is questionable whether such practices defeat the spirit of Hatch-Waxman, and the balance between rewarding innovation and encouraging generic competition, that the legislation attempted to strike. 3.1. FTCs First-Generation Activities: Bilateral Agreements Raising Antitrust Concerns Under Hatch-Waxman According to the FTC, the Commissions first-generation activities involved settlement agreements arrived at during patent litigation, entered into between the pioneer drug manufacturer and the generic drug manufacturer, which allegedly delayed market entry of the generic product (13). This section first examines two such agreements, each involving a pioneer and a generic manufacturer, which resulted in FTC action. It will then turn to a third example involving a different scenario: an agreement entered into between two generic manufacturers to limit the number of generic versions of a pioneer drug introduced on the market. 3.1.1. Agreements Between Pioneer and Generic Manufacturers Hoechst Marion Roussel, Inc./Carderm Capital L.P./Andrx Corporation In a March 16, 2000, complaint against Hoechst Marion Roussel, Inc. (HMR, now Aventis Pharmaceuticals, Inc.),* Carderm Capital L.P. (Carderm), and Andrx Corporation (Andrx), the FTC made allegations related to paying a generic drug manufacturer to keep its generic version of a drug off the market (14). The agreement entered into involved the drug known as Cardizem CD, a once-a-day diltiazem drug, which is used in the treatment of hypertension and angina (15). HMR was the leading manufacturer of Cardizem CD, which accounted for more than 70% of the total sales of once-a-day
*This section will continue to refer to the party as HMR, as opposed to Aventis.
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diltiazem (16). In late 1995, Andrx (the generic drug manufacturer) filed the first ANDA for its generic version of Cardizem CD, which included a paragraph IV certification (stating the product in the ANDA did not infringe any Cardizem CD patents) (17). In January 1996 HMR and Carderm (Carderm as the holder of the rights to three patents for Cardizem CD)(18) filed a patent infringement suit against Andrx, which triggered the 30-month stay provision of Hatch-Waxman until July 1998 (19). On September 24, 1997, HMR, Carderm, and Andrx entered into a Stipulation and Agreement (Agreement), whereby the parties agreed that Andrx would not bring its generic version of Cardizem CD (covered in the ANDA in issue) to market until the earliest of (a) an entry of final judgment in the lawsuit that had been filed against Andrx, (b) Andrx obtaining a license from HMR per the Agreement, or (c) HMR providing notice that it would sell its own bioequivalent or generic version of Cardizem CD or would license a third party to do so* (20). In this Agreement, Andrx also agreed that it would not sell any other bioequivalent or generic version of Cardizem CD, even if it would not infringe HMRs or Carderms patents (21). In exchange, HMR agreed to pay Andrx $10 million per quarter, to begin when Andrxs ANDA was finally approved by FDA; this payment would continue until one of the three events listed above occurred. Andrx would also receive $60 million per year during this same time period if HMR were to lose the infringement suit it had filed (22). In addition, Andrx would have an option to get a license from HMR for HMRs Cardizem CD intellectual property (23). If Andrx breached the Agreement, it would have to repay the money it received (24). FDA granted Andrx final approval for its generic version of Cardizem CD on July 9, 1998; however, per the Agreement, Andrx did not begin selling its product. Rather, Andrx began receiving payments from HMR (25). In mid-1999, HMR and
*This was not an agreement to settle litigation; the parties agreed to continue the lawsuit. In the Matter of Hoechst Marion Roussel, Inc., Carderm Capital L.P., and Andrx Corporation. Docket No. 9293. Complaint. March 16, 2000. http://www.ftc.gov/os/2000/03/hoechstandrxcomplaint.htm. 23.
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Andrx entered into another agreement whereby Andrx began marketing a generic version of Cardizem CD (26). The FTCs complaint further alleged that the activities of the companies had the purpose or effect, or the tendency or capacity, to restrain competition unreasonably and to injure competition and consumers by preventing or discouraging the entry of competition in the form of generic versions of Cardizem CD into the relevant market (27). Furthermore, the purpose and intended effect of the quarterly payments was to provide an incentive for Andrx to refrain both from entering the relevant market, and from taking any steps, including relinquishing its right to a 180-day Exclusivity Period, to permit or facilitate the entry of any other generic manufacturer (28). Finally, the FTC alleged that the Agreement entered into constituted an unreasonable restraint of trade and that the activities engaged in constituted unfair methods of competition, both in violation of Section 5 of the Federal Trade Commission Act, as amended (29). The FTC issued its consent order against HMR, Carderm, and Andrx in May 2001* (30). The order states that the parties must cease and desist from entering into any agreement between a pioneer company and a generic company that puts restrictions on relinquishing 180-day exclusivity rights and that restricts entering the market with a noninfringing product, subject to certain exceptions (31). Furthermore, if any of these three companies are the NDA holder or the alleged infringer in a patent infringement case, they are to cease and desist from entering into an agreement in which the parties do not agree to dismiss the litigation, the NDA holder provides anything of value to the alleged infringer, and the alleged infringer agrees not to sell the product at issue or another product containing the same active chemical ingredient during litigation, subject to certain exceptions (32). The consent order will last for 10 years, terminating on May 8, 2011 (33).
*Note that two separate consent agreements were reached, one by HMR and Carderm, the other by Andrx. The one consent order issued, however, is identical for all parties.
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As is apparent, this Agreement between the parties serves as an example of how companies may financially compensate one another to remain off of the market and, in effect, park the 180-exclusivity period so that no other generic drug manufacturer can enter the market, either.* The pioneer drug manufacturer benefits, because its monopoly remains intact for a longer period of time; the generic drug manufacturer benefits because it receives financial compensation that it would otherwise have received had it brought the generic version of the drug to market. While these companies initially may have thought they had found a way to game the system, it is clear, in the end, that they did not. Ultimately, in such situations, the American consumer is the party that is harmed, since it is the consumer who benefits from the timely introduction of generic drugs to the market. Abbott Laboratories/Geneva Pharmaceuticals, Inc. A second example involving Abbott Laboratories (Abbott) and Geneva Pharmaceuticals, Inc. (Geneva) raises many of the same issues. Terazosin hydrochloride (terazosin HCl) is a drug primarily used to treat hypertension and benign prostatic hyperplasia (BTH) or enlarged prostate (34). Abbott was the manufacturer of the pioneer drug Hytrin, first introduced in tablet form in 1987 and later in capsule form in 1995 (35). In the first half of 1999, Abbott reported that its U.S. sales of Hytrin represented more than 20% of the net sales for its pharmaceutical division (36). Geneva was the first generic drug manufacturer to file an ANDA for both the tablet and capsule forms of Hytrin, in early 1993 and late 1995, respectively (37). In early 1996, Abbott listed a new patent covering Hytrin in the Orange Book; Geneva subsequently filed a paragraph IV
*It should be noted that two other generic drug manufacturers submitted ANDAs as well. In January 1997, Purepac Pharmaceutical Co. filed an ANDA, and in June 1997 Biovail Corporation International filed an ANDA. These companies did not receive FDA approval on their ANDAs until Andrxs 180-day exclusivity period expired, in December 1999. (In the Matter of Hoechst Marion Roussel, Inc., Carderm Capital L.P., and Andrx Corporation, Docket No. 9293, Complaint, March 16, 2000, http://www.ftc.gov/os/2000/03/ hoechstandrxcomplaint.htm, 16, 19, 20.)
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certification (38). Abbott then sued Geneva, claiming that Geneva infringed the Hytrin tablet product. However, no infringement claim was made against Geneva regarding the capsule product (39). As a result, FDA was prohibited from approving Genevas tablet product ANDA for 30 months, but the capsule product could be approved right away (40). This approval of the capsule product ANDA was granted on March 30, 1998 (41). The agreement entered into between the parties resembles that entered into by HMR and Andrx. The day FDA granted Geneva approval of the ANDA covering its generic capsule product, Geneva contacted Abbott and indicated it would market this product unless Abbott paid Geneva not to do so (42). Abbott estimated that Geneva would earn revenues of $1$1.5 million per month once it began marketing its generic version (43); Abbott further estimated that generic entry would eliminate more than $185 million in sales of Hytrin in 6 months (44). As a result, the FTCs complaint alleges that Abbott was willing to pay Geneva a premium over that [$1$1.5 million per month] not to compete (45). In the end, Abbott agreed to pay Geneva $4.5 million per month in nonrefundable payments until a decision was reached in the patent litigation (46). In exchange for these payments, Geneva agreed not to enter the market with its generic version, either capsule or tablet, until either (a) final resolution of the patent litigation or (b) entry of another generic version of Hytrin, whichever occurred first. Abbott further insisted that Geneva agree not to transfer, assign, or relinquish the 180-day exclusivity period to which it would be entitled (47). Once the parties became aware that the FTC was investigating their arrangement, the agreement was canceled; Geneva introduced its generic capsule onto the market in August 1999 (48). The FTC alleged in its complaint that (a) the parties agreement was an unreasonable restraint on trade, (b) the parties acted with specific intent that Abbott would monopolize the relevant market, (c) Abbott had monopoly power and monopolized the market, and (d) the activities had an anticompetitive effect and constituted unfair methods of competition, all in violation of Section 5 of the Federal Trade Commission
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Act, as amended (49). The FTC issued a consent order against each party, which were substantially similar to each other in many respects. Both included a prohibition against entering into certain types of agreements in the future (50), and both banned private agreements regarding payments to keep a generic version of a drug off the market during patent litigation (51). Furthermore, Geneva agreed to relinquish its eligibility for the 180-day exclusivity period for the terazosin tablets (52). It is clear from both of these examples that drug manufacturers have discovered ways to keep generic products off the market. These are also illustrations of how the 180-day exclusivity provision can be parked, since the company agreements in both cases involved generic companies agreeing not to assign their rights to the 180-day exclusivity period. This ultimately meant that, even though the generic manufacturers had received ANDA approvals for their generic products, the generics would not be marketed. As a result, no other generic drug could be approved by FDA, either. The tolling of the 180-day clock had simply been forestalled. It is this type of scenario that those wishing to reform Hatch-Waxman would like to preclude in the future. 3.1.2. Agreements Between Generic Drug Manufacturers: Biovail Corporation/Elan Corporation, PLC While agreements between pioneer and generic drug manufacturers to side-step the legal effects of Hatch-Waxman may make intuitive sense, since both parties can ultimately profit from keeping a generic drug off the market entirely, it is not unheard of for two generic drug manufacturers to enter into agreements as well. In the case of Biovail Corporation (Biovail) and Elan Corporation, PLC (Elan), two generic drug manufacturers agreed not to compete with one another, thus limiting the number of generic versions of a pioneer drug that were on the market. Prior to the issuance of the consent order against the two companies, the FTC called the proposed consent order the Commissions first enforcement action regarding an
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allegedly anticompetitive agreement between two competing generic drug manufacturers (53). In its complaint, the FTC described that nature of the agreement entered into by Biovail and Elan (54). The agreement involved the pioneer drug known as Adalat CC (Adalat), which is used to treat hypertension (55). In 1993, Bayer AG first introduced this product, which is available in the United States in dosages of 30, 60, and 90 mg (56). Elan filed the first ANDA for a 30 mg generic Adalat product in April 1997; Biovail was the second company to file an ANDA for this strength in December 1997. Final FDA approval for Elans 30 mg generic product was granted in March 2000, and Elan entered the market that same month. Biovail, being the second generic manufacturer to file an ANDA for the 30 mg product, received FDA approval in December 2000, but has never entered the market (57). The two companies were in the opposite positions regarding the 60 mg product: Biovail filed the first ANDA in April 1998, which was both FDA approved and marketed by Biovail in December 2000. Elan was the second company to file an ANDA on the 60 mg product in June 1999. The ANDA was approved in October 2001, but Elan has never marketed the 60 mg generic version of Adalat (58). Before either Elan or Biovail received final FDA approval of their ANDAs for the 30 mg and 60 mg generic Adalat versions, respectively, the two companies entered into an agreement in October 1999 (59). Under the agreement, which had a minimum lifetime of 15 years, Biovail was made the exclusive distributor of Elans 30 mg and 60 mg generic Adalat products (60). Since neither Elan nor Biovail distributed products themselves in the United States, a third party, Teva Pharmaceuticals, Inc. (Teva), became the subdistributor, under Biovail, of Elans 30 mg product (Teva was already Biovails distributor). Whenever Elan notified Biovail that the 60 mg product was ready for marketing, Biovail further agreed to appoint either Teva, or some other company, to be the subdistributor (under Biovail) for the 60 mg product as well (61). Although the agreement had been twice modified, the FTCs complaint alleged that these modifications did not lessen any of the agreements anticompetitive features (62).
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At the time the complaint was filed, Biovail had paid Elan approximately $33 million related to the distribution of Elans 30 mg product by Teva; Biovail had also paid Elan $12.75 million to be able to distribute Elans 60 mg product (63). The results of this agreement meant that (a) Teva could distribute Biovails 60 mg product and Elans 30 mg product, (b) some other company could distribute Biovails 30 mg product and Elans 60 mg product, and (c) Biovail would receive profits on all of the products (64). The net effect upon the American public, however, was that even though FDA had approved two ANDAs for generic versions of 30 mg Adalat and two ANDAs for generic versions of 60 mg Adalat, Biovail and Elan agreed to market only one 30 mg and one 60 mg generic version (65). However, according to the complaint, even if both companies marketed 30 mg and 60 mg versions of Adalat, the agreement allows Biovail to control or influence pricing and other competitive features of both its and Elans 30 mg and 60 mg generic Adalat products (66). Furthermore, the FTC alleged that the agreement restrained competition and injured consumers by (a) denying consumers, and other parties such as pharmacies and hospitals, the benefits of having access to multiple versions of Adalat, (b) forcing pharmacies, hospitals, and other parties to pay artificially high prices for generic Adalat, and (c) forcing consumers either to pay artificially high prices for generic Adalat, or not to buy the product at all because of not being able to pay for it (67). In August 2002, a consent order was issued by the FTC against both Biovail and Elan* (68). According to the order, which will last for 10 years (69), the parties must terminate their agreement and not engage in such conduct in the future (70). Furthermore, Elan shall use best efforts to manufacture and market its own 30 and 60 mg generic Adalat products through a distributor other than either Biovail or Teva (71). In addition, Biovail is also required to use such best efforts to manufacture and market its own 30 and 60 mg generic Adalat products through a party other than Elans generic
*Note that Teva was not a party.
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Adalat distributor (72). In order to prevent any disruption in the availability of generic Adalat products during this period of dissolution of the agreement and product launch by both parties, the order attempts to maintain[] commercial suppl[ies] of the products presently on the market, and eliminates the anticompetitive obstacles to entry of additional generic versions of Adalat (73). This example illustrates yet another type of agreement that drug manufacturers may enter into in order to extend the market life for their products. In the Biovail/Elan situation, the arrangement entered into by the parties involved putting a hold on introducing additional generic versions of a pioneer drug product. Thus, although one generic version was on the market, the agreement between the parties limited the competition, and likely any further price reduction, that additional generics would offer to the American public. In general, a generic drug may cost 2550% less than a pioneer drug, with the price dropping further as more generic competitors enter the market. This agreement had prevented further reductions in price, as normally occurs. While this scenario did not involve Hatch-Waxman in a direct manner, as did the HRM/Andrx or Abbott/Geneva situations outlined above, the agreement entered into between the companies was still, arguably, made in violation of the spirit of Hatch-Waxman, which was meant to promote competition of generic and pioneer drugs. 3.2. FTCs Second-Generation Activities: Unilateral Hatch-Waxman Abuse Through Improper Orange Book Listings The FTC has recently been active in another area of antitrust enforcement: improper listing of patents in FDAs Orange Book. The agency has called its efforts on this front secondgeneration activities (74). In this section, the chapter addresses two recent allegations made by generic drug manufacturers of improper Orange Book listings by pioneer drug manufacturers, both listings made in efforts to extend the lives of the drug patents beyond the 30-month stay provided
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for by the Hatch-Waxman Amendments. This section also surveys the FTCs actions in curtailing such efforts. 3.2.1. Andrx Pharmaceuticals, Inc./Biovail Corporation In recent years, Andrx Pharmaceuticals, Inc. (Andrx) and Biovail Corporation (Biovail) have become involved in litigation involving the delisting of a patent in the Orange Book. The FTC has also taken action, since the agency alleged that Biovail, the pioneer drug manufacturer, illegally acquired an exclusive patent license to a product it subsequently wrongfully listed in the Orange Book (75). According to the FTC, this was its first complaint and proposed consent order with a drug manufacturer for such actions (76). Diltiazem hydrochloride (diltiazem) is the active ingredient in the drug Tiazac, manufactured by Biovail. Biovail had sales of Tiazac, which is used in the treatment of angina and high blood pressure* (77), of almost $200 million in 2000, which accounted for 38% of gross sales for the company (78). Biovail received NDA approval for Tiazac (covering aspects of the extended-release formulation) on September 11, 1995, and certified to FDA that U.S. Patent No. 5,529,791 ( 791) claimed the drug that was the subject of this NDA. The 791 patent issued on June 25, 1996, and was listed in the Orange Book (79). After Andrx filed an ANDA containing a paragraph IV certification on June 22, 1998, Biovail sued Andrx for patent infringement, triggering a 30-month stay. Andrx won the infringement suit in district court, and the decision was affirmed in the U.S. Court of Appeals for the Federal Circuit on February 13, 2001 (80). Andrxs ANDA for the generic version had been tentatively approved on September 29, 2000, with final approval pending the expiration of the 30-month stay that was triggered by Biovails lawsuit against Andrx. This time period ended around February 13, 2001 (the date of the decision of the appellate court in the infringement
*Note that the complaint refers to angina as chronic chest pain.
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lawsuit) (81). However, other events prior to February 2001 prevented the immediate marketing of the approved generic version upon resolution of the patent dispute in the courts. After the 791 patent issued in 1996, another patent, U.S. Patent No. 6,162,463 ( 463) was issued on December 19, 2000 to Dr. Arnold Lippa, founder and CEO of DOV Pharmaceuticals, Inc. (DOV) (82). This patent covered an extendedrelease form of the drug, comprising both quick-release and slow-release preparations of the drug (83). In January 2001, Biovail acquired an exclusive license from DOV for the 463 patent (84). Biovail subsequently filed a certification which supported the Orange Book listing of the 463 patent. Andrx argued that this 463 patent did not claim Tiazac, and requested delisting of the patent by FDA (85). However, Biovail again certified that the 463 patent claimed the drug for which the NDA on Tiazac had originally been submitted (86). Therefore Andrx, in addition to filing suit against Biovail to delist the 463, filed a paragraph IV certification for this second patent (87). Andrx sought to have this second 30-month stay period shortened under the authority of the Act (88). The Act states that the 30-month stay provision may be modified in length to such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action (89). After the 463 patent issued, Biovail changed its process for Tiazac production and sought approval to market the formulation covered by the 463 patent. However, FDA indicated that it would require a supplement to Biovails NDA in order for Biovail to make such a change (90). Andrx claimed that Biovail had changed the formulation of Tiazac to fall within the scope of the 463 patent for purposes of receiving an additional 30-month stay period from FDA (91). The district court ruled in favor of Andrx, stating that
its [Biovails] overall conduct in listing the 463 patent based upon a manufacturing change that the FDA has concluded is a major change requiring a supplement to Biovails New Drug Application, and that with this change, Biovails Tiazac drug is not an approved drug, was not done to reasonably cooperate
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in expediting the action. . . . it is clear that Biovails actions with regard to obtaining the 463 patent after tentative approval of Andrxs generic drug and changing the formulation of its own approved drug, Tiazac, to come within the newly obtained patent were done to impede or delay the expeditious resolution of the patent actions between Biovail and Andrx over approval of Andrxs generic equivalent to Tiazac (emphasis in original) (92).
Furthermore, the district court ordered that the stay provided for by the Act should end on September 27, 2001, much earlier than August 8, 2003, when a second 30-month stay would have ended (93). On appeal, the appellate court vacated the district courts decision as being an overly broad reading of the Act and remanded the case to the district court for further proceedings (94). While the district court apparently concluded it could shorten the 30-month period because of the delay in the overall patent dispute between the two companies, the appellate court concluded [w]e find no such authority in the statute, which is addressed only to delay related to the particular infringement action (95). Furthermore, the appellate court stated that, per its decision in Mylan Pharmaceuticals v. Thompson (96) a district court has no authority in an infringement action to shorten the stay period because of allegedly improper conduct before FDA (97). Finally, the appellate court reiterated that while its Mylan decision held that the Act did not provide a private cause of action for delisting, Mylan did not stand for the proposition that an ANDA applicant could not sue FDA directly for improper actions. In other words, under the Administrative Procedures Act (APA), an ANDA applicant may sue FDA to force the agency to approve an ANDA if FDAs actions were arbitrary, capricious, or not otherwise made in accordance with the law (98). The FTC decided to take its own action against Biovail for allegedly anticompetitive behavior in its dealings with Andrx and FDA. The FTC focused its allegations on the exclusive license arrangement Biovail had entered into with DOV and the listing of the 463 patent in the Orange Book. According to the FTCs complaint, at the time the 463 patent was listed in the Orange Book, Biovail was aware that it did not cover
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the formulation of Tiazac that was on the market and that without the exclusive license from DOV, Biovail could not have listed the 463 patent at all (99). When Andrx inquired about getting a license from DOV in early 2001, DOV indicated to Andrx that it had made an exclusive license arrangement with Biovail (100). The FTC alleged that Biovails actions violated the law in two ways. First, the FTC alleged that the exclusive license constituted an asset acquisition as defined in the Clayton Act, codified at 15 U.S.C. x 18 (101). The agency stated that Biovail did not need any license to market the Tiazac product that had already been approved by FDA and that was on the market. The exclusive license raised substantial barriers for another party to enter the market, in violation of the Clayton Act and the FTC Act (102). Second, the FTC alleged that Biovail engaged in acts to willfully maintain its Tiazac monopoly, including acquisition of the exclusive license to the 463 patent, wrongfully listing the patent in the Orange Book as claiming Tiazac so that the company could gain another 30-month stay, and giving non-responsive answers to questions raised by the FDA about the propriety of listing the 463 patent in the Orange Book so as to avoid de-listing (103). According to the agency, Biovails March 26, 2001, declaration to FDA, which certified that Biovail believed the 463 patent was eligible for listing with respect to Tiazac, did not clarify if Tiazac, as Biovail intended it to be understood by FDA, meant the FDAapproved form of Tiazac on the market or the modified form of Tiazac covered by the 463 patent (104). The complaint further stated that, as was determined in the lawsuit that had been filed by Andrx to delist the 463 patent, FDA understood that Biovail had meant this declaration to refer to the Tiazac product that was currently approved (105). The FTC issued a consent order against Biovail on October 2, 2002, which will last for 10 years (106). According to its terms, Biovail is required to divest absolutely, in good faith, and only in a manner that receives the proper approval of the Commission, all exclusive licenses to the 463 patent owned by DOV (107). Biovail shall not place restrictions on DOVs use of this patent, and Biovail shall not initiate, maintain,
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or be a party to legal action to enforce the 463 patent (108). Furthermore, if Biovail does not divest within the specified time period and in the manner dictated by the order, the FTC may appoint a trustee to divest the assets to DOV (109). Biovail shall not take action that furthers the listing of any Orange Book patent that violates the law, and Biovail may not acquire a patent or exclusive license to a patent if the company seeks or secures listing of the patent in the Orange Book for an NDA that has been approved by FDA without providing a notification to the FTC (110). 3.2.2. Bristol-Myers Squibb A recent consent order issued by the FTC against Bristol-Myers Squibb (BMS) provides a final illustration of anticompetitive behavior in the pharmaceutical industry. The FTC wrote a lengthy complaint alleging anticompetitive behavior over the course of a decade by BMS with respect to its three drugs BuSpar, Taxol, and Cisplatin (111). BMS first received FDA approval for BuSpar in 1986. The drug contains buspirone hydrochloride (buspirone) as the active ingredient and is used to treat symptoms of anxiety and anxiety disorders (112). When the product was first approved by FDA, two patents covered the product: U.S. Patent Nos. 3,976,776 ( 776) and 4,182,763 ( 763). In August 1992, Schein Pharmaceutical, Inc. (Schein) filed an ANDA with a paragraph IV certification for a generic version of BuSpar, arguing that the 763 patent claimed a use that was anticipated by the 776 (113). BMS subsequently filed suit (114). The district court granted Scheins summary judgment motion, finding the 763 to be invalid, but the appellate court vacated and remanded for trial (115). Therefore, BMS and Schein entered into a settlement agreement. BMS paid Schein $72.5 million in yearly installments between 1995 and 1998, and Schein agreed not to compete with any generic bioequivalent version of BuSpar until the 763 patent expired (116). The agreement also demanded other actions of Schein, including the companys acknowledgement that the 763 was valid and enforceable (even though this determination had not been reached yet by the courts) and to withdraw
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the paragraph IV certification Schein had submitted to FDA, replacing it with a paragraph III certification (117). BMS also allegedly engaged in other anticompetitive activities, according to the FTC complaint. By the day the 763 patent was to expire, November 21, 2000, FDA had already granted tentative ANDA approval to more than 10 manufacturers to market a generic version of BuSpar (118). Only hours before the expiration of the 763 patent, however, the PTO issued to BMS U.S. Patent No. 6,150,365 ( 365), which claimed only a metabolite of the active ingredient buspirone, and not the use of buspirone (119). Hours after the 365 was issued, BMS in turn submitted the information to FDA so that the 365 could be included in the Orange Book. Even though BMS knew that the 365 covered a metabolite of the active ingredient only, BMS stated to FDA that the 365 was a method-use patent that covered, in part, a method of using BuSpar (the drug, not the metabolite) (120). According to the FTC, this listing of the 365 was improper because it did not satisfy the two-prong approach set forth in the Act: the patent did not claim BuSpar or a method of using BuSpar, and it is not a patent with respect to which a claim of infringement could reasonably be asserted against a seller of BuSpar (121). BMS allegedly lied to FDA further when, on December 4, 2000, BMS provided another declaration that the 365 covered buspirone hydrochloride, not the metabolite (122). According to the complaint, BMSs statements to the PTO are irreconcilable with BMSs sworn declaration to the FDA . . . that the 365 patent contains a claim for the approved uses of buspirone hydrochloride (123). Furthermore, once the 365 was listed in the Orange Book, infringement suits were filed against ANDA applicants which were objectively baseless because . . . the 365 patent could not be both valid and infringed (124). In a district court case brought by Mylan Pharmaceuticals (125) in an effort to have the 365 delisted, BMS was ordered to seek delisting of the patent, which eventually occurred; even though the district court holding was later overturned (126), BMS did not seek relisting of the 365 (as the generic version was already on the market by that time) (127).
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In total, the FTCs complaint alleged five violations, including an agreement in restraint of trade on BuSpar and the monopolization of BuSpar, plus allegations related to actions taken by Bristol-Myers Squibb with respect to Taxol and Platinol (128). The FTC complaint asserted the agencys position that BMS is not immune from liability under the antitrust laws under the Noerr-Pennington doctrine as both a matter of law and a matter of fact (129). This doctrine gives antitrust immunity to those individuals who petition government (130). The agency stated that BMS was not protected by this doctrine for several reasons, including (a) many of the actions taken by BMS do not qualify as petitioning behavior, (b) BMS engaged in objectively baseless sham litigation against its generic competitors, and (c) BMS made false and misleading statements or misrepresentations to the PTO and FDA (131). The FTC concluded that the course of conduct alleged herein constitutes a pattern of abusive filings made without regard to the merits that used administrative and judicial processes (as opposed to the outcome of those processes) as an anticompetitive weapon (132). The consent order addressed specific actions BMS must take with respect to its alleged anticompetitive behaviors involving all three products. For its drug BuSpar, BMS may not list the 365 patent in the Orange Book with regard to any NDA that has buspirone as the active ingredient (133). Furthermore, BMS may not seek to enforce the 365 patent against a drug product or use of a drug product containing the active ingredient buspirone; however, enforcement would be allowed if the drug product also contains the metabolite claimed in the 365 patent and the lawsuit is based on that metabolite (134). BMS also may not act or encourage another party to act by initiating or maintaining a 30-month stay of an ANDA that references the NDA for BuSpar (or Taxol) (135). BMS is also barred from listing patents in the Orange Book that would violate the law (136). The agreement also generally bars a 30-month stay if BMS engages in certain types of misconduct, regardless of whether the patent is listed, including inequitable conduct in dealing with the PTO or making false or misleading statements to FDA (137). BMS is prohibited from asserting fraudulent or
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objectively baseless claims in patent infringement litigation and shall not enforce a patent it knows is not infringed, invalid, or not enforceable (138). Other provisions that appear in the consent order also aim to deter BMS from engaging in the course of conduct it pursued with regard to the three drugs at issue here. The FTC has also indicated that several state attorneys general have filed antitrust suits in federal court, and that the FTC assumed the lead in negotiating the conduct limitation provisions contained in the proposed order (139). The agency further notes that in principle the states have reached agreements to settle, and that [t]he states will enter essentially the same injunctive terms in their orders (140). However, the states will recover substantial monetary relief (141). These examples have been provided to illustrate some of the mechanisms both pioneer and generic drug manufacturers have employed to try to circumvent the 180-day and 30-month provisions provided for by Hatch-Waxman. Because of the enormous profits that can be earned in the pharmaceutical industry, it is not surprising that gaining even a short period of time beyond these two prescribed time frames can mean substantial money earned by a pioneer or generic drug company. Trade associations and legislators would like to stop this abuse of the Amendments through reform efforts.
4. HATCH-WAXMAN REFORM ATTEMPTS In light of this recent litigation and issuance of consent orders by the FTC, there has been debate about how to curtail such scenarios in the future. How can the objectives that HatchWaxman was designed to meetrewarding pioneer drug companies, which take the financial risks in bringing new drugs to market, and encouraging generic drug companies, which take the litigation risks in order to enter the market as soon as possible to provide Americans with lower-priced drugs be balanced? This section of the chapter addresses several proposals that have been advanced which attempt to restore
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this balance, including both regulatory and legislative reform efforts. The focus of this section will be on FDAs recent proposed rule* to eliminate, or at least limit, such gaming, with some of the responses from different sectors of the industry,
*Following the writing of this chapter, FDAs proposed rule was finalized. The final rule was published in the Federal Register of June 18, 2003. Applications for FDA Approval to Market a New Drug: Patent Submission and Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed; Final Rule. 68 Fed. Reg. 36675 (June 18, 2003). The effective date for the final rule is August 18, 2003, with a compliance date of December 18, 2003, for submission of information on polymorph patents. Id. at 36676. According to FDAs Question and Answers on the final rule, [t]he final rule requires information concerning certain polymorph patents to be submitted if they claim the same active ingredient as the approved product. The polymorph patents must be submitted if the NDA holder has test data demonstrating that the drug product containing the polymorph will perform the same as the drug product described in the NDA. The information on polymorph patents must not be submitted if the NDA holder does not have the test data demonstrating that the drug product containing the polymorph will perform the same as the drug product described in the NDA. Food and Drug Administration. FDA Generic Drugs Final Rule Questions and Answers. June 12, 2003. http:// www.fda.gov/oc/initiatives/generics/qna.html. See also Applications for FDA Approval to Market a New Drug: Patent Submission and Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed; Final Rule. 68 Fed. Reg. 36675, pp. 3667836679 (June 18, 2003). The other key features of the proposed rule were adopted in the final rule as well, including restrictions on the types of patents that may and may not be listed in the Orange Book, and limitations on the number of 30month stays to one per ANDA or 505(b)(2) application, provided a full opportunity for a 30-month stay has been afforded. One full opportunity for a 30month stay means a notice of a paragraph IV certification followed by either the full 45 day period, or notice followed by the initiation of patent litigation before the 45 days expire. Id. at 36689. One change made from the proposed rule was FDAs decision to not require submission of a claim-byclaim declaration for all patents. According to FDA, [s]uch detailed information is not explicitly required by the act and is not necessary for a patent to be listed in the Orange Book. . . . Individual patent claims are relevant for purposes of the Orange Book only in the context of method-of-use patents. Id. at 36685. In a Question and Answer piece provided by FDA on the final rule, the Agency makes clear that a pioneer company could still obtain more than one 30-month stay, but not on one application. This could occur since the 30-month stay applies to each ANDA, and there might be more than one ANDA applicant for one listed drug. Food and Drug Administration. FDA Generic Drugs Final Rule Questions and Answers. June 12, 2003.
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including the FTC, provided. Several legislative reform efforts will also be briefly summarized.y 4.1. Regulatory Approaches In October 2002, FDA proposed a rule that would essentially reinterpret Hatch-Waxman as allowing only one 30-month stay period per ANDA and would clarify which types of patents can be listed in the Orange Book (142). Prior to FDAs issuance of its proposed rule, however, the FTC issued its 2002 Study covering the pharmaceutical industry and issues related to Hatch-Waxman; the Study listed suggestions for reinterpreting Hatch-Waxman that the agency claims would help eliminate the sort of industry behavior discussed in the previous section of this chapter (143). While the FTCs Study carries little legal weight, it does provide additional evidence of the Commissions current thinking on this topic, and reflects how that agency may proceed in similar circumstances in the future. 4.1.1. FDA Proposed Rule
On October 21, 2002, President Bush announced during a White House ceremony that FDA was issuing a proposed rule to modify FDAs interpretation of the Hatch-Waxman Amendments. The president cited the FTCs Study of delays in bringing generic drugs to market and stated, I have reviewed the FTC findings and I am taking immediate action to ensure
http://www.fda.gov/oc/initiatives/generics/qna.html. Finally, on the same date FDA announced it had finalized the rule described above, the Agency also announced its initiative on Improving Access to Generic Drugs. This significant effort includes several major efforts, including (a) a proposed increase of $13 million in FDAs budget for generic drug program spending, (b) new regulatory processes aimed to reduce time and costs involved in generic drug approvals, and (c) enhanced public education, as well as scientific study of generic drugs. Food and Drug Administration. FDA White Paper. New FDA Initiative on Improving Access to Generic Drugs. June 12, 2003. http://www.fda.gov/oc/initiatives/generics/whitepaper.html. yThis chapter was drafted prior to passage of Pub. L. No. 108173, 117 Stat. 2066 (Dec. 8, 2003), the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, which significantly changed important aspects of the patent notification and 30-month stay provisions of Hatch-Waxman.
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that lower cost, effective generic drugs become available to Americans without any improper delays (144). FDAs proposed rule was published in the October 24, 2002, issue of the Federal Register (145). The two major goals of the rule include (a) clarifying the types of patents that must and must not be listed in the Orange Book, along with revising the type of information an NDA applicant must include in its patent declaration, and (b) providing for only one 30-month stay period for each ANDA* (146). As of the writing of this chapter, this rule has not yet been finalized.y The first of the goals advanced in FDAs proposed rule, clarification of the types of patents to list in the Orange Book, has its roots in the types of recent industry practice discussed earlier in this chapter. Not all patents are eligible for Orange Book listing; according to current regulations, patent information is required when such patents consist of drug substance (ingredient) patents, drug product (formulation and composition) patents, and method of use patents. Process patents are not covered by this section and information on process patents may not be submitted to FDA (emphasis added) (147). In addition, FDA notes that
both the act and our regulations establish two distinct criteria for a patent intended for listing in the Orange Book: (1) The patent must claim the approved drug product or a method of using the approved drug product; and (2) the patent must be one with respect to which a claim of patent infringement
*The proposed rule also addresses changes to Sect. 505(b)(2) of the Act, codified at Sect. 355(b) of the U.S. Code. Section 505(b)(2) refers to the submission of NDAs that rely on safety and effectiveness data not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. 21 U.S.C. Sect. 355(b)(2). In such a case, an NDA applicant must also file one of the same four certifications described with respect to ANDA applicants. 21 U.S.C. Sect. 355(b)(2)(A). The same 30-month stay that is triggered when filing a paragraph IV certification in an ANDA is also triggered when filing a paragraph IV certification as part of a Sect. 505(b)(2) application. However, because the focus of this chapter is on ANDA/generic drug applicants, the proposed rule will only be discussed in terms of ANDAs. y This rule was finalized following the writing of this chapter. See the footnote beginning on p. 280.
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could reasonably be asserted if a person not licensed by the patent owner sought to engage in the drugs manufacture, use, or sale (148).
By applying this test, FDA has decided to clarify which types of patents can be listed in the Orange Book. In addition to process patents, which are already excluded from Orange Book listing, FDAs proposal would exclude patents claiming packaging, metabolites, and intermediates (149). FDA reasons that, since the Agency does not specifically approve of product packaging or the container per se (even though such information must appear in an NDA), this material is distinct from the approved drug product (150). Likewise, metabolites would not be eligible for Orange Book listing because a metabolite does not exist prior to ingestion and subsequent breaking-down in the body (151). Finally, an intermediate is a material produced while an active drug ingredient is being processed, but which is not a component of the final drug product (152). FDA concluded that all three categories of patents fail the first part of the test, since neither a drug nor a method of using a drug is claimed in any instance (153). Should FDAs proposed rule become final, all three of these categories of claims would be excluded from Orange Book listing. FDA further clarifies two other issues related to patent listing. First, by proposing new language to the current regulation, FDA indicates that product-by-process patents should be listed, since they are product patents. A product-by-process patent is one that covers the final product, when the final product can only be adequately described through the process of making the final product; on the other hand, a process patent claims the process that is used to create a final product, but not the product itself (154). Second, FDA addresses listing patents that claim a different form of a drug substance. FDA would interpret its proposed language to mean that an applicant would be able to submit patent information on a drug substance even when the patented drug substance was a different form than the drug substance that is the subject of the pending or approved NDA as long as the drug substances are the same active ingredient under section 505( j)(2)(A)(ii) of
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the act (155). A determination of what constitutes the same active ingredient would be based on whether two drug substances are likely to have the same characteristics with respect to dissolution, solubility, and bioavailability (156). The key to FDAs logic appears to be its position that products can be therapeutically equivalent, meaning they are pharmaceutically equivalent plus both safe and effective, even if the generic drugs active ingredient is not in the same exact physical form as the pioneer drugs active ingredient (157). In addition to clarifying the types of patents that must not be submitted for Orange Book listing, FDA proposes to amend the requirements for the declaration that an NDA applicant must file in an attempt to ensure that only appropriate patents are listed. The current regulations require that a person submitting an NDA, an amendment to an ANDA, or an NDA supplement submit a signed declaration if the patent is a formulation, composition, or method of use patent (158). FDA designed this declaration to help ensure that appropriate patents are listed and to preclude any need on our part to decide patent issues because we lack the patent expertise, resources, and statutory mandate to scrutinize patent listings (159). FDAs proposed rule would revise the patent declaration requirements by creating a checklist to ensure that applicants submit only appropriate patent information and stand behind the accuracy of that information (160). Although FDA acknowledges that it does not have the ability to examine patent issues, the agency is advocating for these changes in the regulations so that NDA applicants will accurately and thoughtfully include proper patent information in the application, hopefully resulting in improved compliance with the requirements for listing patents in the Orange Book (161). The second major goal of FDAs proposed rule is to alter the Agencys interpretation of how many 30-month stays an ANDA applicant may receive. FDA has consistently interpreted section 505( j)(5)(B)(iii) of the act as allowing multiple 30-month stay periods if a patent that was not part of the original NDA is later listed in the Orange Book (162). However, both FDA and the FTC have found that, over time, the number of 30-month stays allowed for a given drug product
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has increased (163). According to the FTCs Study, the listing of later-issued patents has resulted in FDA approval delays for ANDAs of 440 months beyond the original 30-month stay period (164). As a result of this trend, FDA proposes to change its interpretation of the relevant statutory provisions governing the granting of the 30-month stay. Relying heavily on strict statutory interpretation of the Hatch-Waxman Amendments, FDA proposes to alter its interpretation of the statute by indicating that
the addition of a second paragraph IV certification to an ANDA or a 505(b)(2) application that had already contained at least one paragraph IV certification would not trigger an obligation to provide a second notice to the NDA holder or to the patent owner and would not result in another opportunity for a 30-month stay. . . . the subsequent paragraph IV certification would allow us to approve the ANDA or 505(b)(2) application immediately if the Act would otherwise permit us to do so (165).
Therefore, only if an ANDA did not contain a paragraph IV certification to begin with would an ANDA applicant, who amends their application to include a paragraph IV certification to a later-listed patent by the NDA holder/patent holder, be required to provide the NDA holder/patent holder with notice of this paragraph IV certification* (166). FDA notes that their amended interpretation of the 30month stay provision would not affect the parties ability to sue and be sued for patent infringement. Rather, an NDA holder/ patent holder would still be able to protect the later-filed patent (which was not included in the original NDA) because they would already have received the required notice from the ANDA applicant that an ANDA containing a paragraph IV certification had been filed (167). FDA further claims that the
*In the final rule, FDA provides three examples of situations that might be confusing as to whether or not notice is required, and what the results would be. Applications for FDA Approval to Market a New Drug: Patent Submission and Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed; Final Rule. 68 Fed. Reg. 36675, pp. 3668836689 (June 18, 2003).
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NDA holder/patent holder would not have to rely on any second notice (from the ANDA applicant filing a second paragraph IV certification) in order for them to be able to defend the laterlisted patent(s) (168). Finally, FDA asserts that this change in interpretation of the 30-month stay provision will not affect how the 180-day exclusivity period will be applied. This would be expected because the 180-day exclusivity period is awarded to the first generic manufacturer filing an ANDA with a paragraph IV certification regardless of whether that certification would result in a requirement to notify the NDA holder/patent holder or whether the applicant would be subject to being sued for patent infringement (169). 4.1.2. FTC Proposals In its 2002 Study, the FTC makes several recommendations regarding these pioneer drug/generic drug issues that the agency believes would reduce the number of situations of abuse that have been uncovered. The FTCs first recommendation, similar to FDAs proposed rule, is to limit the number of automatic 30-month stays to just one per drug per ANDA. However, the FTCs proposal would go further: the Commission would allow such a stay to be granted only if the paragraph IV certification filed by the ANDA applicant was filed on an existing Orange Book patent (i.e., a 30-month stay would not be granted if the certification was made to a later-listed patent, after the ANDA was filed) (170). The FTC believes that allowing one 30-month stay per ANDA should eliminate most of the potential for improper Orange Book listings to generate unwarranted 30-month stays (171). The Commission addressed several issues in arriving at this recommendation. The first issue the agency looked at regarded the fact that those patents that are later-listed may not meet the requirements FDA has set forth with respect to listing a patent in the Orange Book. FDA has attempted to remedy this problem in part by proposing to amend its regulations for Orange Book listing, as discussed above. The problem of improper Orange Book listings may not be entirely remediable, however. First,
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FDA has repeatedly stated that it does not have the expertise necessary to review every patent that is submitted for Orange Book listing (172). In FDAs final rule adopting regulations implementing Hatch-Waxman, FDA noted that [t]he agency believes that its scarce resources would be better utilized in reviewing applications rather than reviewing patent claims (173). Only if a pioneer drug manufacturer amends or voluntarily withdraws an Orange Book listing will FDA change patent information listed in the Orange Book (174). Second, recent litigation has determined that Hatch-Waxman does not provide a private cause of action which ANDA applicants may use to challenge an allegedly improper Orange Book listing. This decision was reached in Mylan Pharmaceuticals, Inc. v. Thompson, discussed previously (175). The second point the agency noted in arriving at its recommendation to limit the 30-month stay period was that by limiting the number of 30-month stays to one, the time period is not out of line with the length of time it takes FDA to approve an ANDA. For example, the FTC reported that the current 30-month time period was not very different from the length of time it took FDA to approve an ANDA containing a paragraph IV certification when the generic drug manufacturer was not sued (25 months and 15 days from filing date) (176). Therefore, the FTC concluded that a single 30-month stay provision would not delay the entry of generic drugs onto the market (177). However, in the future, [g]eneric applicants may rely on expiration of the 30-month stay more frequently as the first point at which they may decide whether to enter the market, rather than to wait for a court decision on ANDA-related patent litigation that may take longer than 30 months (178). The second recommendation the FTC made in its Study was that legislation should be passed to require pioneer companies and first generic drug applicants to provide copies of some agreements to the FTC and the Department of Justice (DOJ) (179). Such submitted agreements would encompass those situations where a pioneer and a generic manufacturer attempt to alter the 180-day exclusivity period, as discussed in previous sections of this chapter. As a result, the FTC
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supports the Drug Competition Act of 2002, a bill that was introduced in (and passed by) the Senate (180). This bill would require both parties to an agreement relating to the 180-day exclusivity period or concerning the manufacture, marketing, or sale of either the pioneer or generic drug to file a copy of the agreement with the FTC and the DOJ (181). This bill, S.754, represents one legislative attempt to eliminate the Hatch-Waxman abuses that have recently been uncovered. The key features of this and other recent legislation are discussed next in an attempt to illustrate that HatchWaxman reform may come either at the agency (regulatory) level, or at the congressional (legislative) level. 4.2. Legislative Approaches In addition to possible regulatory changes in how HatchWaxman is interpreted, several bills have been introduced in Congress that would make legislative changes affecting HatchWaxman.y While none of these have been enacted into law, they do reflect congressional thinking on how the recent problems highlighted so far in this chapter pertaining to distortion of the original goals of the Amendments can be rectified. One of these attempts to limit abuses was the introduction of S.754 (the Drug Competition Act of 2001) in the Senate on April 6, 2001, by Sen. Patrick Leahy (D-VT)* (182). The bill passed the Senate and was referred to committee in the House (183). The purposes of the bill are to provide timely notice to the FTC and the DOJ about agreements that pioneer and generic drug companies may enter into, which will enhance the effectiveness and efficiency of the enforcement of the antitrust and competition laws of the United States (184). Each party to such an agreement (a generic drug manufacturer who has submitted a paragraph IV certification in an ANDA and a
*As introduced, the bill was entitled Drug Competition Act of 2001, but as it passed the Senate, the year was changed to 2002. yThis chapter was drafted prior to passage of Pub. L. No. 108173, 117 Stat. 2066 (Dec. 8, 2003), the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, which significantly changed important aspects of the patent notification and 30-month stay provisions of Hatch-Waxman.
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pioneer drug manufacturer), where the agreement refers to (a) the manufacture, marketing, or sale of a pioneer drug or a generic drug that is the subject of the ANDA for the generic drug, or (b) the 180-day exclusivity period as it applies to the ANDA or other ANDA based on the same brand name drug, would be required to file the text of the written agreement (or a written description of a nontextual agreement) with the FTC and the DOJ not later than 10 business days after the execution of the agreement (185). An agreement would not have to be filed that solely concerns purchase orders for raw material supplies, equipment and facility contracts, employment or consulting contracts, or packaging and labeling contracts (186). Any party that does not comply would be subject to a civil penalty not greater than $11,000 for each day during which the party is in violation of the act (187). In January 2003, the Greater Access to Affordable Pharmaceuticals Act of 2003 was introduced by Sen. Charles Schumer (D-NY) (188). This bill is nearly identical to a bill that Sen. Schumer introduced in the last Congress* (189). S.54 attempts to accomplish several reforms, including (a) prohibiting an extension of the 30-month stay period for a new drug where the ANDA or NDA contains a paragraph IV certification and a patent(s) is subsequently issued (190), (b) requiring the first generic applicant who files a paragraph IV certification to forfeit their right to 180-day marketing exclusivity to a later generic applicant if the first applicant acts in a manner preventing the generic drug from being brought to market in a timely manner (191), and (c) allowing a private cause of action when needed to correct information contained in the Orange Booky (192). S.54 has been referred to committee (193). It is clear that, despite resistance by some to use legislative means
*S.812 passed the Senate in July 2002. (S.812, Bill Summary and Status, http://thomas.loc.gov/). However, the House version of S.812 (H.R.1862) was not passed; a floor vote was forced despite a lack of favorable committee action. S.812, Bill Summary and Status, http://thomas.loc.gov/. See also Bruce Kuhlik and Richard Smith, Legislative Proposals to Change the Hatch-Waxman Act: Misguided and Unnecessary, FDLI Update, March/April 2003, 2224, p. 22. y The Berman article contains a summary of the key features of S.54, while the Kuhlik and Smith article provides a summary of S.812.
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to address Hatch-Waxman abuses, this is not an issue that will leave the halls of Congress in the near future. 4.3. Government and Industry Responses 4.3.1. FTCs Comments on FDAs Proposed Rule* The FTC has submitted comments to FDA on FDAs proposed rule for reinterpretation of the regulations related to HatchWaxman (194). Not surprisingly, the FTC advocates changes to FDAs regulations that are more in line with the Commissions own 2002 Study. First, while the FTC believes that limiting pioneer drug manufacturers to only one 30-month stay would be beneficial, it will not completely limit the possibility of gaming the system to delay generic drug entry onto the market (195). Therefore, the FTC suggests that FDA should adopt even stricter regulations than it sets forth in its proposed rule. This would include adoption of the FTCs approach to the 30-month stay issue: a pioneer drug company would be eligible for the stay only if the patent(s) at issue was listed in the Orange Book before the ANDA was filed (196). Second, the FTC makes several suggestions for ways FDA should change the proposed rule with respect to listing of patents in the Orange Book. The FTC supports FDAs proposal of not allowing NDA applicants to list patents in the Orange Book that claim packaging, metabolites, or intermediates (197). The FTC also suggests that FDA refine its approach in requiring the listing of product-by-process patents in the Orange Book in order to prohibit pioneer drug manufacturers from disguising process patents (which are prohibited from listing) as product-by-process patents (which are required) (198). Towards this end, the FTC suggests that FDA specifically require, in the patent declaration that FDA
*In recent testimony to the U.S. Senate Judiciary Committee on June 17, 2003, FTC Chairman Timothy Muris generally praised the new rule, even though it is not identical to the one the FTC recommended in its study. According to Muris, it is an important reform that would eliminate most of the potential for unwarranted delay of FDA approval for generic drugs the FTC study identified. FDA Webview. FDA Balancing Innovation and Generic Approvals: Troy. June 18, 2003. http://www.fdaweb.com.
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seeks to amend through this same rule, that there be a question on product-by-process patents that would provide certification that it is the product that is claimed in the patent, not a process (199). The FTC also suggests that FDA should revise the language of the regulation, as proposed, to state that only product-by-process claims in which the product is novel should be listed (200). In addition, the FTC takes a different stance than FDA does on the listing of patents that claim a different form of a drug substance from what was approved in the NDA. Whereas FDAs proposal would amend the listing regulations so that listing these patents in the Orange Book would be required, the FTC argues that the plain language of the listing statute and the purpose of Hatch-Waxman do not support the change FDA has proposed (201). Finally, with respect to Orange Book listings, the FTC would also include a requirement in the proposed regulation that double patenting, or obtaining a second patent that claims subject matter that is the same as or obvious in light of the claims of an earlier patent granted to the same applicant, should be prohibited (202). Third, regarding the patent declaration provision, the FTC supports a redesign of the information the NDA applicant is required to submit; however, they would suggest even more stringent certification requirements (203). Such additional requirements would include that the person who attests to the certification specifically be a patent attorney someone who has knowledge of and familiarity with patent issues. The Commission would include an attestation requirement that the person submitting the information is familiar with the relevant regulations and the scope of the claims for the patent in issue, and would also require two other declarations on product-by-process claims and terminal disclaimers (204). Importantly, the FTC stresses that FDA has caused potential confusion by its proposed changes to the regulations governing the patent declaration: while FDA puts new emphasis on individual claims of a patent and not on the patent in its entirety, it is unclear whether the FDAs regulation now treats individual claims of the patent to be listable, or whether the patent itself is listable given the presence of a single listable claim (205).
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4.3.2. GPhAs Response* The Generic Pharmaceutical Association (GPhA) is the industry trade association for manufacturers and distributors of generic drugs, manufacturers and distributors of bulk active drug ingredients, and suppliers of goods and services to the generic drug industry.y Not surprisingly, GPhA has been vocal in expressing the generic drug industrys position relative to these suggested changes to Hatch-Waxman and to FDAs interpretation of the Amendments. In materials submitted to FDA for a January 30, 2002, meeting with the agency, GPhA outlined in detail its position on Hatch-Waxman regulatory and legislative reform (206). In setting forth its views, GPhA made it clear that [b]oth legislative and regulatory action is urgently needed to restore the balance of the Hatch-Waxman Act and the policy objectives behind it (emphasis in original) (207). First, GPhA supports only one 30-month stay period per ANDA. As a legislative approach, GPhA backs S.812 and backs FDAs interpretation of Hatch-Waxman to limit the number of 30-month stays to just one (208). GPhA notes that
[i]n 1984, the supporters of the 30-month stay argued that because generic drug companies were small and essentially judgment-proof, the prospect of damages in a patent infringement action would not deter infringement by these companies. S.812 recognizes, however, that the generic industry has matured considerably since 1984 and that, because generic companies are substantial enterprises, traditional patent law remedies are generally a significant and sufficient deterrent to infringement (209).
The group further comments that other patents have never been subject to a 30-month stay and that there is no need to
*GPhA has noted that the final rules patent listing clarification and patent certification requirements are important, but that additional measures that are beyond the authority of the Agency will be necessary to ensure that consumers have access to generic drugs in a timely manner. FDA Webview. Polymorph Listings Tougher in Generics Final Rule. June 12, 2003. http://www.fdaweb.com. y For additional information on GPhA, visit http://www.gphaonline.org/ index.phtml.
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treat pharmaceutical patents differently. The group cites both statutory and regulatory language in support of its interpretation of Hatch-Waxman as allowing only one 30-month stay (210). Since the submission of these comments to FDA (prior to the publication of FDAs proposed rule), FDA has essentially adopted similar reasoning by way of its 2002 proposed rule. GPhA also supports FDA regulatory change in how Orange Book listings are treated. The groups two-step approach involves, first of all, placing the burden of establishing that a patent is eligible to be listed in the Orange Book on the NDA applicant. Second, FDA must review the information the NDA applicant submits, but FDA would not have to independently review the patent (211). To these ends, GPhA would strengthen the requirements for the information included in the patent listing declaration, which would include information on the type of patent claim that is being submitted (to eliminate the possibility of process patents, which are not allowed to be listed in the Orange Book, masquerading as product-byprocess patents, which are required to be listed). The declaration would also include a certification that the information is submitted under penalty of perjury. As a result, it would no longer be possible for a proponent of an Orange Book listing to state in a conclusory manner that the patent meets the HatchWaxman criteria. Rather, the proponent would have to demonstrate that this is so . . . (212). FDAs proposed rule has since addressed some of these issues. GPhA has responded to FDAs proposed rule positively, stating that it applauded the intent of FDA to close loopholes in the Amendments (213). But GPhA believes that FDAs proposal to limit brand companies to a single 30-month stay per generic drug application could cause further imbalance in the Hatch-Waxman system by impeding the ability of generic companies to obtain timely resolution of legitimate patent disputes (214). As a result, GPhA believes that by preventing gaming of the system, the partial removal of the 30-month stay inhibits the timely resolution of patent disputes. Thus, as GPhA sees it, the two fundamental purposes of Hatch-Waxman would still be unbalanced should FDAs proposed rule become finalized.
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4.3.3. PhRMAs Response* Like the FTC, the Pharmaceutical Research and Manufacturers of America (PhRMA) submitted comments in response to the publication of FDAs proposed rule (215). PhRMA is the industry trade group for research-based pharmaceutical and biotechnology companies.y PhRMAs comments address each of the major points covered in FDAs proposed rule. First of all, PhRMA focuses on the fact that NDA holders/ patent holders should have one meaningful opportunity to receive the benefit of a 30-month stay (216). The group provides several examples of ways in which the generic drug manufacturer could game the system to its advantage if the proposed rule is finalized. For example, PhRMA suggests a situation in which an ANDA applicant files both paragraph III and IV certifications in its application (217). If the NDA holder/patent holder decides that it cannot sue on the paragraph IV certification, there would be nothing to stop the ANDA applicant from then converting the paragraph III certification to a paragraph IV certification. If this were to occur, then, according to FDAs proposed rule, the ANDA applicant would not have to provide notification to the NDA holder/ patent holder that it had made this change, since the NDA holder/patent holder had already been notified once that a paragraph IV certification in an ANDA had been filed. Therefore, there would not even be a single 30-month stay in this situation. PhRMA suggests that any amendments that are made to an ANDA to change a patent certification should relate back to (and should substitute for) the original certification, thus triggering a new notice obligation (218). As FDAs proposal stands, PhRMA believes that [t]his potential for abuse is real. Under FDAs proposal, there would be little
*Alan Holmer, the President of PhRMA, has stated, with respect to the final rule, that [t]he new FDA rule revising Hatch-Waxman requirements is lengthy and complex, and we are studying it closely. We need to be sure that the rule clarifies current law in a way that supports continued development of new and better medicines that patients need. FDA Webview. Polymorph Listings Tougher in Generics Final Rule. June 12, 2003. http://www.fdaweb.com. y For additional information on PhRMA, visit http://www.phrma.org/.
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reason for an ANDA or 505(b)(2) applicant ever to make more than one paragraph IV certification in an initial application (219). With the changes PhRMA recommends, however, NDA holders would not be able to abuse the system; the ANDA applicant would ultimately be the party to determine whether or not to change a prior certification (220). Related to the 30-month stay provision, PhRMA also advocates for NDA holders/patent holders to be notified about a paragraph IV certification made in an amended ANDA, even though the NDA holder/patent holder had been notified previously about a paragraph IV certification and even though a new 30-month stay would not be triggered (221). PhRMA takes issue with FDAs assumption that NDA holders/patent holders will somehow learn about these subsequent paragraph IV certifications so that they can enforce the statutory patent rights afforded to them (and to all patent holders). PhRMA would resolve this issue by having FDA post these certifications on the FDA website, or by making the information otherwise public (222). Second, PhRMA addresses the issues in the FDA proposed rule related to Orange Book listings. Not surprisingly, PhRMA (unlike GPhA) believes that FDAs requirement for listing patents that claim a form of a drug substance that is the same as the active ingredient in an NDA is entirely appropriate and consistent with the statute: it would be improper for FDA to consider different forms of a drug substance to be the same active ingredient under the ANDA approval provisions of the Act, and yet somehow not to be the same for determining whether a patent may be listed under the Acts closely related patent listing provisions (223). In addition, PhRMA does not believe that FDA has to outline any new methods of determining what is a process patent, which is not listable, and what is a product-by-process patent, which is listable. If FDA did so, it might plunge the agency inappropriately into complicated issues of patent law and introduce listing criteria alien to the statute (224). Finally, PhRMA addresses the proposed changes to the patent declaration of an NDA by focusing on FDAs proposed change to require a submission of a claim-by-claim declaration.
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While FDA argues that such a measure will aid in the listing of only proper patents, PhRMA argues that FDA provides no support for its position (225). Furthermore, according to PhRMA, FDAs claim that such listing may reduce the number of patent infringement cases reflects an inappropriate attempt by the agency to influence patent infringement litigation, and is unrelated to the role assigned the agency under law with respect to patent listing (226). 5. CONCLUSIONS This chapter has attempted to accomplish several objectives. First, it has provided a brief overview of some of the key provisions of the Hatch-Waxman Amendments, particularly the 180-day exclusivity and 30-month stay provisions, that have been the subject of recent industry abuse. Second, the chapter highlighted some of the recent court cases and FTC-issued consent orders related to allegedly anticompetitive behavior by both pioneer and generic drug manufacturers. Finally, it has outlined some of the recently proposed attempts at reform, including FDAs 2002 proposed rule to reinterpret Hatch-Waxman and the responses of various segments of the industry to this proposed rule. In doing so, this chapter has hopefully illustrated the complexity of the issues related to maintaining the balance that Hatch-Waxman sought to establish: the balance between pioneer drug manufacturer innovation and generic drug manufacturer ability to enter the market in a timely manner to provide American consumers with less expensive drug options. Given the recent activity in this area by many sectorsFDA, the FTC, Congress, and the drug manufacturers themselvesit is very likely that the debate on how to reform Hatch-Waxman, if at all, will continue for some time.
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30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 910. 196. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 9. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 1012. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 13. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 15. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a
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New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 15. 201. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 15. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 2021. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 22. Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 22.
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Comments of the United States Federal Trade Commission. In the Matter of Applications for FDA Approval to Market a New Drug; Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/ 02N-0417_emc-000001-01.pdf. p. 24. Generic Pharmaceutical Association. Generic Pharmaceutical Association (GPhA) Materials for January 30, 2002 Meeting with FDA. January 18, 2002. http://www.fda.gov/cder/ogd/ GPHA_Jan_21.htm. Generic Pharmaceutical Association. Generic Pharmaceutical Association (GPhA) Materials for January 30, 2002 Meeting with FDA. January 18, 2002. http://www.fda.gov/cder/ogd/ GPHA_Jan_21.htm. Generic Pharmaceutical Association. Generic Pharmaceutical Association (GPhA) Materials for January 30, 2002 Meeting with FDA. January 18, 2002. http://www.fda.gov/cder/ogd/ GPHA_Jan_21.htm. Generic Pharmaceutical Association. Generic Pharmaceutical Association (GPhA) Materials for January 30, 2002 Meeting with FDA. January 18, 2002. http://www.fda.gov/cder/ogd/ GPHA_Jan_21.htm. Generic Pharmaceutical Association. Generic Pharmaceutical Association (GPhA) Materials for January 30, 2002 Meeting with FDA. January 18, 2002. http://www.fda.gov/cder/ogd/ GPHA_Jan_21.htm. Generic Pharmaceutical Association. Generic Pharmaceutical Association (GPhA) Materials for January 30, 2002 Meeting with FDA. January 18, 2002. http://www.fda.gov/cder/ogd/ GPHA_Jan_21.htm. Generic Pharmaceutical Association. Generic Pharmaceutical Association (GPhA) Materials for January 30, 2002 Meeting with FDA. January 18, 2002. http://www.fda.gov/cder/ogd/ GPHA_Jan_21.htm. Generic Pharmaceutical Association. GPhA Applauds Intent of Proposed FDA Rule Reforming Hatch-Waxman. News Release. Dec. 23, 2002.
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Generic Pharmaceutical Association. GPhA Applauds Intent of Proposed FDA Rule Reforming Hatch-Waxman. News Release. Dec. 23, 2002. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ ohrms/dockets/dockets/02n0417/02n-0417-c000027-vol1.pdf. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www. fda.gov/ohrms/dockets/dockets/02n0417/02n-0417-c000027vol1.pdf. p. 3. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www. fda.gov/ohrms/dockets/dockets/02n0417/02n-0417-c000027vol1.pdf. p. 6. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http:// www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417-c0000 27-vol1.pdf. p. 68. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule:
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Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http:// www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417c000027-vol1.pdf. p. 7. 220. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417c000027-vol1.pdf. p. 9. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417c000027-vol1.pdf. p. 11. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417c000027-vol1.pdf. p. 11. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not
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be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417c000027-vol1.pdf. p. 1314. 224. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/ dockets/dockets/02n0417/02n-0417-c000027-vol1.pdf. p. 16. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417c000027-vol1.pdf. p. 1718. Comments of the Pharmaceutical Research and Manufacturers of America (PhRMA) on FDAs Proposed Rule: Applications for FDA Approval to Market a New Drug: Patent Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying that a Patent Claiming a Drug is Invalid or Will not be Infringed. Docket No. 02N-0417. Dec. 23, 2002. http://www.fda.gov/ohrms/dockets/dockets/02n0417/02n-0417c000027-vol1.pdf. p. 18.
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The Influence of the Prescription Drug User Fee Act on the Approval Process
MARC J. SCHEINESON Alston & Bird LLP Washington, D.C., U.S.A.
1. SUMMARY OF THE PRESCRIPTION DRUG USER FEE ACT OF 1992 (PDUFA I) (OCTOBER 1, 1993SEPTEMBER 30, 1997) 1.1. Nature of the Deal In 1991, when Dr. David Kessler sat in his new desk chair in his downtown Washington, D.C., office, shortly after being nominated and confirmed as the Commissioner of Food and Drugs, he asked himself the recurring question, How can so few
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employees with such a limited federal budget perform all the responsibilities expected of us? At that time, the U.S. Food and Drug Administration (FDA) had fewer than 8,000 employees in 25 districts across the United States. Its budget was just over $850 million. Its jurisdiction included inspecting the entire domestic processed food supply, sampling and inspecting imported products under its jurisdiction, reviewing and approving the export of regulated products to foreign countries, inspecting every product manufacturing establishment every 2 years and the countrys entire blood supply, reviewing and approving applications and labeling and promotion for new prescription drugs, generic drugs, animal drugs, biologics, vaccines, medical devices, completing over-the-counter drug regulations, conducting surveillance on those approved products, soliciting and investigating adverse reaction reports, supervising the labeling and sale of medical foods, infant formulas, teas, dietary supplements, cosmetics, regulating every product that emits radiation (including light bulbs, cellular telephones, lasers, microwave ovens, television sets), inspecting the kitchens of commercial aircraft and cruise ships, and, with whatever time was left, making sure that product advertising was truthful, fairly balanced, and not false or misleading. This was a relatively paltry budget, especially when compared to the $2 billion budget of the U.S. Department of Agriculture to support hundreds of thousands of employees with a tenth of the jurisdiction. FDA states that it regulates products that comprise $.25 of every consumer dollar spent. In reality, it regulates nearly one quarter of the American economy. On top of all this pressure, Dr. Kessler was bombarded with industry and congressional pressure to streamline and expedite the review of promising new life-saving prescription drugs and biologics. Those approvals were averaging 23 years following submission of complete new drug applications (NDAs) and what are now called Biologics Licensing Applications (BLAs). Nonpriority applications for me-too drugs could take 5 years or more to preview and approve. Dr. Kessler convened his policy, legal, and legislative team. Viewing proposals by other agencies to adopt user fees to pay the cost of specialized government services that benefited
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identified categories of Americans, the terms of his offer to industry soon became clear. Would companies be willing to pay for the review of their product applications if it meant faster review? Those additional resources would, in turn, be dedicated to paying the salaries of additional product reviewers. All applications would be assigned to expanded agency personnel immediately. They would not wait for months, and sometimes years, until a reviewer was available to pick it up and read it. Gerald Mossinghoff, president of what was then the Pharmaceutical Manufacturers Association and is now PhRMA, was called in by the Commissioner and his team. Mossinghoff, a former commissioner of the Patent and Trademark Office (PTO), was initially skeptical. PTO had made a similar proposal to expedite review of patent applications. Applicants opposed the measure. Then when a nominal fee structure was adopted, all the new money flowed directly into the general federal treasury; it had not been dedicated to supplementing PTO resources. Even if money could be so dedicated, wouldnt HHS budget cutters just reduce FDAs appropriated funds by the amount of revenue from private sources. This would be a zero-sum gain. He also didnt believe that companies should have to pay the government to do its job. Wasnt that what taxes were for? Finally, an industry committee was formed to work with FDA and the Congress. A creative new proposal was worked out. PhRMA and the Industrial Biotechnology Association (a predecessor of the Biotechnology Industry Association) agreed on behalf of its member companies to support significant fees in the hundreds of thousands of dollars for NDAs, BLAs, and establishment registrations if the fees met the following criteria. They had to be (a) additive to existing FDA baseline appropriations; (b) fully dedicated to the approval of new drugs and biologics; (c) reasonable amounts; (d) based on a long-term government commitment to specific improvements in the approval process; and (e) part of performance goals that should be established by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to evaluate improvements in the review and approval process.
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These parameters were creatively hammered out into specific legislative language in a series of painstakingly long drafting sessions. Meetings were held in the office of the House Legislative Counsel, David Meade, between representatives of FDAs Office of Legislative Affairs, the PhRMA/IBC working group, the Department of Health and Human Services Assistant Secretary for Legislation, Bill Schultz (Rep. Henry Waxman), Mark Childress (Sen. Edward Kennedy), and Anne LaBelle (Sen. Orrin Hatch). Innovative new provisions insured that the industrys fees did not disappear into general government coffers or that direct FDA appropriations were not reduced by the amount of private funds received. FDAs existing fiscal 1992 appropriations became a baseline that had to increase by at least an established cost-ofliving adjustment every year or the authority to assess private user fees would terminate. Legal commitments were made that the fees would supplement FDAs direct appropriations. CDER and CBER developed specific plans to hire 600 new full-time equivalent employees. FDA refused to commit to statutory language requiring specific time frames for application review. It agreed, however, to issue a side letter to congressional committee chairmen containing nonbinding performance goals. These goals would include a designated percentage of applications that would be reviewed and acted upon within one year of submission for standard applications and within 6 months of submission for priority applications (involving drugs to treat serious and life-threatening illnesses for which no comparable therapy was currently available). The law would expire in 5 years. It would require periodic congressional reauthorization as a mechanism to force FDA to be accountable for these performance goals or risk losing hundreds of millions of user fee funds that would support hundreds of new employees and infrastructure improvements. Once the deal was reached behind the scenes between industry, FDA, and the Democratic and Republican Committee leadership, legislation was introduced. It was reviewed in cursory hearings and passed in Congress with remarkable speed. On October 29, 1992, the President signed the Prescription Drug User Fee Act of 1992 in the Rose Garden of the White
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House amid great fanfare and celebration. If CDER and CBERs detailed action plans could be administered properly, the new law would revolutionize the American drug review process. It would push the industry, and the quality of American health care, ahead of our European counterparts. Drug applications would be reviewed immediately upon completion and filing. Review time would be cut in half. An efficient new system would restore resources and accountability to FDA. Pharmaceutical manufacturers were not buying approvals. The insular FDA Center review structure would not allow that to happen. They were, however, dedicating large sums of money in fees for the opportunity to participate in a more interactive process potentially marketing their new drugs years in advance of the prior system. Patients would no longer be required to wait additional years to gain access to life-saving new therapies. FDA would quantify its progress through written reports to congressional oversight authorities on an annual basis. If the experiment didnt work, the parities would pull the plug after the initial 5 year term. The authorization bill creating the user fee program still required separate appropriations legislation to allow the government to fund FDA and collect the private funds. On July 2, 1993, the President signed a supplemental appropriation bill allowing FDA to collect user fees due from October 1, 1992, through September 31, 1993, the government fiscal year (FY). 1.2. Type of User Fees In order for these fees not to be viewed as taxes (and thereby incur the jurisdiction of the congressional taxing committees which did not support the concept of dedicated user fees), the new law was intended to divide the fee burden across existing manufacturers. Segments were created which relied directly on the payment for real FDA services, including (a) the review of drug/biologic applications (application fee), (b) insuring safe manufacturing processes (establishment fees), and (c) monitoring adverse reports, recalls, labeling, etc. (product fees). These three segments insured that a company with a lot of product applications but few products on the market
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currently or with no existing manufacturing facility would not bear the entire burden of funding FDA review operations. Likewise, if a company marketed many products or maintained numerous facilities, it could afford to sustain FDA CDER and CBER operations more easily than a new company with few products. Therefore, the fees were divided into three segments, as summarized below. 1.2.1. Application Fees Who Pays? Fees are assessed for the submission of certain human drug or biological applications. Human drug applications include: new drug applications (NDAs), Pre-Licensing Applications and Establishment Licensing Applications for biologics which have been consolidated into Biological Licensing Applications (BLAs), and initial certification of antibiotic drugs (which became NDAs in the FDA Modernization Act in 1997). Also included are product efficacy and manufacturing supplements. Expressly excluded from application fees, and also from FDA performance commitments, were (a) over-the-counter drugs, which commonly do not require advance FDA approval (except for Rx-to-OTC switches, which do commonly contain clinical information and are included), (b) generic drug applications (ANDAs), (c) animal drug applications (NADAs), (d) blood products, (e) allergenic extracts, (f) in vitro diagnostics, and (g) large-volume parenterals. Fee Schedule One third of the total annual revenue was required to come from each fee. For the term covered by PDUFA I, these fees, which were calculated to meet the total designated income required to hire 600 additional reviewers based on the number of applications actually filed, as well as support staff and computer back-up, included $100,000 per application (FY 1993), $162,000 (FY 1994), $208,000 (FY 1995), $204,000 (FY 1996), and $223,000 (FY 1997). For applications not requiring review of clinical data, fees were reduced by one half.
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Payment Terms One half of the fee was due on submission. One half of the amount submitted was returned if the application was not accepted for filing by FDA. The remaining payment was due within 30 days of when FDA sent its action letter, or when the applicant withdrew its application. 1.2.2. Drug Establishment Fees
Who Pays? A Rx drug user fee was due from each person (corporation) that owned an establishment in which at least one Rx drug (or biologic) was manufactured during the relevant fiscal year. If the drugs made in the establishment are all subject to generic competition, no fee would accrue. So that the user fee would not be deemed a tax, the payor had to have at least one application pending for FDA review after September 1, 1992. FDA later interpreted this requirement to mean that if the other establishment fee criteria were met, an original application or supplement (with or without clinical data) that was pending after that date would trigger establishment fees for all qualifying establishments. Contract manufacturers that were not registrants on a FDA application were exempt from this fee. Prescription Drug Establishment A separate fee was due on each establishment maintained by the applicant. Both foreign and domestic establishments were subject to a fee if the products they made were marketed in the United States (1). One or more buildings located within 5 miles of each other were classified as one establishment. The facility had to make one or more Rx drugs manufactured in finished dosage form, interpreted by FDA to mean in a form approved for administration to a patient without further manufacturing (2). Finally, it had to be under the management of the applicant listed on the NDA or BLA. FDA later interpreted this to mean that the applicant need not be the holder of the approved NDA or BLA for the product manufactured at the establishment.
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Fee Schedule Payment was due annually on each Rx drug establishment, as billed by FDA based on its establishment registration list, as adjusted at the end of the previous year based on the fees needed to reach the total income amount required by this segment of the user fee. Those amounts were $60,000 (FY 1993), $88,000 (FY 1994), $129,000 (FY 1995), $135,300 (FY 1996), and $138,000 (FY 1997). Payment Terms The establishment fee is due on or before January 31 of each calendar year. FDA routinely sends out an invoice based on establishments contained in its establishment registration list. Many of those establishments listed and billed may not conform to the requirements of PDUFA. The initial FDA mailings were overly broad. Therefore, manufacturers should have notified FDA regarding incorrect or unauthorized billing. 1.2.3. Drug Product Fees A separate annual fee was assessed to each manufacturer based on the number of Rx drug products listed in FDAs product registry. Who Pays? The fee is assessed to each person named as an applicant on a human drug application for each Rx drug (or biologic) listed on FDAs product registration list. The applicant is required to have at least one application or supplement pending agency review in the year the product fee was assessed (beginning after Sept. 1, 1992). A listed product is exempt from the fee once it has generic competition (3). Innovator antibiotic drug products (approved under x507) are subject to product fees. Generic antibiotic drug products (those that are not the first approval of a particular antibiotic drug) are not subject to product fees (4).
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Fee Schedule The fee for each listed drug included: $6,000 (FY 1993); $9,400 (FY 1994); $12,200 (FY 1995); $12,600 (FY 1996); $14,000 (FY 1997). Payment Terms Product fees were due at the time of the first product listing in each calendar year. The product must be listed as required by x510 to be subject to the product fee. FDA considers a product to be listed on the date of receipt of the initial submission of information, whether or not the agency finds that the information submitted was complete or requests additional information (5). A product is considered delisted, and no longer assessed a fee, on the date of the agencys receipt of the submission deleting the product from the Drug Listing. A product is subject to the fee if it is listed under x510 whether or not it is actually marketed or even if it is only marketed abroad. If a product is transferred from one NDA/BLA holder to another during a fiscal year, the first holder will be assessed the product fee in that fiscal year.
1.3. Performance Goals In negotiating the user fee program, FDA was determined to informally offer nonbinding goals. It refused to include inflexible standards in the language of the statute. In a compromise, industry acquiesced to a side letter sent to the Chairman and the Ranking Member of the House Committee on Energy and Commerce, Rep. John Dingell (D-MI) and Rep. Norman Lent (R-NY). These goals provided the expectations of regulated industry and the Congress concerning review times that would deem the program successful and allow its reauthorization for successive 5 year terms. PhRMA and BIO reportedly believed that if the resources of its member companies failed to shorten review times in accordance with the written goals included in the letter, it could successfully persuade the Congress to shut down the program.
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The letter to the Congress stated the following: 1. The additional user fee revenues would be dedicated to expediting the drug review and approval process. Priority NDAs and BLAs that were complete would be reviewed and acted on (through the issuance of an action letter) within 6 months of submission. Standard NDAs and BLAs that were complete would be reviewed and acted on within 12 months of submission. Priority supplements and amendments (or those not requiring review of clinical data) would be reviewed and acted on within 6 months of submission. Standard supplements and amendments would be reviewed and acted on within 6 months of submission. Applications resubmitted following the receipt of a nonapproval letter would be acted on within 6 months of submission. Application backlogs were to be eliminated within 18 months to 2 years. The goals were to be achieved based on a staggered schedule with 55% compliance with applications received in 1994 moving to 90% compliance in 1997.
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1.4. Small Business Exception The law allowed a company to pay one half of the prescribed application fee, not payable until one year following the submission (6), if it maintained fewer than 500 employees (including affiliates) and had no Rx or biologic drug product on the market (7). An affiliate was defined as one business with direct or indirect control of another, one business with the power to control another, or a third party that controls or has the power to control both businesses (8). For these qualifying small businesses, FDA sends an invoice one year following submission for the first installment of the fee, whether or not an action letter was issued. The second installment is due at the
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same time if an action letter was already issued. The number of an applicants employees is calculated using the procedures of the Small Business Administration contained in 13 C.F.R. Part 121. The suggested procedure to request the exemption is to submit an application to FDAs Office of the Ombudsman. The written request must contain the details of the applicant and fee for which a waiver or reduction is requested. It must also contain information and analysis showing that the statutory criteria for the waiver or reduction have been met (9). The request for the small business exemption should be submitted approximately 90 days before the application is submitted. It must also contain a statement from a responsible officer of the company that it has fewer than 500 employees, has no Rx drugs on the market and does not intend to introduce any within the next 12 months, and expects to submit an application within 90 days (10). The Office of Ombudsman as waiver officer will review the request, review product listings, and refer the small business criteria consideration to the SBA. A written acknowledgement of the decision will be made. If the request for exemption is denied, an approval process is available as summarized in FDAs draft interim guidance. 1.5. Fee Waiver or Reduction A fee may be waived or reduced if (a) FDA did not spend substantial time or resources in reviewing the application before it was withdrawn, (b) it is necessary to protect the public health, (c) the fee would present a significant barrier to innovation, (d) the fee would exceed the cost incurred in reviewing the application, (e) a competing copy of the drug is not subject to the fee, or (f) the fee was paid previously and the applicant is resubmitting the application (11). These provisions allow FDA to consider the limited resources of the entity when evaluating requests for a fee waiver or reduction. It requests a range of information to evaluate whether user fees present a barrier to an entitys ability to develop or market specific products or otherwise continue to pursue innovative technology. The criteria used by FDA include the following:
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1.5.1. Protect Public Health; Significant Barrier to Innovation FDA believes that the annual establishment fee is the greatest barrier under this category. Therefore, most of the fee waivers or reductions granted for public health or innovation reasons relate to small entities where annual establishment fees would be disproportionate in relation to revenues. FDA requests a certified statement from the entity and its affiliates concerning annual revenues both domestic and foreign. Commercial and financial information is not releasable to the public under the Freedom of Information Act (12). FDA evaluates the annual cost of user fees v. the entitys gross annual revenues, the resources of the entitys parent and other major funding sources. Lack of profitability is not considered evidence of limited resources. 1.5.2. Fees Paid Would Exceed Cost of FDA Review In order for a government assessment to constitute a true fee for the use of services and not a tax, the law insures that the cost of those services approximate the level of the fee. Therefore, FDA may waive all or a portion of the user fee amount if the fee exceeds the anticipated cost of rendering application review and related services (13). FDA was attempting to quantify the cost of the major elements associated with its review of common applications and supplements (14). Few if any fee reductions have been based on this provision, in part because FDA interpreted the provision to determine not just the agency cost of reviewing the one application for which the fee was assessed, but also the cost of reviewing all active applications of that person, including INDs, NDAs, BLAs, supplements, and amendments (15). The agency made it clear, however, that an applicant can apply for such a fee reduction if its application was not accepted for filing and the fee was paid (16). 1.5.3. Reduction because of Paper NDA for Same Product A fee waiver or reduction request can be made by an NDA sponsor who submitted an application under x505(b)(1)
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(full-NDA) if assessing such fee would be inequitable because an application or supplement for a product containing the same active ingredient was filed by another person under x505(b)(2) (paper NDA) of the Act (17). 1.6. Increases and Adjustments The law provides an annual total amount of user fees that are established each fiscal year by congressional appropriation committees. FDA then sets the level of its specific application, establishment, and product fees in November for the next fiscal year to raise the annual user fee level appropriated by the Congress. FDAs scheduled fee rates are announced by a notice in the Federal Register. The application fee rates were set by statute, but are to be adjusted annually for cumulative inflation. Total application fee revenues are structured to increase or decrease each year as the number of fee-paying applications to FDA increases or decreases. Each year, FDA is required to set establishment fees and product fees so that the estimated total fee revenue from each of these two categories will equal the total revenue FDA expects to collect from application fees that year. This procedure continues the arrangement under which one third of the total user fee revenue is projected to come from each of the three types of fees. 1.7. Appropriated Fee Amounts Each year that user fees are authorized, they must be contained in the annual appropriations legislation for FDA (appropriated by the Agriculture, Rural Development and Related Agencies Subcommittees of Appropriations). In PDUFA I (for the fiscal years October 1, 1993, through September 30, 1997), the appropriated amounts for total Rx drug user fees, as adjusted for the number of applications actually filed, were as follows: $36 million (FY 1993), $56,284,200 (FY 1994), $77,415,000 (FY 195), $79,981,200 (FY 1996), and $84 million (FY 1997).
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1.8. Effect of Failure to Pay Fees Under the initial user fee legislation, unless fees were paid timely when assessed, applications would not be accepted for filing or review would be discontinued. 1.9. Annual Reports Two annual reports were required to be prepared by FDA and submitted to the House Energy and Commerce Committee and to the Senate Labor and Human Resources Committee. The first report would quantify FDAs progress in achieving its performance goals and would be filed within 60 days following the end of the first fiscal year (by November 29, 1993). This became known as the Performance Report and has been filed annually since. A second report was required to review implementation of FDAs new authorities under the Act and how it used fees collected. This became known as the Financial Report and has been filed annually since. This report was due within 120 days after the end of the fiscal year (by March 29, 1994). Annual FDA PDUFA reports are available at www.fda.gov/cder/pdufa/mainpduf.htm. 1.10. Five-Year Sunset The Act was terminated after 5 years, effective on September 30, 1997. The purpose of this sunset was to provide an opportunity for Congress and industry to meet with FDA to assess the program and FDAs progress in expediting application review. Since FDA hired more than 600 FTEs, the agency has enormous pressure to meet its obligations or risk losing significant funding, which sustained that increased workforce. If the program was not reauthorized at the end of that term, FDA would likely be forced to fire its new reviewer workforce. Since enactment of this FDA legislation was considered mandatory every 5 years, its reenactment for two successive 5 year periods has been used as a vehicle to pass other FDA and health-related reforms. 1.11. Animal Drug Study Finally, since manufacturers of animal drugs were not invited to participate in the PDUFA program, the legislative drafters
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agreed, at the request of industry, to require FDA to prepare a study evaluating whether to impose user fees on new animal drug applications to improve existing review processes. The report was due to Congress by January 4, 1994.
2. SUMMARY OF FDA MODERNIZATION ACT OF 1997 (PDUFA II) (OCTOBER 1, 1997 TO SEPTEMBER 30, 2002) 2.1. Modifications of Prior Law Based on FDAs significant progress to reform its review of Rx drug and biologics applications, Congress reauthorized PDUFA as part of broader FDA Reform Act legislation (FDAMA). This new Title 1 of FDAMA (called PDUFA II) amended PDUFA I and extended it through September 30, 2002. In July 1998, FDA released a Five-Year Plan for PDUFA II that presented the major assumptions FDA was making and how it intended to use its additional resources in order to achieve the new goals associated with the amended Act. 2.2. New Fee Amounts 1. Application Fees: $256,846 (applications including data), $128,423 (applications without data and supplements with data) (FY 1998); $272,282 (applications including data), $136,141 (applications without data and supplements with data) (FY 1999); $285,740 (applications including data), $142,870 (applications without data and supplements with data) (FY 2000); $309,647 (applications including data), $154,823 (applications without data and supplements with data) (FY 2001); $313,320 (applications including data), $156,600 (applications without data and supplements with data) (FY 2002). 2. Establishment Fees: $141,966 (FY 1998), $128,435 (FY 1999), $141,971 (FY 2000), $145,989 (FY 2001), $140,199 (FY 2002).
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3. Product Fees: $18,591 (FY 1998), $18,364 (FY 1999), $19,959 (FY 2000), $21,892 (FY 2001), $21,630 (FY 2002). 2.3. Performance Goals As part of the consideration of PDUFA II, FDA again agreed to a series of performance goals against which its performance would be measured when reauthorization of a successive 5 year term was considered in 2002. Those goals for CDER and CBER review included:
Original NDAs, BLAs, and efficacy supplements FY 1998 FY 1999 FY 2000 FY 2001 FY 2002
Standard application 90% in 12 months 30% 90% 50% 90% 70% 90% in in in in in in 10 12 10 12 10 12 months months months months months months
Priority application 90% in 6 months 90% in 6 months 90% in 6 months 90% in 6 months 90% in 6 months
90% in 10 months
Ninety percent of manufacturing supplements requiring approval were to be reviewed in 6 months, with a sliding scale to be reviewed in 4 months (30% in FY 1999, 50% in FY 2000, 40% in FY 2001, and 90% in FY 2002). Resubmission of original NDAs/BLAs were to be considered in 6 months, with a sliding scale to be considered in 4 months and then 2 months. Other performance goals unrelated to application reviews were built into the PDUFA II regime. FDA was required to monitor responses to requests for meetings (70% of requests were to be responded to within 14 days moving to 90% by 2001). Type A meetings were to occur within 30 calendar days of the agency receiving the meeting request, Type B meetings within 60 calendar days, and Type C meetings within 75 calendar days. FDA meeting minutes were to be available to the sponsor within 30 calendar days after the meeting. They would clearly
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outline the important agreements, disagreements, issues for further discussion, and action items from the meeting in bulleted form, and need not be in great detail (18). Procedures for clinical holds were also carefully delineated. FDA Centers would respond to a sponsors complete response to a clinical hold within 30 days of the agencys receipt of a sponsors response. Ninety percent of such responses must be timely after FY 1999. Procedures for major dispute resolution were also quantified. By 2001, 90% of procedural and scientific matters would be responded to within 30 days, which involved drug reviews that could not be resolved at the divisional level and for which a formal dispute resolution petition was filed. A series of conditions was provided, which included (a) disputes should first be worked through the review chain from the reviewer to the Division Director, (b) FDA-timed responses to grant or deny the appeal could be oral (followed by written confirmation within 14 days) or written, and (c) reasons for a denial must be provided. Many of these conditions conform to FDA guidance for formal dispute resolution. Sponsors frequently consult review staff seeking comments on protocol design. The PDUFA II performance standards contain a 45-day time frame and procedural outline for this feedback process. Miscellaneous issues also include using user fee resources to update FDAs information management infrastructure to allow for paperless INDs and human drug applications, use of complete response letters in lieu of action letters, separate information request letters from each discipline reviewing an application, and a definition of terms used in this document.
3. SUMMARY OF PRESCRIPTION DRUG USER FEE AMENDMENTS OF 2002 (PDUFA III) (OCTOBER 1, 2002SEPTEMBER 30, 2007) 3.1. Modifications of Prior Law In 2002, the Prescription Drug User Fee Amendments of 2002 were included as Title 5 of the Public Health Security and
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Bioterrorism Preparedness and Response Act of 2002. Rx drug user fees were reauthorized for another 5 years until September 30, 2007. The level of fees increased to reflect a decline in the number of applications filed with the agency. In addition, a detailed letter dated June 4, 2002, was prepared for the regulated industry and the Congress under the signature of HHS Secretary Thompson (19). The letter transmitted detailed new performance goals and procedures prepared by the agency (20). 3.2. New Fee Amounts 1. Application fees: $533,400 (applications including data), $266,700 (applications without data and supplements with data)(FY 2000) (FY 2001) (FY 2003) 2. Establishment fees: $209,900 (FY 2003) 3. Product fees: $32,400 (FY 2003) 3.3. Performance Goals Application review times maintained the final schedule proposed as part of PDUFA II: original standard applications and efficacy supplements with data90% within 10 months; original priority applications and efficacy supplements with data90% within 6 months; class 1 resubmissions90% within 2 months; class 2 resubmissions90% within 6 months; and resubmitted efficacy supplements (class 1) reduced from 6 to 2 months for review. Meeting management goals were refined in the PDUFA III document. CDER and CBER committed to notifying parties requesting meetings, teleconferences, or videoconferences within 14 calendar days of receiving an industry request for a formal meeting with the date, time, place, and expected FDA attendees. Meetings continued to be classified as Type A, B, or C, and detailed procedures for requesting the meetings were provided. Procedures similar to PDUFA II were provided for clinical hold responses, major dispute resolution, and protocol design review. FDA also agreed to conduct two pilot programs to evaluate the development of a continuous marketing application.
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3.4. Impact of User Fees on Rx Drug Approvals There is no question that the enactment and implementation of PDUFA led to the dramatic restructuring of the agency and its industry relationship. Reviewers and their superiors within the FDA product centers were accountable for the pace of their work for the first time. Review time decreased from a median time in excess of 2 years or more to within 1 year for standard applications and 6 months for priority applications. Hundreds of new employees were retained to review data and to interact with the regulatory officials of constituent product sponsors. FDA has consistently reported to the Congress in its annual Performance and Financial Reports that it met and exceeded all its performance goals under PDUFA I, II, and III (for drugs but not biologics). It has noted a trend, however, of fewer original applications and efficacy supplements that pay the largest component of application fees under the Act. The number of original new product applications submitted and filed each year increased steadily in the early years, from 88 in FY 1993 to 133 in FY 1997. From FY 1997 to FY 2000, the growth reportedly leveled off, and in FYs 2001 and 2002 application submissions and filings dropped substantially (21). Twenty-five percent fewer applications were filed with FDA in 2001 than in 2000. The number of priority applications was down more than 60% in 2001 from the previous year and was less than half the level of any year since FY 1997 (22). Since priority applications often represent significant therapeutic gains, the Congress commissioned a report by the General Accounting Office (GAO) to evaluate the cause of this decline. At the same time, FDA continued to report increased productivity. In recent congressional testimony, FDA Deputy Commissioner Lester Crawford reported approval of 66 new drugs in 2001, 24 of which were new molecular entities (23). Ten of the 66 new drugs (7 of the new molecular entities) received priority review and were reportedly reviewed and approved in the median time of 6 months. CBER reviewed a total of 16 complex BLAs in the median time of 13.8 months and approved them in the median time of 20.3 months. Two priority BLAs were reviewed in the median time
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of 11.5 months and approved in the median time of 13.2 months. Finally, FDA reported that in recent years 50% of all new drugs worldwide were launched in the United States, and American patients have access to 78% of the worlds new drugs within the first few years of their introduction (24). The agency advocated a need to use some PDUFA resources for rigorous safety monitoring of newly approved drugs in the first few years after a product is on the market to quickly detect unanticipated problems.
4. EVALUATION OF THE PROGRAM BY THE GENERAL ACCOUNTING OFFICE In September 2002, the GAO issued a report entitled Effect of User Fees on Drug Approval Times, Withdrawals, and other Agency Activities (25). The report concluded that PDUFA has been successful in providing FDA with the funding necessary to hire additional drug reviewers, thereby making new drugs available in the United States more quickly. But while the median approval time for NDAs for standard drugs dropped from 27 months to 14 months from 1993 to 2001, the new priority time for priority drugs remained stable at 6 months after 1997. The median approval times for standard new molecular entities (drugs containing active ingredients that have never been marketed in the United States in any form) increased from 1998 from about 13 months to 20 months. In contrast, median approval times for BLAs have fluctuated since 1993, ranging from a low of 12 months in 1997 to a high of about 32 months in 1995. In 2001 that time had slipped to about 22 months. FDA reportedly had to increase the amount of its appropriated funds, outside of user fees, to drug and biologics reviews to compensate for the minimum allocation of funds required by PDUFA. FDA also reportedly used user fee proceeds to fund employee pay raises that were generally not covered by annual appropriations. PDUFA II increased reviewer workload by shortening review times and establishing
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new performance goals to reduce overall drug development times. This resulted in higher attrition rates for drug reviewers than comparable occupations in the federal workforce. Finally, GAO reported that a higher percentage of drug applications had been withdrawn from the market for safetyrelated reasons during the most recent term of PDUFA (5.3% from 1997 to 2000) compared to 1.6% in the period immediately after PDUFA implementation (19931996). Using 8 year periods before and after enactment of PDUFA, the rate of postapproval drug withdrawals increased from 3.1 to 3.5%. Some drugs were withdrawn because doctors and patients did not use them according to approved labeling, while others were found to have rare side effects that were not detected in clinical trials. GAO recommended that FDA strengthen its postmarket surveillance activities. It plans to spend approximately $71 million in user fees over the next 5 years to better monitor safety and track adverse events. Under PDUFA III, FDA was given the authority for the first time to utilize user fees for these postmarket surveillance and compliance activities. The industry had aggressively resisted use of its own proceeds to pay for agency compliance activities.
5. STRATEGIES TO USE PDUFA TO EXPEDITE REVIEW AND APPROVAL 5.1. Evaluate Whether the Application Will Be Subject to Rx Drug User Fees These fees, and the performance standards associated with them, generally apply only to original NDAs and BLAs and supplements to those filings. Remember, these are user fees and not taxes for government services. Therefore, FDA has to justify its imposition by utilizing the services of data reviewers hired with the fee proceeds. 5.2. Attempt to Negotiate the Lowest Possible Fee User fees are substantial. They include a $533,400 application fee in FY 2003, a $209,900 fee per manufacturing establishment,
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and a $32,400 fee per listed product. One half of the application fee is due on submission of the application, and one half is due within 30 days of the date of the action letter (which has become a complete response letter). If the applicant is a small business (fewer than 500 employees with no Rx or biologic product on the market), only half of the fee is owed, and not until one year following the date of submission (and only if the application is accepted for filing). A major manufacturer should consider allowing a smaller entity from which it is licensing the product to become the sponsor of the application. Corporate structuring might be possible to save a significant portion of this fee. An application for fee waiver or reduction might be available under the criteria included in Sec.1.5. Specifically, if the fee precludes the application because of an orphan or small market or fewer agency resources are required for a narrow review, the fee might be reduced. In the current budget climate, and with fewer applications, FDA may not give in easily in this regard, but the law might be on your side. Also remember that once a drug has generic competition, or even if a paper NDA is on the horizon, the fee might not be due. Likewise, the definition of an establishment might be reduced for purposes of the fee. Buildings making multiple drugs might count as a single establishment if they are located within a 5-mile radius. The plant must make finished dosage forms to count. Contract manufacturers or makers of ingredients do not count. Foreign plants only count if their product is imported into the United States. Finally, product fees can be reduced if a manufacturer limited or aggregated the product listing of multiple dosages or dosage forms of its products. These might be included in one product listing. Antibiotics do not count if they were not approved by NDAs. Once a generic competitor is approved, the innovator product no longer has the fee assessed. Finally, since a drug-maker must use the product review services of the agency to owe a fee (remember the law created a user fee and not a product tax), no fee is owed unless the company has at least one application or supplement pending for agency review in the year of the fee assessment.
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5.3. Create a Priority Application Performance goals are not legally binding on FDA, but the agency is under great pressure from industry and the Congress to review most priority applications within 6 months of filing. The review divisions have discretion about how they classify new applications. Seek priority designation wherever possible (separate and apart from fast-track review for drugs treating serious or life-threatening illness). This discussion should occur in pre-NDA/BLA meetings with the review staff. If the drug is a new chemical compound, meets an unmet medical need, or treats a debilitating disease, the sponsor should create an organized presentation to the agency to request this designation. 5.4. Refer to Agency Performance Goals During the Product Review The sponsor must create a complete application as quickly in the process as possible so it is accepted for filing and the FDA clock begins to run. Experienced regulatory lawyers or professionals maintain constant contact and interaction with product reviewers so that reviews progress efficiently. FDA has preserved considerable flexibility to meet its statistical user fee goals while stopping its review clock with informational requests to the sponsor. In order to obtain an approvable letter and avoid a delaying complete response letter that requests additional information, this interaction must be maintained. The company must be responsive and anticipate the need for additional data, analyses, or clarification. The quicker and more lucidly this information is provided, the better the chance of making it under the review goal. FDA must account for meeting its PDUFA goals in annual performance reports to the Congress. Once the FDA clock has shifted back to the sponsor and the performance goal has been met in the firstreview cycle, many of the benefits of PDUFA have been lost to the product sponsor. Multiple review cycles delay product approval significantly. Prepare quality applications, anticipate questions or information requests, and do not file the application until all your ducks are in a row.
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5.5. Employ Formal Dispute Resolution or Congressional Oversight in Appropriate Circumstances PDUFA is the product of a delicate compromise between the Congress on behalf of industry and the agency. FDA has become much more interactive in order to relieve last-minute pressures to meet tighter PDUFA performance goals. If scientific differences arise, use the formal dispute resolution guidance that FDA has provided. If policy differences arise, seek congressional oversight and support as appropriate.
REFERENCES
1. If an Rx drug, as defined in PDUFA, was made in a foreign plant for foreign marketing under an approved NDA, the foreign establishment was subject to establishment fees if it was owned by an NDA/BLA holder that had a pending NDA/BLA or supplement after Sept. 1, 1992. Thus, for example, if a product is sterilized by filtration and placed into vials by a contract manufacturer that has no pending NDAs, BLAs, or supplements after September 1, 1992, then no establishment fee was due for either the contract manufacturer or the facility that performed the rest of the manufacturing steps. Attachment D, Application, Product, and Establishment Fees, Common Issues and their Resolution, revised as of Dec. 16, 1994. FDA has interpreted the generic exemption narrowly. Therefore, me-too products that are the same as a listed Rx product but were approved under the NDA provision of x505(b)(1) do not qualify for the exclusion. If a listed product has a competitor approved under x505(b)(2)(paper NDA) or ( j)(ANDA), that drug is exempt. If the x505(b)(2) or ( j) applications have been approved and not withdrawn, the first approved product is excluded from fees even if the generic product is not presently marketed. Tentative approvals of a 505( j) application are not considered approvals. Finally, according to FDA, products listed that were approved by a paper NDA before 1984 when x505(b)(2) was added to the FDCA are not eligible for exclusion from product fees.
2.
3.
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4.
FDAs interpretation of PDUFA did not allow innovator antibiotic drug products to become exempt from the product fee even after subsequent generic antibiotic drug products were approved, when they were approved under x507. However, since 1997 generic antibiotics have been approved under x505( j), and should therefore trigger the exemption of the innovator product. Likewise, bulk antibiotic drugs should not be subject to product fees because they are not products in finished dosage form. Id. The date of submission, according to FDA, is the date the application is received by FDA and stamped as received in the CDER or CBER central document control center. Attachment G, Draft Interim Guidance Document for Waivers of and Reductions in User Fees, July 16, 1993, p. 11. This is distinguished from filing, which occurs after FDA determines that the application is sufficiently complete to permit a substantive review. See 21 C.F.R. x314.101. 21 U.S.C. x379h(b)(2). The Act did not provide a small business exception for supplement applications. Id. Id. at 2432. This draft guidance document is available at www.fda.gov/cder/pudfa/mainpduf.htm. Id. at 28. x379h(d). See 5 U.S.C. x552, and FDA implementing regulations at 21 C.F.R. Part 20. Supra note 6 at 15. x379(h)(d). Supra note 6 at 1819. Id. Under x379h(a)(1)(D), FDA refunds 50% of the application fee paid for any application and supplement refused for filing. That amount actually represents only 25% of the total application fee since only 50% of the total fee is due upon submission. Id. at 19.
5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
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17. 18. 19. 20. 21. 22. 23.
x379h(d)(4). PDUFA Reauthorization Performance Goals and Procedures; III. C., www.fda.gov/cder/news/pdufagoals.htm. See www.fda.gov/oc/pdufa/transltr.html. See www.fda.gov/oc/pdufa/pdufaIIIgoals.html. FY 2001 and FY 2002 Performance Reports to Congress, p. 4. Id. Statement of FDA Deputy Commissioner before the House Appropriations Subcommittee on Agriculture Rural Development, FDA and Related Agencies, March 21, 2002, p. 10, www.fda.gov/ola/2002/fy2003.html. Id. at 20. GAO Report No. 02-958, Report to the Chairman of the Senate Committee on Health, Education, Labor and Pensions, FDA Effect of User Fees on Drug Approval Times, Withdrawals, and Other Agency Activities, September 2002.
24. 25.
10
Clinical Research Requirements for New Drug Applications
GARY YINGLING and ANN BEGLEY Kirkpatrick and Lockhart LLP Washington, D.C., U.S.A.
1. INTRODUCTION The U.S. Food and Drug Administration (FDA) has as its legislative mandate the regulation of all drugs manufactured or marketed in the United States. When the agency uses the term drug, it includes within that definition biologics. The regulation of drugs is basically separated into two categories: those for which preapproval is not required, which includes those that are considered generally recognized as safe and effective (GRASE), and those that require preapproval in the form of the submission of a New Drug Application (NDA) or an
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Abbreviated New Drug Application (ANDA) (1). For those that fall into the category of being under review or GRASE, including all those subject to the over-the-counter (OTC) Monograph system, there is no preapproval requirement and, therefore, no submission of information required for the product to enter the marketplace. For those drugs that require the submission of a drug application, it is highly likely that the application will be dependent on the submission of clinical data or bioequivalence studies to demonstrate that the product is safe and effective. Just as the submission of the application is subject to various statutory and regulatory requirements, the clinical or bioequivalence testing necessary for obtaining approval of an NDA or ANDA is covered by a number of statutory and regulatory provisions. To fully appreciate the clinical requirements, one needs to recognize that, for a drug requiring preapproval, it is a violation of the Federal Food, Drug, and Cosmetic Act (FFDCA) to ship an unapproved new drug in interstate commerce, unless it is the subject of an Investigational New Drug (IND) application (2). The statute states that, in order to obtain approval, the sponsor or the applicant must submit a drug application under xx 505(b)(1), 505(b)(2), or 505(j) of the FFDCA. When one considers the filing of a 505(b)(1) application, one is looking at submitting an application for a new chemical entity, a novel dosage form, or a very significant labeling change that will require preclinical animal data and clinical studies. The clinical studies will probably be organized into three phases: phase 1 being basic toxicology studies, phase 2 being dose-range studies, and phase 3 being the pivotal clinical study or studies that allow that agency to approve the application. A 505(b)(2) application will, in all likelihood, require less clinical data and could be approved based on a single phase 3 study or even a bioequivalence study. This is because the 505(b)(2) application relies on the fact that the active pharmaceutical ingredient that is the subject of an approved drug application is well known to the agency so that it is not necessary to obtain the detailed data (e.g., animal studies, phase 1 and phase 2 studies) that would be required for a 505(b)(1) application.
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If the application is a 505(j), or what is called an Abbreviated New Drug Application (ANDA), the required data will consist of a bioequivalence study to demonstrate that the applicants drug is equivalent to the product already marketed. Under the ANDA regulations, it is possible for the bioequivalence study to be a single-dose, crossover, limited patient study looking at blood levels or a 500- or 600-patient clinical study comparing the referenced listed NDA to the proposed abbreviated application. Whatever the form of the application, in all likelihood there will be the necessity to do clinical research, and FDA has set forth detailed regulations and guidances controlling clinical and bioequivalence studies that support new drug applications.
2. SPONSORS The firm or organization that bears the responsibility for the clinical study is called the sponsor. The sponsor is the organization that will file the drug application, whether it is a complete 505(b)(1), a 505(b)(2), or an ANDA. As the sponsor, the organization will be charged with obtaining the data to submit in the NDA or ANDA for the purpose of gaining FDA approval. This undertaking becomes a multistep process, from deciding what drug the firm will file an application on, to gathering the supporting scientific data to submit to the agency for the purpose of obtaining approval. For a firm filing a 505(b)(1) application, usually for a new chemical entity, the initial question is what amount of basic research needs to be done before tests can be conducted in humans. This pre-submission data stage involves in vitro and animal testing and is normally characterized as pre-IND data. The sponsor does not need to notify FDA of its interest in working on the chemical entity and is under no obligation to update the agency on its development plan at the pre-IND stage. However, once a sponsor decides that it has obtained enough in vitro and animal data to believe there is benefit in conducting human testing, it becomes necessary for a firm to submit an IND application. The IND application is the submission that allows a firm to
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ship an investigational new drug for the purpose of conducting research. As noted earlier, it is illegal to ship a drug that has not been approved unless it is the subject of an IND application (3). The statute specifically provides that the Secretary will promulgate regulations to allow sponsors to conduct studies for the purpose of gathering data so that applications can be submitted for approval. FDAs Code of Federal Regulations (CFR) (4) sets forth the basic requirements for the submission of an IND application and the various requirements that arise from that submission. The sponsor will need to prepare an actual IND application, which will include the animal studies that have been conducted, any data of which the sponsor may be aware concerning studies outside of the United States, and the protocol (study plan) for the first studies which the sponsor intends to conduct. Under the current user fee program, which is designed to create a cooperative working relationship between the agency and the sponsor, often a sponsor will request, or the agency may seek, a pre-IND meeting to discuss the nonclinical data that have been collected to date, the ingredients being used in the proposed product, and the clinical testing, particularly the studies involved in phase 1 and phase 2 development. If the sponsor and the agency engage in a pre-IND meeting, it will be necessary for the sponsor to prepare a summary of the information that it would submit in the IND application. It is to the sponsors advantage to provide FDA with a very detailed summary, so that the agency does not require testing that may be unnecessary or fail to appreciate if there are data that will suggest an issue. If a pre-IND meeting is held, there is usually a fairly substantial level of agreement between the agency and the sponsor before the actual IND application is submitted. However, it is not necessary to request a pre-IND meeting, and it is not unusual for firms, particularly if they are seeking 505(b)(2) applications, not to request a pre-IND meeting. After receiving an IND application, the agency then has 30 days to review the IND application to determine whether there is enough preclinical data to assure that the product is safe enough to allow the conduct of human clinical studies.
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There is also a careful review of the clinical studies, whether it be one or more studies, to determine if the study design will result in data that will allow the drug development to move forward. If the proposed phase 1 study fails to provide enough data and information in its design to move to phase 2 studies, there is no benefit to subjecting human patients to the drug. Therefore, the agency will carefully look at the proposed protocol. If it is not satisfied with the study design, FDA may notify the sponsor of a clinical hold. A clinical hold means that the sponsor cannot go forward with the studies. Clinical holds seldom occur when there have been pre-IND meetings where the agency and sponsor have worked out the study design. Again, it behooves the sponsor to be as detailed as possible regarding the first studies so that the agency has a complete understanding of the pre-clinical data and proposed design of the studies. For those sponsors that find themselves in a clinical hold, the agency has created a fairly elaborate review process to assure that the agencys clinical hold decision can be reviewed and that the sponsor will have an adequate opportunity to explain why the proposed protocol is adequate. However, one needs to recognize that FDAs review process is inherently slow and that every effort should be made to avoid this detour by assuring that the protocol design is one that the agency will accept. After submitting the IND application, a sponsor must comply with a 30-day waiting period before it can initiate the study. If, at the end of the 30 days, the sponsor has not heard from the agency, in theory the sponsor may go forward with the clinical study. However, the sponsor should be very reluctant to go forward with a clinical study at the end of the 30 days if it has not heard from the agency. Under these circumstances, there is a possibility that the agency has some concern that it has not been able to articulate within the 30-day period, and that shortly after the 30-day period expires the agency will notify the sponsor that the study is on clinical hold. If the sponsor has already started the study, both the sponsor and the agency face major problems in that the agency is unhappy with the study design and the sponsor has already entered patients. This can be avoided by making contact with
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the agency shortly after the IND application is submitted to be absolutely sure the agency has received the IND application and that it is being reviewed. Then the sponsor should make contact again, as the 30-day period is winding down, to confirm that the agency will not have problems such that it will consider placing the study on a clinical hold. While sponsors often identify the clinical investigators at the time they are preparing the studies and will often have the major clinical investigator accompany them if they have a pre-IND meeting with the agency, it is not necessary to identify up front any or all of the investigators who will participate in the clinical studies. The sponsor does bear the responsibility for the eventual selection of the clinical investigators who will actually do the studies. It is unusual in todays marketplace for a sponsor to have a medical staff capable of doing the studies or that will even play a major role in overseeing the actual conduct of the study. However, it is not unusual for a sponsor to have numerous contacts in the clinical community and to have identified any number of individuals they believe are appropriate for the purpose of being clinical investigators in the study. In todays clinical research environment, sponsors typically have a small, specialized medical staff for the purpose of assisting in study design, reviewing study results, and playing an active role in planning. The actual protocol for the study will probably be prepared by a contract research organization (CRO) or a clinical investigator working with a CRO. There are a number of very large CROs as well as a number of mid-sized and small CRO firms that specialize in clinical studies, as well as highly specialized firms that conduct studies on particular organs or disease conditions or patient populations. Therefore, the sponsor often has many options from selecting either a single large CRO, which may have multiple sites at which a study can be done and can therefore increase potential enrollment, to selecting a small CRO for the purpose of going to particular parts of the country or identifying specialized practices. The sponsor can actually transfer its responsibilities for a study over to a CRO. FDA regulations (5) specifically provide for the authority of the sponsor to transfer responsibility. The transfer must be in writing, and it is to the sponsors
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advantage to delineate exactly what activities have been transferred. While the sponsor can transfer the activities, it is not able to transfer its responsibility for the clinical trials. Therefore, it needs to assure itself that the selected CRO understands the importance of having good investigators, of following the protocol, and of conducting the study in a manner that FDA will find satisfactory. The agency requires that the sponsor monitor the investigators to be sure that the investigators and their staff are conducting the study in accordance with the protocol and with the sponsors and the agencys expectations. Again, the sponsor can contract with a CRO or a third party for the purpose of monitoring, or it may have monitors of its own. The monitors role is very important in a clinical study, because it is the monitor who visits the study site to determine whether or not the clinical investigator fully understands the protocol and whether the investigator and the investigators staff are conducting the study in accordance with the sponsors and the agencys expectations. In the past it was not uncommon for the monitor to function mostly as a study promoter, making sure the investigator was actively involved in enrolling patients and in correcting record-keeping errors and oversights of the staff. While monitors today may fulfill some of those roles, FDAs heightened expectations for monitoring to assure quality of data have resulted in monitoring being a much more important activity. The monitor is the person who is able to identify investigator sites where patients are being entered who fail to meet the study criteria, to identify staff errors and/or malfeasance, and to correct staff and investigator misunderstandings with regard to the protocol and the way the study is being conducted. More and more, when it finds problems at a study site, the agency asks why monitoring did not identify and correct the problem or discontinue the investigation. As the agency becomes more resource conscious, it will turn increasingly to using its enforcement tools to ensure sponsor compliance with all of the requirements within the IND regulations. In addition to the monitoring activity required of the sponsor or CRO, there is an expectation that all of the information
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required to be reported in the Case Report Forms (CRF) or patient medical records (source documents) will be properly recorded (i.e., written down or entered in the computer system). Only information that is actually reported can be used by FDA in its evaluation of the clinical data. The popular phrase is, If it isnt written down, it didnt happen. The agency is extremely strict with reporting requirements. Efforts by investigators to explain a particular set of events or activities at a later date will be dismissed because there was a failure to record the information properly at the time it should have been recorded. As with all statements that appear to be absolutes, there is a certain level of flexibility in relationship to written records, as long as the reporting is done in the manner required and is corrected in the manner that is appropriate. For instance, a study nurse records the patients blood pressure as 120/80 in the patients chart and as 80/140 in the CRF records. Some days later, in reviewing the records, the study coordinator notes the error and, at that time, the incorrect record may be corrected if a single line is drawn through it, the correction is recorded, it is initialed, dated, and there is an explanation either on the CRF or on a separate memorandum that explains what has occurred and why the correction was made. While the agency will accept such corrections, there is an expectation that they will be minimal and that they will be properly recorded, dated, and signed. It is understood that neither the sponsor nor the CRO will be doing the actual writing in the patient records or CRF and that, in fact, most of the time the clinical investigator will not be making those recordings either. This task will often be done by staff. Therefore, monitoring mandates a review of the sites compliance with record-keeping and record-retention requirements. Review of the record is for the purpose of catching the type of error described above or to look for patterns or problems in a clinical study. The review may be done by the clinical investigator or staff, the CRO, or the sponsor. Today, with many records created and transferred electronically, it is possible for the sponsor or CRO staff to do an almost instantaneous review of records for completeness and to ensure that there are no apparent discrepancies. It is the agencys
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expectation that the records have been reviewed and monitored to assure that the required information is recorded. There is also a record-keeping requirement that the retainer of the records, whether the clinical investigator or the CRO or perhaps even the sponsor, will retain the records for a period of 2 years after the drug is approved or 2 years after the study is completed if there has been a decision that the drug will not be the subject of an application and FDA has been notified. FDA regulations outline record-retention time frames (6). The sponsor or CRO must be extremely vigilant in relationship to the record-keeping and record-retention requirements. In addition to the monitoring, the reporting requirements, and the record review, there is a need to keep track of the actual study drug. The sponsor provides the study drug for the purpose of the study. In addition to the drug itself, it will often be necessary to provide a placebo that is indistinguishable from the drug so that the study can be blinded. To ensure that the study is properly blinded, it must be coded, and coding may be the sponsors responsibility or that of the CRO. Once the drug is sent to the clinical investigator, the responsibility for keeping track of the drug falls to the investigator. That which is not dispensed at the end of the study should be sent back to the sponsor so that it can make records of the drug that was manufactured, dispensed, used, and returned. There is one quirk in the process: for those manufacturers involved in ANDAs, even if they are biostudies that are basically clinical studies in design and length, the retention samples cannot be sent back to the sponsor but must be retained by the clinical investigator, the CRO, or an independent third party (7). Failure of the retention samples to be in the possession of an independent third party can and has resulted in clinical studies being called into question by the agency.
3. CLINICAL INVESTIGATORS While sponsors are responsible for the development, monitoring, and submission of clinical studies in an NDA or ANDA, the clinical investigators are responsible for the actual conduct
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of the study. Prior to allowing the clinical investigator to participate in the clinical study, the sponsor or CRO must obtain a signed Form FDA 1572, in which the clinical investigator commits to performance of a number of study-related responsibilities. The clinical investigator is responsible for understanding and complying with the investigational plan, obtaining Institutional Review Board (IRB) approval before beginning the study, protecting the rights and welfare of the participating research subjects, and assuring that legally effective informed consent is obtained from each subject. In addition, prior to commencing the study, the clinical investigator must provide the sponsor with sufficient financial information to allow the sponsor to make complete and accurate certification or disclosure statements under 21 C.F.R. part 54 concerning potential financial conflicts of interest. The clinical investigator must also commit to update this financial information if relevant changes occur during the course of the study and one year following the completion of the study. The lead clinical investigator is usually referred to as the principal investigator (PI), and those clinical investigators who work under the PIs supervision, if any, are referred to as subinvestigators. PIs with significant research practices will likely have a clinical research team composed of a clinical research coordinator (CRC), who is generally responsible for managing the research team, one or more subinvestigators, and one or more study nurses to assist in the conduct of the research. While the PI can delegate appropriate research responsibilities to the team members, ultimately the PI is responsible for supervising all members of the research team and for assuring that they understand their obligations in conducting the research. For example, research nurses may be responsible for recruiting research subjects, obtaining informed consent, providing the study drug, and maintaining appropriate documentation, while subinvestigators may be responsible for conducting the physical exam necessary to determine the potential subjects eligibility for the study. However, it is the PI who commits to personally conducting or supervising the clinical study in signing a Form FDA-1572, and so it behooves the PI to maintain a level of involvement
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in the study that assures sufficient supervision of the team members. One traditionally thinks of informed consent in terms of the document, signed and dated by the participant, setting forth the purpose, benefits, risks, and other study information necessary to allow the participant to make an informed and voluntary decision to participate in the clinical study. In reality, informed consent is a process that applies to each communication with the participant, commencing with the subject recruitment material and the initial telephone screening of potential subjects, through the conclusion of the study. If new information that may affect a participants willingness to continue in the study arises during the conduct of the study, clinical investigators have a responsibility to inform the participant of the new information. As to the informed consent document itself, clinical investigators must assure that it complies not only with the content requirements set forth in 21 C.F.R. part 50, but also with applicable state law requirements. For example, California requires, in addition to the informed consent document, that clinical investigators provide all research participants with an Experimental Subjects Bill of Rights. The clinical investigator also has significant recordkeeping and reporting responsibilities. As briefly discussed above, clinical investigators are responsible for controlling distribution of the study drug through the maintenance of adequate records identifying dates, quantity, and use by the research subjects. The PI must create and maintain records to document receipt of the drug and will need to have appropriate storage facilities so the drug can be secured and not accidentally dispensed to a patient outside the study. During the study, the drug must be tracked so that records will accurately reflect how much of the drug was taken by the patient. Part of the study protocol may require questioning the subject about taking the drug. Any drug not taken by the patient should be returned to the PI and accounted for. At the conclusion of the investigators participation, any unused study drug must be returned to the sponsor or disposed of as directed by the sponsor.
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In addition to study drug accountability records, the clinical investigator must prepare and maintain adequate and accurate documentation reporting all observations and other data of significance for each research participant in the clinical study. Such documentation includes, but is not limited to, informed consent, CRFs, medical records, and laboratory results. The sponsor must collect CRFs at the conclusion of the study. However, the investigator must maintain other documentation for 2 years following the date of the applications approval or, if the application was not filed or there was no such approval, 2 years after the conclusion of the study and after FDA has been notified. The clinical investigator should submit progress reports to the sponsor as specified in the investigational plan. In addition, the clinical investigator must report such adverse experiences to the sponsor that may reasonably be regarded as caused by, or probably caused by, the study drug. At the conclusion of the study, the investigator must issue a report to the sponsor discussing the investigators participation in the study. Finally, the clinical investigator has reporting responsibilities in relationship to the Institutional Review Board (IRB, or Board). The investigator must promptly report all changes in the research activity and all unanticipated problems involving risk to human subjects or others. Thus, the clinical investigator must provide the IRB with adverse experience information that occurs at the clinical investigators site. The clinical investigator would also generally be expected to report to the IRB adverse experience information that occurs at other sites in a multi-site study. Changes in the study such as a change in protocol must be reported to, and approved by, the IRB before making the change unless the change is necessary to eliminate apparent immediate hazards to human subjects (8). The clinical investigator must also comply with other IRB-specific reporting requirements. These may include intermittent progress reports, continuing review reports, and study close-out reports. Failure to comply with IRB reporting requirements can result in termination or suspension of the IRB approval.
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4. INSTITUTIONAL REVIEW BOARD In the process of setting up the clinical study and arranging for manufacture of the drug, creation of the protocol, identification of the PI, and creation of the informed consent, it will be necessary for the sponsor, CRO, or PI to seek the services and oversight of an IRB. Under 21 CFR part 56 of the agencys regulations, five subparts set out the requirements for IRBs. In 21 CFR x 56.102 of the definitions section, the agency discusses what a clinical investigation is and defines an IRB. It notes that the primary purpose of such a review by a Board is to ensure the protection of the rights and welfare of the human subjects. The agency specifies the composition of the IRB membership under 21 CFR x 56.107 and states that each IRB shall have at least five members with various backgrounds to evaluate different aspects of the proposed study. The Board reviews the protocol for the clinical study and the informed consent to determine whether the protocol is appropriate as to gathering clinical data and whether subjects are properly informed of the risks they are being asked to undertake as part of the clinical investigation. In theory, the IRB has a direct working relationship with the PI, and in practice that is largely true. An often-overlooked fact is that the protocol and informed consent have been created by the sponsor or CRO who has been in contact with the IRB and therefore the relationship between the PI and the IRB occurs because of the work of the sponsor/CRO. While the agency recognizes the relationship between the IRB and the PI, it often ignores the IRBs relationship with the CRO/ sponsor. Usually, a good working relationship between all of the parties exists to ensure that any information the IRB needs to review will be received. In addition to approving the study initially and looking at the informed consent, all of the serious, unexpected adverse events that the clinical site identifies are supposed to be immediately reported to the IRB. Because the IRB has as its primary mandate the protection of the human subjects, it is necessary for the IRB to recognize when assumptions made in relationship to the safety of the study turn out not to be accurate and the risk-benefit ratio
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changes such that the informed consent is no longer valid. A case in point would be a clinical study that envisioned the likelihood of a serious adverse event as extremely rare but when the study is performed, the study has two patient adverse events, both of them life threatening. Suddenly the informed consent is no longer accurate and all of the study sites involved in the study need to be informed of the fact that the study needs to be immediately stopped until new information can be reviewed and evaluated to determine whether the clinical study can go forward. Clearly, the PI would be reporting the information to the IRB as required by the agencys regulation, but also to the sponsor, because the sponsor or CRO is equally concerned about the patients involved in the clinical study. Like the clinical site, the IRB has a record-keeping and record-reporting requirement. First of all, it must document that it has reviewed the protocol and informed consent. In the minutes of the IRB meeting, to the extent there are issues discussed, the minutes should reflect that discussion. The IRB is also required to review, at least yearly, any studies that are continuing to be sure that nothing has changed in the specified period of time that would impact continued approval. The frequency of this continuing review is based on the study risks. To make sure the IRB fully understands the status of the study, it needs a report from the clinical site. To the extent the clinical site does not provide that report, the IRB may be forced to withdraw its approval. If it withdraws its approval from the site, it must notify FDA so that the agency is aware of the fact that the IRB of record no longer approves the clinical site. To be sure that the IRB has proper procedures in place, FDA regulations require it to develop standard operating procedures, or SOPs. These SOPs will outline the IRB meeting procedures, preparation of the minutes, how the minutes will be developed, reviewed, and stored, the procedure for notifying sites if the IRB has questions, methods for reviewing adverse events, methods of seeking continuing review and research change information from the clinical investigational sites, procedures for doing the continuing reviews, and procedures for withdrawing approval of the IRB in relationship to a clinical investigational site.
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Because FDA has recognized the need for the IRB in its regulations, and to the extent that it has created the entity within the context of the regulations, it will inspect the IRB to look at its method of reviewing clinical studies to determine whether or not the Board is meeting the agencys expectations. Failure to allow the FDA to inspect or to follow FDAs regulations could result in an FDA refusal to accept the studies approved by that IRB in support of an application. As with a clinical site, this will be, for the most part, a record review looking at the IRBs meeting minutes, correspondence with clinical sites, and whether the IRB has taken appropriate action in response to problems or issues that have arisen.
5. FDA OVERSIGHT/MONITORING The FFDCA and its implementing regulations provide FDA with the authority to inspect sponsors, CROs, clinical investigators, and IRBs (9). Where FDA identifies violations of clinical research regulations, it has a number of statutory and regulatory remedies at its disposalfrom letters requiring corrective action to criminal proceedings resulting in jail time and significant fines. FDA inspections in the clinical research area are coordinated under the Bioresearch Monitoring Program (BIMO), an agency-wide program coordinated by both the FDA Commissioners Good Clinical Practice Program and the Office of Regulatory Affairs. Under BIMO, inspectional guidances are available to assist FDA field investigators in their inspection of sponsors, monitors, CROs, investigators, and IRBs (10). In addition, each FDA Center has its own bioresearch monitoring branch, which, in cooperation with BIMO, evaluates the results of inspectional investigations of sponsors, CROs, investigators, and IRBs, and reviews data submitted in support of an application. For drug studies, the Center for Drug Evaluation and Researchs (CDER) bioresearch division, the Division of Scientific Investigation (DSI), is responsible for directing inspection requests to the field, conducting inspections with investigators from the appropriate field office, reviewing the
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inspection reports, assigning classifications to the inspection reports, and initiating appropriate regulatory action, as necessary. Following the conclusion of an inspection, a field officer may issue the site a form FDA-483, which lists inspectional observations that the field officer believes rise to the level of a violation of clinical research requirements. In addition, the field officer writes a much more lengthy Establishment Inspection Report (EIR) and submits this to DSI for review. DSI then assigns a final classification to the report, which is used to determine whether regulatory action must be taken against the site. There are three possible classifications: 1. No Action Indicated (NAI) means that no objectionable conditions were found during the inspection. While an NAI classification may result in an FDA letter to the site, it will not rise to the level of a Warning Letter, and no response is required from the site. 2. Voluntary Action Indicated (VAI) means that the inspection disclosed objectionable conditions that departed from the regulations. A VAI classification is more likely to result in an untitled FDA letter. Unless the written response to the FDA-483 has left no matter requiring a comment, a response to such an untitled letter is generally required. 3. Official Action Indicated (OAI) means objectionable conditions or practices that represent serious departures from the regulations were discovered. In this case, the imposition of administrative/regulatory sanctions may be required. An OAI classification is much more likely to result in an FDA Warning Letter and additional enforcement action if FDA deems it appropriate. 6. FDA ACTIONS FDA has a number of administrative and regulatory remedies at its disposal when it determines that a sponsor, CRO, investigator, or IRB is failing to act in accord with requirements
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under the FFDCA and its implementing regulations. An FDA Warning Letter can be issued, demanding immediate corrective action. If the violation is serious enough, criminal prosecution can be pursued by recommending the matter to the Department of Justice for violations of the FFDCA, its implementing regulations, and possibly violations under Title 18 of the U.S. Code (USC). In addition, several remedies are specific to the parties involved. As to sponsors, FDA can impose a clinical hold, which either delays commencement of a clinical investigation or suspends an ongoing investigation. When a clinical hold is ordered, research participants cannot be enrolled in the study or given the study drug, and patients already in the study must be taken off the study drug unless FDA specifically permits continuation of the therapy for patient safety reasons. Among other factors, FDA can impose a clinical hold whenever human subjects are or would be exposed to an unreasonable and significant risk of illness or injury. The clinical hold can be complete or partial. If all investigations under an IND are subject to the clinical hold, it is deemed a complete clinical hold, whereas if only specific study sites in a multi-site investigation are subject to the clinical hold, the hold is deemed partial. Serious sponsor or CRO monitoring failures could result in a complete hold. Investigator misconduct is more likely to result in a partial hold specific to that investigators research site. An investigation may only resume after FDA has notified the sponsor that the investigation can proceed, which will only occur after FDA is satisfied that the reason for the clinical hold no longer exists. Sponsors can also be subject to an IND termination if FDA determines that the IND is deficient or the conduct of the study is deficient. Except where FDA concludes that an immediate and substantial danger to the health of individuals exists, it must first provide the sponsor with a proposal to terminate the study and give the sponsor an opportunity to dispute the need to terminate. Termination is only pursued by FDA if the clinical hold procedures are insufficient to address the serious deficiencies identified by FDA. If FDA determines that sponsor or CRO failures in their oversight or monitoring duties result in the submission of
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new drug applications containing false data, the agency could invoke the Application Integrity Policy (AIP). The drug application system is based on a system of trust, in that FDA will accept the truthfulness and accuracy of the data presented in a new drug application unless FDA is given reason not to have such trust. When that trust is broken, and FDA subjects a sponsor to the AIP, it treats the data and information in all new drug applications submitted by the sponsor as suspect, and thus, FDA first assesses the validity of data and information contained in a drug application prior to conducting the substantive scientific review. In addition, if FDA investigations identify deficiencies in previously approved drug applications, FDA can proceed to withdraw drug approval, require new testing, and/or seek recalls of marketed products. An FDA invocation of the AIP can be financially crippling to a company because it brings the drug approval process to a stop and may affect the marketing of approved drugs. A recent case in point concerns a medical device firm. During a 3-month inspection of the firm, FDA determined that the firm had improperly substituted reread data for original data without notification to FDA in an application to support the efficacy of its antiadhesion gel. In issuing an AIP letter, FDA suspended review of three premarket approval submissions. Further, re-launch of the firms only U.S. product was made contingent on submission and approval of an AIP corrective action plan. After the firm submitted a corrective action plan, FDA did not accept it until a year later. In light of the AIP and other FDA actions against the company, the firm was forced to file for chapter 11 bankruptcy. Debarment is another enforcement option for FDA if a company or person has been convicted for misconduct related to the development or approval of a drug application (11). When a person or company is debarred, they are essentially barred from participating in the pharmaceutical industry. Debarred companies cannot submit, or assist in the submission of, an ANDA, and debarred persons cannot provide services in any capacity to a person that has an approved or pending drug application. Each time a drug company applies for approval of a drug, it must submit to FDA a signed statement
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that no debarred persons worked on the application. Drug companies that use debarred persons can be subject to stiff civil penalties (12). As required by the FFDCA, FDA publishes a list of debarred persons on its website at www.fda.gov/ora/compliance_ref/debar/default.htm. As a practical matter, FDA has never debarred a company, instead focusing its enforcement resources on debarring persons within a company who were convicted for conduct related to the development, approval, or regulation of a drug product. The statutory debarment provisions historically were used to debar pharmaceutical industry personnel, particularly those connected with the generic drug industry. However, in recent years debarment of clinical investigators, as well as clinical research staff, has been more common. For example, a California doctor and three members of his research staff were debarred following criminal convictions associated with the fabrication of research data. The physician was president of a research company in California that, beginning in the 1990s, conducted more than 200 studies for as many as 47 drug companies. FDA inspection of his research facility revealed extensive deficiencies, including the use of fictitious patients, fabrication of data by substituting lab specimens and manipulating lab instrumentation, and the prescription of prohibited medications to manipulate data. Investigator disqualification is another enforcement remedy that can be pursued by FDA if it has information that a clinical investigator has repeatedly or deliberately failed to comply with the requirements set forth in 21 C.F.R. parts 312, 50, or 56, or has submitted to FDA or the sponsor false information in any required report (13). A disqualified investigator is ineligible to receive investigational drugs. When pursuing this remedy, FDA must provide the investigator with written notice of the basis for seeking disqualification and give the investigator an opportunity to respond in writing or, if requested by the investigator, at an informal hearing. If FDA does not accept the investigators explanation, the investigator will be offered the opportunity to pursue an administrative hearing under 21 C.F.R. part 16. At the conclusion of FDAs investigation, if it determines that disqualification is appropriate, it will notify
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the investigator and the sponsor of any investigation in which the investigator has been named as a participant that the investigator is not entitled to receive investigational drugs. FDA publishes a list of disqualified investigators at www.fda. gov/ora/compliance_ref/bimo/dis_res_assur.htm. As to FDA actions against IRBs, FDA may limit an IRBs ability to continue to operate by withholding the IRBs authority to approve new studies, directing that no new subjects be added to ongoing studies subject to the IRBs review, terminating studies subject to the IRBs review, and notifying state and federal regulatory parties and others with a direct interest in the matter about concerns with the IRBs operations. Such remedies must be presented in a letter to the IRB and to the parent institution, and a response describing corrective actions must be provided to FDA within a specified period of time. While it has never pursued this regulatory enforcement option, if the IRB fails to provide FDA with an appropriate response letter and its corrective actions are insufficient, FDA can pursue disqualification proceedings. Such proceedings will be instituted in accordance with FDAs requirements for regulatory hearings under 21 C.F.R. part 16. The IRB can then be disqualified if FDA determines that the IRB has refused or repeatedly failed to comply with any of the regulations set forth in 21 C.F.R. part 56, and that this noncompliance adversely affects the rights or welfare of the human subjects in a clinical investigation. FDA will notify the IRB, the parent institution, and other affected parties, such as sponsors and clinical investigators, of the disqualification. In addition, it may publish the IRB disqualification in the Federal Register. FDA will not approve an IND for a clinical investigation that is under the review of the disqualified IRB, and it may refuse to accept data in support of a drug application from a clinical investigation that was subject to the disqualified IRBs jurisdiction.
7. OTHER OVERSIGHT BODIES In addition to FDA oversight, clinical studies may also be subject to oversight by the Department of Health and Human
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Services (HHS) Office for Human Research Protections (OHRP), particularly if the studies are conducted at institutions that receive funding from the HHS. OHRP has compliance oversight authority over all institutions that conduct HHS-funded research. In order to participate in HHS-funded research, an institution must obtain an approved Assurance from the OHRP. The Assurance formalizes the institutions commitment to protect human subjects and generally contains a voluntary agreement that all research conducted at the site, regardless of funding, is subject to OHRP oversight and research regulations set forth at 45 C.F.R. part 46. Thus, a drug study sponsored by a pharmaceutical company may be subject to OHRP oversight even if there is no government funding. When OHRP initiates an investigation, it is usually in response to an allegation or indication of noncompliance. However, investigations can also occur in the absence of noncompliance. Generally, OHRP notifies the institution in writing of the investigation and provides it with an opportunity to respond. The investigation may occur completely by letter or telephone correspondence, or an on-site evaluation may be involved. At the conclusion of the investigation, no matter what the outcome, the OHRP issues a determination letter. Thus, even where full compliance is determined, the institution will receive a determination letter. If less than full compliance is found, OHRPs determination letter may cite remedies that can range from requiring improvements at the institutional site to withdrawal of the institutions Assurance. OHRP can also recommend debarment of the institution or individual investigators, rendering them ineligible to receive any government funding. Sponsors and investigators conducting clinical research concerning recombinant DNA human gene transfer should also be aware of their responsibilities under the National Institutes of Healths Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) (14). The NIH Guidelines articulate standards for investigators and institutions to follow to ensure the safe handling and containment of recombinant DNA and products derived from recombinant DNA. They outline requirements for institutional oversight, including
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Institutional Biosafety Committees (IBCs), and describe the procedures of the Recombinant DNA Advisory Committee. Even where the study is privately funded, it may be subject to the NIH Guidelines if the site at which the research is conducted receives any NIH funding. The sponsor, CRO, investigator, and IRB should also be aware of state laws and regulations concerning the conduct of clinical research. While most states exempt research that is subject to and in compliance with federal research requirements from state laws and regulations, several states have a number of clinical research requirements that exceed federal requirements. For example, California requires that all informed consent documents be signed by a witness. In addition, some states require state approval of research occurring with certain patient populations. Also, certain issues affecting informed consent are state specific. Age of consent varies from state to state ranging from 14 years in Alabama to 21 years in Puerto Rico. Where a patient is unable to provide informed consent due to mental or physical incapacity, legally authorized representatives must be utilized, and it is imperative that the investigator understand the order of priority with regard to who can act as a legally authorized representative. Investigators must also comply with state medical record privacy requirements and sexually transmitted disease-reporting requirements.
8. THE HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT OF 1996 As to medical records privacy, it is important for the sponsor, CRO, clinical investigator, and IRB to be aware of privacy requirements under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) (15). HIPAA was implemented to improve the efficiency and effectiveness of the healthcare system by requiring HHS to adopt national standards for electronic health-care transactions. However, in order to assure the continued privacy of health information, HIPAA included a provision that required HHS to adopt federal privacy
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protections for individually identifiable health information. Regulations adopted by HHS, which became effective on April 14, 2003, require covered entities (i.e., health plans, health-care clearinghouses, and health-care providers who conduct certain financial and administrative health-care transactions electronically) to implement standards to protect and guard against the misuse of individually identifiable health information. Individually identifiable health information (protected health information) is health information that is collected from an individual patient that either specifically identifies the patient (e.g., name, address, social security number) or that could reasonably be used to identify an individual (e.g., gender and age information in connection with an unusual disease condition) (16). Because filing for insurance reimbursement is the type of electronic transaction that triggers the applicability of HIPAA, most health-care providers are considered covered entities and thus subject to HIPAA requirements. For the purpose of research, if a clinical investigator is a covered entity, the clinical investigator must (17): 1. Provide all patients with a written notification of the offices privacy practices and the patients privacy rights (while not required, clinical investigators are encouraged to obtain the signature of all patients acknowledging receipt of the privacy notice); 2. Unless an IRB or privacy board waiver is approved, obtain written authorization from all research participants (i.e., a subcategory of patients) before disclosing information for research purposes; 3. Have written agreements with all parties to whom it releases confidential information (Business Associates) that satisfactorily document that the Business Associate will appropriately safeguard the protected health information. Because it is possible that sponsors or IRBs may receive protected health information, it is likely that clinical investigators could require them to sign a Business Associate agreement. If the investigator learns that a Business Associate fails
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to comply with the written agreement, the investigator must take reasonable steps to cure the breach or end the violation. If such steps are unsuccessful, the clinical investigator must terminate the Business Associate contract or, if termination is not viable, report the problem to the HHS (18).
9. INTERNATIONAL GOOD CLINICAL PRACTICE Going back a number of years, FDA had as a policy that all clinical investigations that were submitted in an NDA needed to be conducted on patients in the United States. Foreign data from sites outside of the United States were not considered acceptable. The concern was that patient populations were different, and that use of the drug could be different, and diet and other environmental factors were such that information obtained on subjects outside of the United States might not be valid for the U.S. population. Such an approach to clinical research has been set aside, and clinical data from all over the world are now used to obtain approval of drugs in the United States. While the data may come from Europe, Russia, China, South America, and Africa, the standards used in obtaining the data are the same as to the need for a protocol, informed consent, and proper record-keeping. Much of the international agreement on standards is the result of most of the countries in the world establishing policies that are consistent with the clinical standards recognized in the United States. While it is clearly possible to conduct a study almost anywhere in the world and submit the data for approval to the U.S. FDA based on agreements with the clinical sites in the countries in which the studies are being performed, many countries are looking to the establishment of international standards. The leading body in creating international clinical standards is the International Conference on Harmonization (ICH). ICH was organized in April 1990 and has as its sole and primary purpose the creation of international standards for the purpose of pharmaceutical research. The main bodies
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participating in the creation of ICH standards are the United States, the European Union, and Japan. In addition to these countries and their government delegates, ICH is heavily supported by the pharmaceutical industry [in particular the Pharmaceutical Research and Manufacturers of America (PhRMA)] in the United States, the European Federation of Pharmaceutical Industries and Associations (EFPIA) in Europe, and the Japan Pharmaceutical Manufacturers Association (JPMA) in Japan. Further, the World Health Organization (WHO), the European Free Trade Area (EFTA), and Canada hold observer status in the ICH. The creation of ICH is a recognition of the fact that the pharmaceutical industry is an international business and that diseases and conditions being treated in the United States are not significantly different from those being treated in other parts of the world. Though clear differences in disease patterns exist (i.e., there are few tropical diseases in the United States), given the modern scale of human interaction through travel and commerce, the need for and use of pharmaceuticals is recognizably global. There is no practical reason to do the same clinical study on a Japanese population, a European population, and a U.S. population. If there are adequate clinical data to show that the drug works in the patient population for whom the drug can be prescribed, the quickest and most expeditious way of conducting the research will benefit the pharmaceutical industry, the governments, and the populations that they serve. While only a small part of this chapter is devoted to international clinical research issues, the reader should understand that there has been an increasing demand for international harmonization of clinical research and drug development practices. Already, FDA has adopted a number of the ICH Guidelines as FDA Guidance documents, including the ICH Guideline for Good Clinical Practice. Thus, although we expect that FDA will maintain its deep involvement in the development of new international standards, we also expect that the future of clinical research will be largely driven by international standards and expectations, as opposed to national standards alone.
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REFERENCES
1. There is a group of drugs that, in FDAs view, do not qualify as GRASE, but which continue to be marketed in the absence of an NDA or an ANDA as a result of an FDA enforcement discretion policy. Compliance Policy Guide 7132c.02. These drugs are part of FDAs Drug Efficacy Study Implementation (DESI) and its Prescription Drug Wrap-up (DESI II) programs, and FDA will take appropriate action in connection with these products as it determines their status. Federal Food, Drug, and Cosmetic Act (FFDCA) xx505(a) and 505(i), 21 U.S.C. x355 (2000). FDA, by regulation, has waived the requirement to submit an IND application for certain bioequivalence studies. 21 C.F.R. x320.32. FFDCA x505(i), 21 U.S.C. x355 (2000). Investigational New Drug Application, 21 C.F.R. part 312 (2002). 21 C.F.R. x312.52 (2002). 21 C.F.R. xx312.57 and 312.62 (2002). FDA Policy on Retention Samples, available at http://www.fda. gov/cder/ogd/retention_samples.htm (last modified March 8, 2001). Institutional Review Boards, 21 C.F.R. part 56 (2002). FFDCA xx505(i) and 505(j), 21 U.S.C. x355 (2000). Bioresearch Monitoring (BIMO) Compliance Program Guidance Manual available at http://www.fda.gov/ora/cpgm/ default.htm#bimo (last updated April 26, 2002). FFDCA x306, 21 U.S.C. x335a (2000). FFDCA x307, 21 U.S.C. x335b (2000). 21 C.F.R. x312.70 (2002). National Institutes of Health, NIH Guidelines for Research Involving Recombinant DNA Molecules, available at http://www4.od.nih.gov/oba/rac/guidelines_02/NIH_Gdlnes_lnk_ 2002z.pdf (updated April 2002).
2.
3. 4. 5. 6. 7.
8. 9. 10.
11. 12. 13. 14.
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15. 16. 17. 18.
Health Insurance Portability and Accountability Act of 1996, Pub. L. No. 104191, 110 Stat. 1936 (1996). 45 C.F.R. x164.501 (2002). 45 C.F.R. parts 160, 164 (2002). 45 C.F.R. x164.504(e)(1) (2002).
11
Active Pharmaceutical Ingredients
MAX S. LAZAR FDA Regulatory Compliance Consulting Surprise, Arizona, U.S.A.
1. INTRODUCTION Active pharmaceutical ingredients (APIs), which have been refered to under a number of different names over the years, play a critical role in the review and approval process used around the world for pharmaceutical dosage (galenic) forms. APIs have been called bulk actives, bulk pharmaceutical chemicals, and even bulk chemicals. No matter what they are called, these materials are critical to the drug approval process in all regions of the world. Since APIs are the compounds that actually provide the activity and effectiveness of all drugs, they are subject to a significant amount of review during the filing and approval processes.
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In addition, unlike inactive ingredients, APIs are subjected to ongoing Good Manufacturing Practice (GMP) examinations and inspections during a drug products life cycle. To simplify the discussion in this chapter, we will focus on terms and approaches that are common in the United States. Where appropriate, other terms or practices may be identified to help understand how API practices used by other countries or regions may differ from that of the United States.
2. APIs IN THE UNITED STATES While there are no specific regulations that apply exclusively to APIs in the United States, API manufacturing sites have been expected to meet the spirit or intent of the Drug GMP (21 CFR Part 211). FDA authority over APIs comes directly from the U.S. Food, Drug and Cosmetic (FD&C) Act, and regulators always cite the FD&C Act during inspections. In November 2000, the International Conference on Harmonization issued Q7A, which is a guidance addressing API GMP. FDA as one of the members of ICH has now adopted these GMPs as official guidance for the United States. Therefore, FDA is now expecting to observe compliance with Q7A during any inspections of API facilities. FDA has for many years reviewed API manufacturing and control issues during the review process. Specific API filing issues were identified in the 1987 guidance issued by FDA. The agency has continued to refine its expectations and is working on new guidances on this subject, including ICH guidance on the Common Technical Document (CTD).
3. APIs IN OTHER PARTS OF THE WORLD Other countries and regions of the world have either developed their own review processes or adopted systems similar to that of the United States. Although terms may differ, the basics remain very similar.
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No matter what specific system has been established in any one country or region, the information normally contained in a DMF, NDA, or ANDA (see below) is usually expected for regulatory submissions around the world. Whether prior approvals or actual reviews take place is dependent on each individual country or region. In some cases, the approval of one country or the APIs presence in a compendium is enough to permit regulatory approval in a country.
4. REGULATORY ISSUES 4.1. Filings Numerous regulatory and pseudo-regulatory issues impact API and, more importantly, impact the drug development and approval process. Among the various issues are that regulatory filings can have a long-term impact upon firms because of the inspectional reviews that take place at the manufacturing sites producing APIs. All drug filings include API information. This information is usually included in documents that are referred to under different names. These can include: Drug Master Files (DMF) New Drug Applications (NDA) Abbreviated New Drug Applications (ANDA) New Animal Drug Applications (NADA) Dossiers 4.2. Compendia In addition to government-required filings, API standards of quality are frequently included in publications called Compendia. In the United States the U.S. Pharmacopoeia (USP), in Europe the European Pharmacopoeia (EP), and in Japan the Japanese Pharmacopoeia (JP) all publish drug product and API standards of quality. Other pharmacopoeias are published by countries around the world. What is important for industry is that doing business in countries with a pharmacopoeia usually means that their products must comply with that
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countrys compendia in addition to other requirements. Meeting the requirements of the different regulatory authorities has been one of the greatest challenges facing API developers and manufacturers. 4.3. GMP While there are no regulations covering GMP for APIs in the United States, FDA does expect GMP compliance with Q7A. This expectation will become more apparent as investigators are trained in the guidance and FDA issues more FDA-483 and Warning Letters to API producers. The majority of API producers for the U.S. market are from countries outside of the United States (1). Many API manufacturers are in Europe, where there has been an anticipation of a United StatesEuropean Union Mutual Recognition Agreement (MRA). While work continues on this MRA, its actual implementation appears in doubt. If in fact an MRA does not become a reality, Europe will continue to see FDA investigators using Q7A as a GMP expectation. FDA has influenced European and world GMP standards over the years. Its investigators positions and expectations will continue to impact world behavior in API GMP. Although the Pharmaceutical Inspection Convention (PIC) and the World Health Organization (WHO) continue to have Good Manufacturing Practice documents, the expectations established by Q7A will become the primary driver for API GMP. It is important that the expectations established by the ICH Expert Work Group that developed the API GMP be remembered and understood. Without that understanding, actual GMP can vary significantly due to misinterpretation by individual investigators from different countries. What is also critical is that expectations normally appropriate for drug products not be misapplied to APIs. All parties must remember that unlike dosage forms, API manufacturing usually includes purification steps that can allow for flexibility that is not possible for dosage form manufacturing. API manufacturers will need to be flexible in the review processes that will be applied to them by regulators
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and customers. Provision of data that can support processes and controls will be expected. These data would normally be examined during both filing and inspectional reviews.
5. APIs AND DRUG MASTER FILES OR NEW DRUG APPLICATIONS In the last 50 years, the majority of APIs have moved from being manufactured by the original developing companies to being outsourced from third-party manufacturers from around the world. According to FDA, the vast majority of APIs come from manufacturing sites outside of the United States. With the major growth of the generic industry, sources of APIs have shifted from innovator firms to new third-party manufacturers and developers. API materials that are the active for new drugs are covered by NDA documentation. Details of requirements are aptly covered by numerous FDA guidances, including the February 1987 Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances (2). Innovator companies would use their IND or NDA filings to provide the expected details covering an API, while all others would establish and submit a DMF with the FDA or other appropriate country authority, such as EMEA in Europe. DMFs have no legal or regulatory basis in the United States; however, they do provide companies a relatively easy and confidential way to provide confidential information about a process without making it available to other commercial companies. The DMF should contain all of the detailed information expected by the regulatory authorities so that a DMF reference in an NDA or ANDA can be used to complete an agency review process (36). In addition to physical characteristics of an API, which can affect the performance of a dosage form, regulators are always concerned with potential impurities and impurity profiles associated with an API and its mode of manufacturing.
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Since this issue can significantly impact the review and approval process of a drug, it is strongly suggested that filers comply with agency guidance on this subject (7). FDA refers applicants and submitters of a DMF to the ICH Q3A guidance for an understanding of impurity issues (8). DMFs are an essential element in the drug review and approval process. What is important to understand is that each region of the world has a different approach to writing and filing of a DMF. In the United States there is no approval process for a DMF. In fact, DMFs are only examined when referenced in other regulatory filings, such as an NDA or ANDA; only then is the content of a DMF reviewed. If requested by FDA headquarters, an FDA inspection may take place at an API manufacturing site after a review of the DMF. Similar practices may or may not exist in other regions of the world. For example, it is only in the last 10 years that any significant API inspection activities took place in Europe by regulatory agencies other than the FDA. While certain countries around the world may be exceptions, the U.S. FDA has been the most assertive in performing such inspections as part of the approval process for drug products. Firms that reference a DMF should be sure that the company and the manufacturing site being used as a supply have an approved FDA GMP review. If not, the DMF holder is likely to be inspected by FDA prior to an approval of any application. DMF and application holders need to be sure they understand and comply with FDA expectations before initiating any changes to their suppliers or processes used to make APIs (9). Another area for careful focus includes changes to existing, already approved API processes. For a number of years, FDA has been working on establishing guidelines that more clearly identify what changes can and cannot be initiated by a manufacturer without prior approval from FDA. Although industry has pressed for definitions, which would include changes up to the final API, FDA has only been willing to establish a guidance that discusses intermediates in drug substances (10). This guidance has been referred to as BACPAC I. It can also be used by DMF holders for guidance on the subject of postapproval changes.
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While API producers tend to experience less frequent inspections of their facilities than drug product manufacturers, some of the more significant violations occur when it is determined that a DMF holder is violating its submission. These violations include having modified operations without prior notification or approval as expected by FDA. Such actions by the API producer can have significant negative impact on the drug product NDA or ANDA holder. Serious deviations can even result in the FDA expecting the company to conduct a major recall. For this reason, care must be exercised to assure compliance with change control and filing requirements. If not, significant liability exposure could surface.
6. THE DMF Since the DMF plays such an important role in the API approval process, we need to examine it more closely. A Drug Master File is a submission to FDA of information concerning the chemistry, manufacturing, and controls (CMC) of a drug product or a component of a drug product to permit the FDA to review this information in support of a third partys submission (11). While there were originally five types of DMFs, currently only four are active. FDA no longer requests a Type I DMF (which provided plant information) since investigators in the field easily obtain all appropriate facility information. We will focus here on the Type II DMF that covers API and CMC issues. According to FDA (11), of the more than 6000 active DMF, almost 4000 are Type II. What is important to understand is that there is no requirement in the United States for submitting a DMF to FDA. Such submissions are commonly done to permit review of third-party information during an NDA or ANDA examination. It is the simplest way to provide this information in a confidential way to regulators in the United States. Submission of a DMF does not mean FDA will ever review it. Such a review usually only occurs when it is referenced in other applications for drug approval. Many over-the-counter (OTC) products are not reviewed, and therefore the API
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referenced in a DMF may never be examined under normal circumstances. Applicants filing an NDA or ANDA will usually reference a DMF as the authorized party if they themselves do not produce the API. The company that submits the DMF usually is the producer of the API and may or may not have a local agent to represent them in the United States. Since API manufacturers may be producing APIs for several users, the DMF provides a way for multiple applicants to reference the same DMF while keeping proprietary information confidential. (For the convenience of the reader, the references included at the end of this chapter can be used to obtain detailed filing information.) The DMF should contain a cover letter and the expected administrative and technical information. Two copies should be submitted to the DMF staff at FDA. Be sure to include a clear statement of commitment as discussed in the referenced guidances. Absence of such a statement will delay acceptance by FDA. Once accepted, the DMF is entered into the agency database and the holder or its agent should receive an acknowledgment letter. The acknowledgment letter will provide the assigned number and will remind the holder to: Submit changes as amendments Notify FDA of changes in (a) holder name/address or (b) agent Submit letter of authorization for each customer authorized Submit an annual report Review of the DMF will only occur once it is referenced in an official application that contains the letter of authorization from the DMF holder. Reviewing chemists must request the DMF from the FDA central document room, whereas an NDA, ANDA, or IND goes directly to the reviewing staff. Any deficiency in a DMF that is found during a review initiated by an application is communicated to the DMF holder. An agent for a DMF is not a requirement, but is suggested since it can facilitate and improve communication with companies not located in the United States. It is important to
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understand that this agent is not the same as an agent required for drug registration and listing. For postapproval changes, BACPAC guidances should be followed as they are issued. Currently, BACPAC only exists for intermediates. Be sure to specify, where appropriate, the API starting material(s) as defined in ICH Q7A, since it has significant future impact on GMP operations of an API facility. This does not mean that a company does not need to provide chemistry information for materials in early stages of manufacturing. It just helps identify a GMP starting point in processes.
7. ADDITIONAL IMPACT ON APIs Both the new Q7A API GMP and the work being conducted by ICH for the Common Technical Document will impact API approvals and filings around the world. API manufacturers and developers will need to prepare appropriate documentation of all development activities and decisions made during development while also preparing full documentation of the established manufacturing and control procedures established for the filed processes. All development activities and processes evaluated need to be documented in development reports. These reports document the API starting materials as defined in the Q7A Guidance and define all critical controls, steps, and conditions. All critical items defined in the development report play a significant role in the level of GMP applied by a firm to their process. Companies must be sure to apply full GMP requirements to all activities defined as critical. This is explicitly expected for compliance with API GMP. For this reason, care must be taken when defining such critical steps, control, or conditions. The amount of extra documentation expected for such steps can be extensive. The more important issue is that regulators will expect to see evidence of the extensive documentation during either preapproval or postapproval inspections. Whether an API is manufactured under an NDA or a DMF, the level of documentation and control procedures should be
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similar for critical items. From a regulatory perspective, governments are beginning to examine manufacturers in a similar manner no matter what type of API filing is made. Governments have become increasingly aware of the importance of the API and its impact on dosage form effectiveness and characteristics.
8. WHAT DOES A FIRM NEED TO INCLUDE IN AN API FILING? Some of the most important information includes the following: Facility and process train description Full description of the synthesis or process used showing reactions and flow diagrams All raw materials, solvents, catalysts API starting materials as defined in Q7A Critical steps, materials, control or operating conditions Impurity profile Reprocessing steps Description of special rework procedure (if it exists) and conditions in which it is to be used Key specifications for all materials Quality of water to be used for processing and/or cleaning Supplier information where appropriate or required Sample batch record 9. OTHER ISSUES FOR API PRODUCERS Like APIs, nonactive ingredients are also part of most dosage forms. While this is not an issue for the API producer, dosage form manufacturers need to determine whether suppliers of nonactive ingredients are supplying reliable materials. Pharmaceutical firms need to establish appropriate quality programs to review and, where appropriate, audit not only
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APIs, but also non-API materials. For the API producer, Q7A establishes expectations for the quality units responsibility. It is expected that API manufacturers have both internal and external auditing programs. Specifically who must conduct such audits can be established by an individual firm, but the review and approval of the firms independent quality unit is always required. API manufacturing and development companies need to have appropriate written procedures for the manufacturing, control, and distribution of the materials they produce and distribute. This includes written recall procedures. Appropriate change control and supplier procedures should be established in writing and approved by the companys quality unit. Agents and suppliers should understand their contractual responsibilities and be in conformance with the requirements of ICH Q7A for agents, etc. Manufacturers must know the source of their materials, including the company and location of the manufacturing sites. Aside from prospective validation packages, firms should have established written procedures for how to treat and process out-of-specification materials. Having such procedures will reduce regulatory conflict during preapproval and postapproval inspections. Establishing a written procedure for the notification of customers using an API is extremely important and expected under DMF guidances. Failure to provide proper notification or to restrict changes until approved by the drug product applicant could result in significant legal exposure.
10.
HARMONIZATION
Harmonization activities have been underway for years primarily under the guidance of the ICH. Progress has been slow primarily because each partner in the process has some unique interests and expectations, making it difficult to arrive at a harmonized guidance. Even with this slow progress, it can be expected that eventually there will be a uniform approach to drug filings. ICH Q7A stands as an example of why, when the need for harmonization becomes strong enough, rapid progress
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will occur. This same driver will eventually lead to worldwide filing formats. It is, however, more doubtful that worldwide approvals will happen given the nature of humankind. On the compendia side of API standards, there exists a greater probability for eventual harmonization. Commercial interests within any given compendia provide the primary constraint in this arena. If economic drivers can be limited, there is a high probability of harmonization within these API standards. Agreement between scientific and regulatory functions is not always easy to obtain. What one considers important is not important to others. Of course, the reverse is also true. This is a primary reason why drugs are approved more quickly in one region as opposed to another area of the world. Technical expertise is similar. What is different is the cultural or local driver in all systems.
11. REGULATORY UNIFORMITY The most difficult issue, aside from technical development activities that can affect API manufacturers and developers, is being able to address the different expectations and requirements that are likely to exist between countries and regions around the world. Obtaining true harmonization with the drug regulatory system is indeed challenging and very difficult. Human differences, expectations, and cultural issues drive most of the problems. Scientific and technical reviewers have expectations that are culturally and economically impacted by local conditions. These differences between people and cultures are very evident when a manufacturer experiences an on-site inspection by foreign investigators. What is expected during such inspections will usually vary significantly from inspections conducted by local country inspectors. While Mutual Recognition Agreements can prevent possible cultural problems in the inspectional area, such MRAs need to exist in the first place. Such an agreement currently does not exist between the United States and Europe and Japan covering API inspections. While MRAs exist between many countries,
Table 1
Application of ICH Q7A API Manufacturing*

Active Pharmaceutical Ingredients Application of ICH Q7A to (shown in bold type) steps used in this type of manufacturing Introduction of API starting material into process Collection of organ, Cutting, mixing, uid, or tissue and/or initial processing Production of API starting material Collection of plants Production of Isolation and Physical intermediate(s) purication processing and packaging Isolation and Physical purication processing and packaging Isolation and Physical purication processing and packaging Further extraction Physical processing and packaging Physical processing and packaging
Type of manufacturing Chemical manufacturing
APIs derived from animal sources
APIs extracted from plant sources Herbal extracts used as APIs APIs consisting of comminuted or powdered herbs Biotechnology; fermentation/ cell culture Classical fermentation to produce an API
Collection of plants
Introduction of API starting material into process Cutting and initial Introduction of extraction(s) API starting material into process Cutting and initial extraction
Collection of plants Cutting/ comminuting and/or cultivation and harvesting Maintenance of Establishment of working cell master cell bank bank and working cell bank Establishment of Maintenance of cell bank cell bank
Cell culture and/or fermentation Introduction of cells into fermentation
Isolation and Physical purication processing and packaging Isolation and Physical purication processing and packaging
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*Application (as indicated by bold type) increases as one proceeds from left to right. Source: Ref. 12.
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these major players have yet to finalize any real agreement in this area. Therefore, manufacturers can expect to be subjected to the problems associated with multinational reviews and inspections until such agreements can be established in the future. As ICH agreements increase in the areas covering filings, it will become easier for firms to standardize what they file with regulators. ICH Q7A has helped level the field of expectations for API GMP. Table 1 helps identify where API GMP needs to be applied internationally. Similar help can be expected as the filing issues are standardized around the world. Then firms will only need to face the normal challenges presented by different individuals interpreting requirements in their own unique way.
12. CONCLUSIONS Active Pharmaceutical Ingredients are not only the heart and brain of drug products, but are also crucial to the regulatory filing success of drug applications. This is true whether or not the API is described in an NDA, ANDA, IND, or DMF. While current U.S. practices do not require prospective reviews and approvals of a DMF, the reliability and quality of a DMF can have a significant impact on the approval and regulatory conformance of drug products. The worldwide regulatory climate is constantly changing, and companies need to be prepared to satisfy government requirements if they want to stay in business and meet the needs of their customers. Following the procedures described in this chapter will help meet those requirements no matter how individual expectations change in the future.
REFERENCES
1. Various FDA Presentation by Edwin Rivera, CDER, Office of Compliance.
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2.
Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances; February 1987; Food and Drug Administration, Center for Drug Evaluation and Research, Office of Drug Evaluation I (HFD-100). EMEA Note for Guidance, European Drug Master File Procedure for Active Ingredients (III/5370/93). Guideline for Drug Master Files, September 1989; Food and Drug Administration, Center for Drug Evaluation and Research, Office of Drug Evaluation I (HFD-100). Guidance for Industry, Drug Master Files for Bulk Antibiotic Drug Substances, November 1999; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry, ANDAs: Impurities in Drug Substances, November 1999; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry, NDAs: Impurities in New Drug Substances, February 2000; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guideline for Industry, Impurities in New Drug Substances, January 1996; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Reprint of ICH Q3A Step 4 Document approved by ICH Steering Committee March 1995. Guidance for Industry, Changes to an Approved NDA or ANDA, Questions and Answers, January 2001; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry, BACPAC I: Intermediates in Drug Substance Synthesis, Bulk Actives Postapproval Changes: Chemistry, Manufacturing, and Controls Documentation, February 2001; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug
3. 4.
5.
6.
7.
8.
9.
10.
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Evaluation and Research (CDER), Center for Veterinary Medicine (CVM). 11. 12. DMF Workshop, Arthur Shaw of FDA, March 25, 2002. International Conference on Harmonization, Guidance for Industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, November 2000.
12
Obtaining Approval of New Drug Applications and Abbreviated New Drug Applications from a Chemistry, Manufacturing, and Controls Perspective
DHIREN N. SHAH Aventis Pharmaceuticals Kansas City, Missouri, U.S.A.
1. INTRODUCTION Chemistry, Manufacturing, and Controls (CMC) is a relatively small section (approximately 1520%) of a typical New Drug Application (NDA), but it often becomes a reason for delay in the approval of NDA/Biologics Licensing Applications (BLAs). For Abbreviated New Drug Applications (ANDAs), however,
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the CMC section is significant (around 8090%). This section also becomes quite important in the postapproval life-cycle management of the products. It should be noted that the CMC section is made up of three distinctly different but overlapping disciplines/sciences: synthetic/fermentation chemistry, analytical chemistry, and formulation chemistry. Also, the CMC section continuously changes with clinical phases. Typically during clinical phase 1 trials, the CMC section is quite small and contains laboratory-scale manufacturing experience for the drug substance and the drug products with quite simple analytical methodologies. During clinical phase 2 trials, the CMC section evolves to pilot-scale manufacturing of the drug substance and the drug products, and the specifications and analytical methodologies become more sophisticated. End of phase 2 (EOP2) usually becomes a pivotal point in the drug development since at this point decisions and major commitments are made to as to whether to go forward with the phase 3 clinical development and marketing authorization application (NDA/BLA). EOP2 means for the CMC section a major shift in planning and execution. The drug substance and drug product manufacture typically need to be moved to commercial site at a commercial scale, and the specifications and the analytical methodologies need to be upgraded and finalized. So, one can see that the CMC section is a moving target. After the completion of clinical phase 3 studies, an NDA/BLA is submitted to the U.S. Food and Drug Administration (FDA) for review and approval. The CMC section of an NDA/BLA should contain all the relevant developmental information that bridges phase 1 through 3 leading up to the NDA/BLA submission. This chapter will systematically analyze and describe the FDA organization, its various regulations and guidances, the industry process by which CMC information is generated and submitted, and various ways to compress timelines and secure timely approvals of NDA/BLAs and ANDAs. As this chapter is being written, it is expected that the CMC review and approval process for new chemical entities and possibly biotechnologically produced drugs and generic drugs at the FDA may undergo a paradigm change. However, the basic principles behind obtaining approval of NDAs/BLAs/ANDAs
Obtaining Approval of a New Drug
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in a timely manner remain the same. It is anticipated that ICH Q8 (Development Pharmaceutics) and ICH Q9 (Risk Assessments) will reflect the paradigm shift at the agency.
2. CURRENT U.S. FDA ORGANIZATION The U.S. Food and Drug Administration is one of the most important customers for pharmaceutical companies. In order to understand the review and approval process for the CMC section of NDAs and ANDAs, one should be familiar with the regulatory authority and the process in the United States. The U.S. FDA is an agency within the Department of Health and Human Services, and it regulates biologics, drugs, food, devices, and veterinary products. It is made up of eight centers/offices. The biologics such as vaccines and blood products are regulated by the Center for Biologics Evaluation and Research (CBER). The Center for Drug Evaluation and Research (CDER), which is the largest of the five centers in the FDA, regulates drugs that include NDAs and ANDAs. The devices are regulated by the Center for Device and Radiological Health (CDRH). Animal products are regulated by the Center for Veterinary Medicines (CVM). The Center for Food Safety and Applied Nutrition (CFSAN) regulates foods and nutritional products. The National Center for Toxicological Research (NCTR) regulates all types of toxicological research. The Office of the Commissioner (OC) and the Office of Regulatory Affairs (ORA) provide administrative and management support. The CDER organization consists of therapeutic area based review divisions. Each review division has the primary responsibility of reviewing submissions and provides an action that could involve approval, approvable, nonapproval, request for more information, etc. The review divisions are staffed by the division director, medical reviewers, pharmacologists, chemists, bio-statisticians, bio-pharm reviewers, project manager staff, etc. The chemistry and bio-pharm reviewers report to the Office of Pharmaceutical Sciences (OPS). The Office of Generic Drugs (OGD) also reports to OPS. The OGD has two
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divisions of chemistry, each made up of five teams. This division of OGD is based on major therapeutic classes. As this chapter is being written, by the middle of 2005 the chemists from review divisions will be combined into one new drug chemistry group under the Office of New Drug Chemistry. The objective behind this change is consistency in reviews and better time management. This step is a predecessor to other CMC review and approval practices changes being planned at the agency. Various regulations as published in the 21 Code of Federal Regulations (CFR), guidances and points to consider (PTC) published by FDA, the Manual of Practices and Procedures (MaPP) published by FDA, and guidelines published by the International Committee on Harmonization (ICH) are important documents that become the foundation of scientifically and regulatorily sound CMC submission documents.
3. FDA AND ICH CMC/QUALITY REGULATIONS AND GUIDANCES FDA regulates new drugs as well as generic drugs under the Federal Food, Drug, and Cosmetic Act enacted by the U.S. Congress. The law, among other things, ensures that drugs and devices are safe and effective for their intended uses and all labeling used is truthful, accurate, informative, and not deceptive. Chapter five and specifically subchapter A of the Act provides for Drugs and Devices. The interpretation of the Act is provided in the Code of Federal Regulations (CFR), which is published annually. There are 50 titles/sections in CFR, and title 21 specifically provides interpretation of the Federal Food, Drug, and Cosmetic Act. Typically the regulations are brief and often difficult to fully interpret for actual implementation. FDA issues guidances and PTCs, which provide further interpretation of the regulations. FDA also publishes MaPPs, which are approved detailed instructions to FDA reviewers in order to standardize reviews of submissions. The reader is encouraged to make use of all FDA guidances and manuals. If properly used, they will ensure the
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quality of CMC submission, which should result in approval by FDA.
4. FDAS QUALITY BY DESIGN (QbD) AND PAT INITIATIVE AS PART OF CENTURY GOOD MANUFACTURING PRACTICES FDA, in its latest initiative for the Twenty-First Century Good Manufacturing Practices has, among other things, two initiatives named Quality-by-Design (QbD) and Process Analytical Technologies (PAT). PAT should not be considered as infinite testing, but it is a part of the QbD. Both of these initiatives go to the basics of product development, whether it is for a new drug or a generic product. By employing basic principles of science-based drug substance and drug product development, one can achieve QbD. The whole idea behind QbD and PAT is to build quality into the drug product from the very beginning of the manufacturing process so that testing for quality at the end may not be that critical. For example, a thorough physical, chemical, and biological (as necessary) understanding of all the components of the dosage form and a complete analysis and knowledge of all the critical manufacturing processes should result in a product in which the quality is built in and there may be limited need for final testing for quality. Properly selected in-process testing and controls should provide the basis for QbD. Process analytical technologies embrace the principles of QbD and include at-line, on-line, off-line, and in-line testing of in-process materials at critical stages of manufacturing. PAT provides for continuous manufacturing and real-time release of the product and the possibility of replacing the conventional validation batches. The reader is encouraged to read and follow FDAs draft guidance on PAT. One of the ways to successfully obtain approval of NDAs is to retro-engineer the drug substance and drug product. Once the sponsor identifies the final characteristics of the drug product to be marketed (dose, dosage type, shape, color, marking, packaging, etc.), a development and regulatory plan should be generated that
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Figure 1 Quality-by-Design and Process Analytical Technologies initiatives.
will determine what kind of CMC information needs to be generatedand whento secure an approval by the agency. Figure 1 summarizes the QbD and PAT intiatives. Aspects of QbD and PAT will be discussed later in this chapter.
5. SPONSOR COMPANY AND AGENCY PROCESSES TO SUCCESSFULLY DEVELOP THE CMC SECTION OF NDAs AND ANDAs BASED ON QbD AND ICH/FDA REGULATIONS The activities at the sponsor company in regards to CMC development from pre-IND through various phases of INDs leading up to the NDA and, in the case of generic drugs, the process leading up to ANDA determine ones success or failure. The product one delivers to FDA is the CMC submission, and its scientific quality determines its successful approval by the agency.
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5.1. Pre-IND Phase In this very early phase of drug development some basic work is performed. Preliminary solubility in various solvents, stability, and other important structural elucidations and characterizations are typically determined, which become the basis for future development of the new molecular entity. Of course, limited work is done at this stage, since the failure rate for new molecular entities (NMEs) is quite high. The CMC information from this stage typically becomes the basis for development pharmaceutics, and as the drug development progresses, additional tests and information are carried out. 5.2. IND Phase 1 This phase is still an early phase of product development and a limited and necessary effort is typically made. Since CMC is a multi-functional section, it will be highly beneficial to put together multi-functional teams consisting of scientists from drug substance synthesis, formulation, analytical, regulatory, writing group, etc. This team of people becomes responsible and accountable for putting together the CMC section of the IND and following the new drugs progress through phases 2 and 3 and making sure an NDA is filed on a quality submission. In some instances, a sponsor may want to request a preIND meeting, which could be in the form of a teleconference, with the agency to seek advice and/or clarification. The agency requires that a briefing document be submitted by the sponsor at least 46 weeks prior to the meeting. The briefing document should contain relevant information on the drug substance and drug product and concise questions about which the sponsor seeks advice from the agency. FDA requires limited CMC information in a phase 1 IND. The main emphasis is on the safety of the volunteers and patients, and hence the sponsor is required to make a connection between preclinical material and the proposed clinical material from impurity and bioavailability points of view. (It is conceivable that the material used in the preclinical safety studies was not as bioavailable as the clinical material posing a safety risk to the patients.) Also, if the clinical material has any impurity with
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safety implications, the agency will want to know more about it. At the time of submitting an original IND, very limited stability information is required. A commitment to generate concurrent stability data during the course of a clinical trial and reporting the data in most cases should suffice. It is the sponsors responsibility to make sure that the NME is stable in the dosage form when given to patients. During this early phase of clinical development, the analytical methods should be capable of determining the assay, impurities, etc., with specificity, accuracy, and precision. A formal validation of methods typically is not required at this early stage of development. Of course, as the drug development progresses, the analytical methods should be progressively validated so that they ensure strength, identity, purity, potency, and quality (SIPPQ) of the product. The sponsor must wait for a period of 30 days before initiating studies on human volunteers and patients. During this period the agency determines whether the sponsor could proceed with proposed studies, and if it has any objection it will instruct the sponsor not to initiate the study (known as clinical hold) until the deficiencies are satisfactorily addressed. The agency has issued a guidance as to the format and the content of the CMC section of IND, and the reader is encouraged to read and apply it to fullest extent as possible. 5.3. IND Phases 2 and 3 IND phases 2 and 3 are pivotal and become the basis for successfully obtaining approval of NDAs, because under these phases critical CMC information that supports SIPPQ is generated, drug substance and drug product manufacturing are optimized, bioavailability of the drug product is established, and primary stability data for the drug substance and the drug product are generated. The multifunctional team plays a critical role in advancing the NME through phases 2 and 3 leading up to NDA submission. Based on input from the clinical studies through phase 2, the safe and effective dose of the drug is chosen and various QbD parameters for the drug substance and drug product are introduced in the product development. The agency requires that during phases 2 and 3 the sponsor
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inform the agency of any new patient safetyrelated information in the form of IND amendments. These amendments to the IND typically do not require a waiting period; however, if the new information is significantly different from the original and if it affects the safety of the patients in the clinical trials, then the agency may advise the sponsor not to implement the change. The usual changes to the CMC, such as optimization to synthesis/manufacture of the drug substance, analytical methods, the drug product, new stability data, etc., could be submitted in IND annual reports to the agency. The sponsor could take advantage of the IND amendments to update the agency on the progress in the CMC and identification of critical issues and proposed/planned solutions to the issues. During phase 2, typically the drug substance and the drug product are produced in a large laboratory to pilot scale. At this phase, the drug substance synthesis/manufacturing, drug product formulation/process, analytical test methods, etc. are fine-tuned and the principles of QbD and PAT may be introduced and implemented. The end of phase 2 or the beginning of phase 3 becomes a pivotal point in the overall drug development process. At this point the NME has shown a certain threshold for safety and desired efficacy and the drug development picks up the speed with which confirmation of clinical results from phases 1 and 2 are reached in a larger patient population in phase 3. The CMC has to match the increased clinical activity of phase 3 by gearing up all three disciplines: drug substance synthesis and manufacturing, drug product formulation and manufacturing, and analytical testing. Typically phase 3 clinical trials are conducted on many hundreds to thousands of patients, leading to marketing application. In this phase the CMC section has to match the expanded clinical trials leading towards commercial distribution. In phase 3, the CMC section should focus on two important aspects of development: combining information and data from all three phases and bridging those with the future commercial product. FDA has issued a guidance for CMC information requirements for phases 2 and 3. The bridging study will be discussed in the next section.
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5.4. Successful Bridging of Pre-IND, Phase 1, Phase 2, and Phase 3 with Commercial Product One of the secrets of obtaining approval of NDAs and BLAs from a CMC perspective is successfully bridging the CMC information and data from preclinical through the three phases of IND and the commercial product. Bridging of critical information on strength, identity, purity, potency, and quality starting from the preclinical phase leading up to commercial product is of utmost importance. Some important characteristics of the drug substance and the drug product are as follows:
Drug substance Structural elucidation Impurity/Related substances Solubility Critical relevant characteristics Critical manufacturing information Stability (RT and accelerated) Drug product Description Degradation products Dissolution
All relevant drug substance and drug product characterization information from all phases of development should be bridged to come up with a complete picture of strengths and weaknesses of the drug substance and the drug product. Key characteristics such as impurity profile, solubility of the drug substance, dissolution-friability balance (DFB) for SODF, accelerated/forced degradation to understand the mechanistic aspects of degradation, design of experiments, etc., should be bridged to get a complete picture of the drug product. The aforementioned information on the drug substance and the drug product from investigational phases is bridged to the planned commercial drug product. All of this bridging information, along with design of experimental data in which the boundaries of success and failures of all critical parameters (drug substance manufacturing processing parameters, formulation components, composition, processing equipment
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and parameters, in-process controls, specifications, etc.) are determined, become part of developmental pharmaceutics and should be included in a New Drug Application. It should be emphasized that bridging in the form of evolution of analytical procedures starting from preclinical phase to phase 3 and commercial product testing should be thoroughly discussed in developmental pharmaceutics. 5.5. Developmental Pharmaceutics and Its Importance to CMC As discussed above, Design of Experiments, Quality-by-Design, Process Analytical Technologies, bridging of all the phases of INDs, technology transfer, etc., become the basis for developmental pharmaceutics, which becomes the foundation of a good CMC section of NDAs and ANDAs. It provides an overview of the thoughts and rationale behind the product development and commercial product to the CMC reviewing staff at the agency and becomes an important tool in the review and approval process. The ICH CTD format also provides for a section for Development Pharmaceutics. ICH Q8 is on developmental pharmaceutics, and once this guidance (which is at early stages of its development at this time) is finalized, it should provide appropriate guidance to the industry. 5.6. Technology Transfer to Manufacturing It is obvious that at the end of phase 3 clinical trials, the most critical and important step is to make sure that the drug product is manufacturable, because without it the new drug could not be commercialized. Over the past 30 years, major pharmaceutical and generic companies have often failed to produce commercial products immediately upon approval of NDAs/ANDAs because companies failed to perform timely technology transfer. Technology transfer involves transferring of information and experience from lab and pilot scales to a commercial level for the drug substance, drug product, and associated analytical testing procedures. All these become the basis for seamless and sound manufacturing of the new drug on a commercial scale.
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5.7. Quality-by-Design and Process Analytical Technologies As this chapter is being written, the Office of Pharmaceutical Sciences (OPS) under CDER is in the process of redesigning and introducing a paradigm shift in the CMC reviews and compliance investigations. It is expected that by the end of 2005 the Agency would have implemented the planned changes in CMC reviews and compliance investigations. The ICH through initiation of Q8 (Pharmaceutical Development) and Q9 (Risk Assessment) is also gearing up towards the same goal of OPS. Both ICH Q8 and Q9 will involve the concept of QbD. Qualityby-Design, which encompasses Process Analytical Technologies and embraces building quality in the process and product throughout the manufacturing process, may be summarized as follows: QbD Preprocess controls PPCs in-process controls IPCs Postprocess controls POPCs PPCs: Preprocess controls (throughout the preclinical, the three phases of INDs, and for commercial production) such as thorough physical-chemical-biological characterization of the (a) drug substance and all its manufacturing/synthesis components and (b) excipients. The drug substance starting materials, its other components (catalysts, solvents, etc.), key and pivotal intermediates, etc., should be thoroughly characterized. The pharmacopoeias provide fairly good chemical characterization, but do not provide thorough functional physical characterization, and it is up to the sponsor to develop that characterization. The drug substance physical and chemical characterization is of critical importance to successful Qualityby-Design. Some examples of PPCs are chemical purity of starting materials and intermediates, purification steps, drug substance particle size and specific
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surface area, density, excipient particle size and shape, density, etc. IPCs: In-process controls is the heart of process analytical technologies. IPCs such as assay, purity, residual solvents, particle size, specific surface area, polymorphism, etc., are critical in the manufacturing of drug substance. For drug products, in-process controls such as granulation endpoints, moisture level, content uniformity, etc., are critical. Process analytical technologies could involve off-line, at-line, in-line, on-line testing of in-process parameters for drug substance and drug product. Carefully and strategically chosen in-process controls, if done in-line or on-line, may obviate final testing because of the large sample size. PoPCs: Postprocess controls play an important role in QbD. Testing of final drug product per specifications, storage conditions, long-term and accelerated stability studies are components of PoPCs. 5.8. Sponsor-FDA Meetings FDA allows several kinds of meetings with sponsors in order to assist and gather information. Meetings such as pre-IND typically are clinical oriented. For CMC section, end-of phase 2 and pre-NDA meetings are important for the CMC section of NDAs and BLAs. (FDA has issued a guidance on sponsor-FDA meetings.) The sponsor should submit a briefing document to the agency at least 6 weeks prior to the requested meeting, and the briefing document should contain relevant background information and questions on which the sponsor is seeking advice. The briefing document should not be voluminous. It should be a focused document that contains specific questions/ issues. The sponsor can easily enhance its NDA/BLA/ANDA submissions by taking advantage of these meetings. 5.9. NDA Submissions NDA submission on a new drug should follow the FDA and ICH guidance. From a technical regulatory perspective, if all
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the work is done properly as described in sections a through h, the NDA submission should become fairly easy and result in approval in a timely manner. The submission should follow the FDA and ICH guidances, and moreover it should be reviewerfriendly. The data should be presented in a clear-cut manner. One should remember that the product that the FDA sees from an applicant is the NDA/ANDA submission. The chemistry reviewers have a responsibility to make sure that the product they approve meets the regulatory requirements as prescribed in the Code of Federal Regulations. Submissions to the FDA should be accurate and of high quality. All submissions to the FDA must meet four important criteria in order to secure approval the first time: (a) Adherence to Regulations and Guidancesstrict adherence to FDA CMC regulations and guidances for format and content, which include those ICH quality guidelines that have reached step 5. It is possible to adopt an approach other than that provided by the FDA guidances; however, it is the applicants responsibility to secure approval on the alternative approach from the FDA reviewing staff (for example, at EOP2 and/or Pre-NDA meeting). Careful and strategic implementation of guidance should be received from the reviewing staff at the FDA; (b) Introductionsubmissions should have an introductory section that clearly provides the purpose, scope, and context of the submission that helps the reviewing team. This introduction should have a clear delineation of any agreement made prior to the submission. The introductory section should provide a higher level overview of the submission, which will lead into the next section, where the nuts and bolts of the submission are provided. This section should end with a summary of the submission; (c) Body of the submissionthis part of a submission is of utmost importance since it provides the main basis for approval. The chemistry review staff has to provide a rationale for their action (approval, nonapproval, approvable, etc.) and a good introduction and summary aids them in making their decision. The information provided in submissions must be focused, relevant, precise, accurate, complete, and of quality. When it comes to quality of the submission, one should adopt the philosophy of quality always. In this main body of the
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submission, one should pay special attention not to provide redundant and unrelated information, because it takes away from the reviewers attention and wastes their precious time. The submission should have a logical flow of information and justified decisions based on scientific rationales. The logical flow of information and justified decisions along with clear objectives and findings that lead to clear conclusions provide a coherent submission. The main body of the submission should follow the time-tested organizational characteristics of a sound beginning, experimental details, organized results, discussion of results, and conclusions. Information should be provided with an appropriate combination of text, figures, tables, etc., which will provide a clear picture of the submission. The information should convey a clear message and conclusion and should follow the usual standards of quality (free of typographical and grammatical errors, clear legends, footnotes as necessary for clarity, etc.); (d) A summary and conclusion section should be provided, including any short- or long-term commitments (such as placing batch(es) of drug product on long-term stability and reporting the data to the agency at a later date, etc.). 5.10. ANDA (505b2) Submissions
The ANDA submission on a generic drug should follow the FDA guidance. FDA has provided a clear-cut format and content guidance on the organization of an ANDA. Section VII of the guidance provides for detailed CMC requirements. The applicant should provide a statement on the components and composition of the product. This should be followed by information on raw materials (active ingredient and inactive ingredients), description of manufacturing facility, information on the outside/contract firms, manufacturing process and packaging instructions, in-process information, packaging material controls, controls for finished dosage form, analytical methods for the drug substance and drug product, stability of finished dosage form, and availability of samples. If the generic product is a parenteral product, the applicant must provide sterilization assurance information and data package. The above CMC
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section is somewhat similar to the NDA requirements, and if it follows the above recommendations, obtaining approval for an ANDA should be easy. The CMC section should be preceded by information on the bioavailability/bioequivlaence of the dosage form in relation to the reference listed drug. 5.11. Quick and Complete Response (QCR) Team Approach to FDA Questions/Comments Once an NDA or ANDA has been submitted by an applicant and filed (meaning accepted) by FDA, during and/or after the completion of the review, FDA might have questions/comments on the submission. The questions/comments may come verbally or in writing. In either case it is very important for the applicant to respond to the questions/comments in a timely, thorough, and accurate fashion. Often applicants form a team (such as QCR) that develops complete and timely responses that aide the agencys review process. The QCR team, if properly organized, could play an important role in obtaining the approval of NDAs in a timely manner.
6. UNDERSTANDING THE CMC REVIEW PROCESS The CMC review process at FDA is quite transparent. The agency publishes its most current ONDC organization chart and several MaPPs. The primary CMC review chemists review the submissions and share their reviews with the chemistry team leaders. Based on their reviews, they may issue information request letters. Alternatively, CMC reviews are further reviewed by CMC division directors and then ultimately by the director of ONDC. Once the reviews are finalized by the CMC reviewers and ONDC management, the review division director will issue appropriate letters (approval, nonapprovals, approvable, etc.). The CMC reviewers issue a review report, which includes their assessment and reasons for their recommendations. As stated earlier, the overall CMC review and approval processes may change in 2005 as a result of
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ICH Q8 and Q9. However, it should be remembered that the basics and fundamentals of CMC reviews (and compliance inspections) will focus on strength, identity, purity, potency, and quality, which are surrogates of safety and efficacy of drugs. The OGD follows a similar review process. Of course, for ANDAs the final reviews stop at the OGD head level. The CMC reviewers have a legal responsibility to review and assess CMC submissions and to make sure that the submissions meet the law and regulations and the product meets the strength, identity, purity, potency, and quality requirements. If for some reason a product is recalled because of SIPPQ, then the reviewing staff that approved the product is in part responsible. Thus, understanding the review process and the responsibility of the reviewing staff is important in obtaining approval of NDAs/ BLAs. As this chapter is being written, the Office of Pharmaceutical Sciences is planning for a paradigm change in the CMC reviews and compliance. The ICH through Q8 (Pharmaceutical Development) and Q9 (Risk Assessment) is also gearing up towards the same goal of OPS.
7. PROBLEMS AND CHALLENGES INVOLVED IN SECURING TIMELY APPROVALS AND POTENTIAL SOLUTIONS Most delayed approvals are due to poor science contained in the submission and poor submission strategy. The poor science may be reflected in instability of the product or unacceptable levels of impurities or poor product bioavailability as measured by tablet dissolution, etc. A good product development plan based on the principles of QbD (see above) should result in an approvable submission. Judicial use of contacts with the agency and maximizing various FDA-sponsor meetings should avoid delays in the approvals of applications. Agency reviewers are available to assist the industry as long as it is done in a professional manner. The Agency is pushing for sciencebased regulations and review practices. Applicants should take
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advantage of this new paradigm to secure approvals in a timely manner. As described in Sec. 5.9, the quality of submission is critical in securing approval of applications in a timely manner.
8. SUMMARY AND CONCLUSIONS This chapter has offered some practical ways to develop a science-based, regulatory-friendly application that should be approved at first submission. By focusing on the fundamental scientific principles and FDA and ICH guidances, it is quite feasible to obtain approval of NDAs and ANDAs. In order to obtain approval of NDAs/ANDAs in a timely manner, one should focus on four pillars: (a) development of CMC based on QbD/PAT, (b) application of FDA and ICH CMC regulations and guidances, (c) bridging of phases 1 through 3 to a successful NDA, and (d) preparing sound CMC scientific and regulatory submissions.
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13
Obtaining Approval of a Generic Drug
LOREN GELBER Andrx Corporation Davie, Florida, U.S.A.
1. INTRODUCTION In order to obtain approval of a generic drug product, a sponsor must submit an Abbreviated New Drug Application (ANDA) to the FDAs Center for Drug Evaluation and Research (CDER), Office of Generic Drugs (OGD). The sponsor can be a drug company that intends to manufacture the generic drug itself and has performed the necessary research to obtain the data required for submission, which will be described in this chapter. Alternatively, the sponsor could be some individual or group that has done the research or obtained the rights to the research performed by others, even if the sponsor does not intend to manufacture the product itself. For simplicity in this chapter, we will refer to the sponsor as the applicant.
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The goal of the applicant is to receive FDA approval of the proposed product with a rating that means that FDA considers the generic drug bioequivalent to the brand drug. If a generic product has such a rating, pharmacists may substitute that generic for the brand product or one bioequivalent generic product for another. In FDA language, this innovator product is called the reference listed drug. Since the generic drug is equivalent to the brand, the former does not have to repeat the preclinical animal studies or the clinical human studies that were performed on the brand in order to prove that the brand product is both safe and effective. In this chapter we will cover several aspects of getting a generic drug product approved. There are a number of essential parts of the process of getting a generic drug approved. First, the applicant must select a product to work on. Second, a formulation and manufacturing process for the generic drug product must be developed that shows promise of producing a product that will be bioequivalent to the reference listed drug. Then one or more batches of generic product must be manufactured. In most cases one or more human bioequivalence trials (biostudies) must be performed on the product manufactured. Various chemical and physical tests must also be performed on this product. When sufficient information has been obtained, an ANDA is prepared and filed with the FDA. We will discuss some general principles related to how to decide what product to pursue, how to develop a formulation, how to perform a biostudy, and how to prepare an ANDA. The information needed to submit the application will be considered in the ANDA preparation section. We will end this chapter with a short discussion of applicant activities between submission of the ANDA and its approval.
2. DECIDE WHAT PRODUCT TO PURSUE The first step in obtaining approval of a generic drug is selecting the product to work on. Each generic drug product is
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declared by FDA to be a form of an innovator product that was originally approved via a full New Drug Application (NDA). Selection of the proper reference listed drug is critical to market success. Depending on the strategy of the firm involved, one may choose the easy route or the hard route. The easy route is to work on a product for which there are already generic equivalents. One of the reasons this is the easy route is because there will be a body of information available from FDA and possibly also in the literature about the product. This information can be very valuable during product development and biostudy testing. FDA will also be familiar with the product and what is required for it to be approved. The hard route is to work on a product for which there are no generic equivalents, usually because the product is still under patent or because it is difficult to formulate a product that is bioequivalent to the innovator product. When considering which product to pursue, one of the first places to look for product information is the FDA Orange Book (1). Fortunately, this is available at the FDA web site, fda.gov, with a link on the Center for Drugs home page, fda.gov/cder/. By searching the Orange Book, one can determine how many generic equivalents of a product are approved and the names of the holders of the approved applications. The patent numbers and expiration dates of all patents that have been listed with the FDA for the product can also be found. If generic equivalents already exist, the Orange Book will indicate what their equivalence rating is to the innovator product. The Orange Book uses two-letter codes for this purpose. If the first letter of the code is A, the products with this code are considered bioequivalent. The second letter of the code represents different dosage forms. Products coded AA, AN, AO, AP, and AT do not require biostudies in order to be approved, because there is no evidence that they have any bioequivalence problems. These products are less expensive to pursue, but there are almost always many competitors for them. Products rated AB require biostudies that demonstrate bioequivalence of the applicants product to the innovator for approval.
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If the first letter of the code is B, the products are not bioequivalent to each other. FDA is in general unwilling to approve any generic products with these ratings and is attempting to upgrade them to AB status if possible. For further discussion of this rather complex topic, see the Preface to the Orange Book. While the issue of pharmaceutical patents is covered in Chapter 5, a discussion of practical aspects will be included in this chapter. The Orange Book listing of patent numbers is provided by the holders of the NDA for the innovator product. Patent lists were established by the Hatch-Waxman Act, passed in 1984 (2). If an applicant has decided to submit an application for a product that has one or more patents listed in the Orange Book, the applicant needs to research the patents and decide whether it wants to, and can, invalidate some or all of the patents or develop a formulation that does not infringe on any of the claims in the patents. There are several ways in which the applicant can approach these patents and deal with, or certify, them in its application. A short discussion of the types of patent certifications appears later in this chapter. One of the reasons that research is needed is that there are several different types of patents listed in the Orange Book. It is the opinion of this author that a patent covering the molecular structure of the drug can only rarely be successfully challenged by generic competitors. The original use for which the product was approved may be in the same patent or a different one. A firm must usually wait for all of these to expire before it can receive final approval of an ANDA that refers to the reference listed drug included in the patent. It often seems to the layman that more than one patent is granted for the same thing; this requires clarification from patent attorneys. Patents for other uses can be overcome by submitting, in the patent certification section of the abbreviated new drug application, a statement that the generic drug application is not requesting approval for the other patented indication or indications. This statement is called a Section (viii) notice. In this case, all references to the patented indication or indications being certified must be removed from the labeling included in the application.
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Formulation patents require analysis by both chemists and attorneys who are experts in pharmaceutical patents. Skilled formulators often devise products that are intended to engineer around restrictions in formulation patents. In many cases, applications that certify that they do not infringe formulation patents result in litigation. The litigation may hinge on the judges interpretation of a few words in the patent being challenged. One must also consider the doctrine of equivalents, discussion of which is beyond the scope of this chapter. To add to the complex situation described above, starting in the 1990s innovator firms began to list patents that have only a tenuous connection to the reference listed drug. These include patents for other crystal forms, isomers and metabolites. Innovator firms have maintained that they interpret the HatchWaxman Act to require them to list any patent connected to the active ingredient in their product, even when the patent does not cover the final dosage form. Generic drug companies have attacked this position both in court and via attempts to revise the Act. As of this writing these attacks have met with some success, but the problem has not been resolved. When the generic drug application contains a certification that a patent listed in the Orange Book is invalid or will not be infringed, there is a requirement that the ANDA applicant notify the patent holder as well as the holder of the approved NDA if they are different (4). The rules for this notification are very complex, and discussion of them is beyond the scope of this chapter. In the majority of cases the ANDA applicant will be sued for patent infringement if the application contains a certification that a patent is invalid or will not be infringed. If this occurs, FDA may not approve the ANDA for 30 months after the date of the receipt of the notice of certification by the patent owner or by the exclusive licensee (or their representatives) unless the court has extended or reduced the period because of a failure of either the plaintiff or defendant to cooperate reasonably in expediting the action(5). This provision is usually referred to as the 30-month stay of approval. In October 2002, FDA proposed a rule amending its patent listing requirements to, among other things, allow only one
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30-month stay of approval for each ANDA filed (6). Most of this rule was included in the Greater Access to Affordable Pharmaceuticals Act which became law in 2003. See Chapter 5 for more details. One can see that filing an ANDA citing a reference listed drug that does not have any approved generic equivalents poses some risk. In an attempt to partially counterbalance this risk, the Hatch-Waxman Act provides a 180-day exclusivity for the first applicant to file a substantially complete application containing the required biostudies. This exclusivity starts when the holder of the exclusivity starts marketing the drug or when the final court decision in a patent challenge is rendered. In addition to the patents listed in the Orange Book at the time the ANDA is filed, the applicant for an ANDA must file a certification amendment if a new patent is listed in the Orange Book before the ANDA is approved. If the NDA holder submits the patent for listing in the Orange Book within 30 days of its issuance by the Patent and Trademark Office and the applicant is sued for infringement of these later listed patents, a new 30-month stay of approval begins. In several cases this has occurred the day before the ANDA was due to be approved by FDA. Even if the original application contained a certification that all patents have expired or that approval is requested when the last patent listed in the Orange Book expires, it is always possible that a new patent will be listed in the Orange Book at any time before approval. When a new patent is listed before an ANDA is approved, the applicant has to file a new patent certification. In most cases, the patent and/or NDA holder will sue for infringement, starting a new 30-month stay. It is not required that the holder of exclusivity market the product; there have been cases where the holder of exclusivity chooses not to market and all other applicants are blocked and cannot market. The FDA rules governing 180-day exclusivity are very complex and have changed several times since 1984, when the Hatch-Waxman Act became effective. There are also economic considerations involved. When patents for a brand product with high sales are due to expire, many other firms are likely to prepare and submit ANDAs. If there is a potential for 180-day exclusivity, one firm may
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make a great deal of money for this period. At the end of this period, or if there are no other patents to challenge and thus no potential for exclusivity, many ANDAs will probably be approved on the first possible day. Having 13 or more enter the market at the same time is possible. In this case competition is fierce and the price drops quickly. The product becomes a commodity, and no one makes very much money. The lower the sales of the brand product, the less likely this is to happen. These niche products can paradoxically produce much better profits than the blockbusters. Another possible strategy is to submit a citizens petition to FDA requesting approval of one of the permitted variations from a reference listed drug. One variation is an additional strength within those supported by the safety and efficacy data pertinent to the reference listed drug. This is also a complex area, discussion of which is beyond the scope of this chapter, and appropriate experts should be consulted. As if this situation were not complicated enough, the Hatch-Waxman Act also granted various types of exclusivity to holders of new drug applications. The most important type of exclusivity is new chemical entity (NCE) exclusivity, because FDA is not allowed to accept an ANDA citing a reference listed drug with NCE exclusivity in force (3). NCE exclusivity is awarded if the active ingredient in a new drug product has never before been approved in the United States. NCE exclusivity is not awarded if another salt or ester of the active ingredient is already approved. NCE exclusivity is granted for 5 years from the date the NDA is approved. There are several other types of exclusivity. For these, FDA may accept an ANDA but may not make its approval effective until the exclusivity expires. Orphan drug exclusivity is granted for 7 years. New indication, new combination, new dosing schedule, new dosage form, new ester or salt of the active ingredient, new product, new patient population, new route, and new strength exclusivities are granted for 3 years. For many of the exclusivities listed in the previous sentence, an applicant can carefully craft the submission not to include the matter subject to the exclusivity. However, occasionally the owner of the reference listed product will sue and/or submit
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a citizens petition to FDA, arguing that the exclusivity should apply to the ANDA so crafted. A newer type of exclusivity is pediatric exclusivity. This is granted if the owner of an NDA obtains certain new information about the use of the product in children via new clinical trials. Pediatric exclusivity is an extension of a previous patent or exclusivity for 6 more months. It is usually granted shortly before expiration of the patent or exclusivity being extended. The prudent applicant checks the exclusivity listings in the Orange Book every month, when updates and supplements are published. The rules for granting exclusivity are, of course, very complex and beyond the scope of this chapter. The main thing the applicant needs to know is what the exclusivity is for and when it expires. This information can be found in the Orange Book. From the above discussion, it is clear that many uncertainties are involved in deciding which product to pursue. Each firm must consider its overall strategy when deciding whether the rewards are commensurate with the risks.
3. DEVELOP A FORMULA Once a firm has picked a candidate product to develop, the next step is to develop a formulation that can pass the bioequivalence studies. The requirements for such studies are described in the next section of this chapter. Patent issues aside, there are many techniques for developing a bioequivalent formulation. Among them are two commonly used approaches: reverse engineering the reference listed drug to better understand its characteristics, or building on a previous formulation or technology for a similar product. These approaches can also be used together. FDA regulations declare, For certain drug products, the in vivo bioavailability or bioequivalence of the drug product may be self-evident. These include liquid dosage forms that are true solutions, contain the same inactive and active ingredients in the same concentrations as the reference listed drug,
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and are used in parenteral, ophthalmic, or otic applications. Products administered by inhalation that contain the same active ingredients as the reference listed drug are included. Topical products and oral solutions (including elixirs, syrups, and tinctures) that contain the same active ingredients as the reference listed drug and do not contain any inactive ingredient that differs from those in the reference listed drug that may significantly affect drug absorption are also considered self-evidently equivalent. All of these products can qualify for a waiver that allows them to be approved without a bioequivalence study (3). Parenteral products are required by FDA to include their qualitative and quantitative compositions in their labeling, so the formulator needs only to follow the labeling to make a product FDA will accept. Ophthalmics or otics will list the concentration of any preservative present in the labeling, and often the osmolality and/or pH, but other ingredients are given only qualitatively. In the reverse engineering approach, simple and sophisticated chemical and physical tests are applied to the reference listed drug product to determine its exact qualitative and quantitative composition. While listing of inactive ingredients in labeling of solid dosage forms is voluntary, almost all innovator firms do it, and this can be a big help when trying to copy it exactly. There is a loophole, however. If the innovator contends that the reference listed drug contains ingredients that are trade secrets, these may be listed as other ingredients. Of course, the most important and unusual ones are listed this way. In the late 1980s, just after the Hatch-Waxman Act passed, several firms tried to use reverse engineering to guide their formulators. It is interesting that solid dosage form products produced in this way failed bioequivalence studies more often than would be expected. As a result, formulators are more likely to use variations on known formulas. If the firm wishing to develop a generic drug already has a successful product that is similar, using a similar formulation for the new product is often a very good starting point. Basic physical pharmacy textbooks and research articles in journals like Pharmaceutical Technology can be good sources for basic formulas as well.
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If the formulator chooses to be creative and use an original formulation, he or she must be aware of FDAs safety rules for generic drug formulations. FDA will not question the safety of an inactive ingredient if it has been used in an approved product and the level in the proposed generic drug product is not higher than the highest level ever approved for patient consumption in that route of administration. Since this information is generally part of the proprietary secrets in many applications, FDA published an Inactive Ingredient Guide, which may be accessed from the FDA web site. This guide was recently revised. While it is not perfect, it is a valuable resource for formulators. How does the formulator know when he has developed a promising formulation? First, the product must be suitable for manufacture on a commercial scale. Extremely fragile tablets, called friable tablets, ingredients that are very hard to blend, blends that do not flow well in manufacturing machinery, or processes that use toxic solvents are the sorts of things the formulator must avoid. Second, one must obtain some information on the nature of the bioequivalence requirements. Then, if a biostudy is required, an in vitro test that can serve as a surrogate for it is highly desirable. The most common surrogate for bioequivalence is the comparative dissolution profile. Typical results obtained for a comparative dissolution profile are shown in Figure 1, in which
Figure 1 Graph of a typical comparative dissolution profile, obtained by measuring the dissolution of the proposed generic product and the reference listed drug every hour for 5 hours.
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the generic drug is the test and the reference listed drug is the reference. A dissolution test measures how much drug dissolves in a specific time using diluents and apparatus defined by the United States Pharmacopoeia (USP) (7). A dissolution profile is a group of measurements on the same dosage unit at various times. Comparative dissolution profiles compare the dissolution profiles for the average of 6 or 12 units of two different products or two different lots or versions of the same product. If a dissolution test method exists in USP or the European Pharmacopoeia (EP) or if the test approved for the reference listed drug can be obtained from FDA via a Freedom of Information request, then dissolution profiles using these conditions are a good place to start developing a predictive test. It is not unusual to find that different conditions are more predictive, in which case profiles under both sets of conditions must be included in the ANDA, using 12 dosage units of each of the lots used in the bioequivalence trials. If there is no established dissolution test, FDA recommends submitting data using USP media at pH 1.2, 4.5, and 6.8 (8). FDA has defined a difference factor and a similarity factor that can be calculated when comparing two dissolution profiles (9). Unfortunately, dissolution is not always predictive of bioavailability or bioequivalence. If it were, there would be no need to ever perform bioequivalence studies.
4. DO A BIOSTUDY Before considering even a pilot biostudy, those involved in the design of the study protocol must find out everything they can about the pharmacokinetics of the drug substance and the drug product. For example, if the drug substance has three characteristics(a) the drug substance is highly soluble in water, (b) biological membranes are likely to be highly permeable to the drug substance, (c) the dissolution of the drug product is highthen absorption of the product from the gut is unlikely to be the rate-limiting step in distribution of the product throughout the body (10). If these conditions are met, any
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formulation that gives adequate dissolution should be bioequivalent to any other formulation. While it is relatively easy to determine drug solubility and product dissolution, it is more difficult to determine membrane permeability. Methods for determining membrane permeability are beyond the scope of this chapter. If an applicant can determine permeability, a biostudy waiver can be requested. If this waiver is approved, the applicant does not need to do any biostudies. Even if the permeability cannot be determined to a degree that will satisfy FDA, such products are very likely to be bioequivalent, and therefore a pilot biostudy may not be necessary. In 2002, OGD declared their intention to provide more details in the Biopharmaceutics Classification Guidance and to look at concerns that it is overly conservative (11). The standard design of a bioequivalence study is a twoway crossover. The subjects are divided into two equal, randomly assigned groups. The first group receives the test product, while the second receives the reference. Blood samples are taken at appropriate intervals and frozen for measurement of the concentration of drug in the sample. If there are important active metabolites, these will be measured as well. After a suitable time period following the first part of the biostudy, called the washout period, the first group receives the reference product and the second receives the test product. When all samples for each subject are collected, the analysis of each persons samples from both periods is done sequentially, to minimize the affect of analytical variability. The results for each subject obtained during the two periods are compared. In order to properly design a biostudy, one must have a good estimate of the expected time of maximum absorption, tmax, and the elimination half-life, t1=2 . The maximum time is needed to make sure that enough blood samples are taken before and around tmax. This is needed to ensure adequate data for determination of the maximum blood concentration achieved, cmax. The elimination half-life is needed to decide how long to take blood samples in order to get a good measurement of the area under the blood concentration curve, AUC. A good estimate of cmax is also needed so that the method used to analyze the blood samples can be validated in the proper
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Figure 2 Graph illustrating the results of a typical biostudy. Drug level in blood is measured at various times, and the cmax, tmax, and AUC of the test and reference products obtained are compared.
range. Figure 2 provides a graphic illustration of tmax, cmax, and AUC. Values for tmax and t1=2 can sometimes be obtained from the labeling of the reference listed drug product and/or from the scientific literature. However, it is not infrequent for these values to differ from those obtained in the specific population to be used for the bioequivalence trials. Unless one has confidence in the data available, or if no data can be obtained, it is quite prudent to run a small bioequivalence study on the reference listed drug in about 4 subjects representative of the population to be used for the studies. Very few generic drug firms do their own biostudies, especially not the clinical portion, because it takes a very large product development program to keep an in-house biostudy clinic busy full time. Instead, these studies are done by separate firms called contract research organizations (CROs). At times the CRO may choose to perform the study needed to get an estimate of tmax and t1=2 in its population under its own auspices, rather than having a customer pay for it.
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Be forewarned, however, that this usually means the CRO anticipates having many customers for its services involving the drug product. Pilot biostudies are conducted on a small number of subjects. More subjects are used when the expected variability between subjects is higher. If an insufficient number of subjects is used, there is a large risk that the conclusions drawn from the results of the pilot study will not agree with the results of the full-size study. The purpose of a pilot study is to obtain a relatively quick and inexpensive estimation of how close the bioavailability of the generic drug product under development is to its reference listed drug. It is advisable to perform a pilot biostudy for all but the simplest and most bioavailable products. It is imperative to perform a pilot study when there is any possibility that the dissolution profile does not reflect the actual bioavailability of the product and for all modified release products. There are three types of bioequivalence studies: fasting single-dose, fed, and multiple dose studies. At least one fasting single-dose study is required for every ANDA, except for products that are self-evidently bioequivalent, as discussed in the previous section, or products whose Orange Book rating is AA rather than AB. An AA rating means that the products are not regarded as having actual or potential bioequivalence issues as long as they meet the appropriate dissolution specifications. Most if not all AA products that are solid dosage forms were originally approved before 1984. The standard for determining whether a biostudy passes is average bioequivalence. This means that, for the fasting single-dose biostudy, the average cmax, measured AUC to the last sample time, and AUC extrapolated to infinity for the test and reference are compared. These values are compared as log transforms. The 90% confidence interval (CI) of the ratio of test to reference must fall between 0.800 and 1.250. Fed bioequivalence studies are required for most oral dosage forms that require biostudies. FDA has released a draft guidance (12), which proposes that three types of immediate release oral products be exempt from the requirement
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for fed studies. The first is products that are exempt from the requirement for fasting studies based on solubility and permeability, as discussed above. The second is a product for which the labeling of the reference listed drug requires that it be taken on a empty stomach. Both of these exemptions are accepted by OGD today. The third, a product for which the labeling of the reference listed drug does not make any statements about the effect of food on absorption or administration, has historically not been accepted by OGD in many cases as a good reason for exempting a product from requirements for a fed bioequivalence trial. There are additional complexities in this area. For example, if the reference listed drug is labeled that it may be administered by sprinkling it on food, the generic applicant must demonstrate bioequivalence under these conditions in addition to all the other requirements. Current policy at OGD is that the cmax and AUCs for test and reference under fed conditions must be comparable. The draft guidance proposes the use of the same confidence interval approach used for the single-dose fasting study. If this proposal is adopted, the number of subjects used in fed studies will increase. Multidose studies have in the past been required for modified release products. The General Considerations Draft Guidance recommends single-dose studies for both immediaterelease and sustained-release products. All of the above presumes that the level of the drug or its major active metabolite can be measured in plasma, serum, or urine. While this measurement is possible for the majority of oral dosage forms, there are quite a few products for which it is not. Among these are endogenous substances such as hormones and products that are not systemically absorbed. Topical, nasal, and inhalation products generally require special approaches. While conventional biostudies can be performed for many transdermal products, adhesion studies as well as skin irritation and sensitization studies are also required. If measurement of the drug or metabolites is not possible, bioequivalence can sometimes be demonstrated using a clinical endpoint. An example would be a product intended to treat
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hair lice. The endpoint must be one that can be clearly related to the function of the product under test. Its evaluation, especially if somewhat subjective, must be performed by a clinical team that is blinded to the identification of the test versus reference product and well qualified to evaluate the endpoint. Both active treatments, test and reference, must demonstrate superiority over vehicle and/or placebo. These types of studies often require larger numbers of subjects than conventional biostudies. As the number of subjects and the length of treatment needed to observe an effect increase, these studies begin to approach clinical trials in cost and complexity. When this happens it is often not practical or cost-effective to perform such studies. Further discussion of this area is beyond the scope of this chapter. When an ANDA is submitted for multiple dosage strengths of the same product, it is usually not necessary to do all studies for each strength. Waivers are available for some strengths of a product line. FDA regulations permit waivers to be granted if the drug product for which the waiver is being requested meets three criteria. First, it must be the same dosage form as the strength on which the biostudy was performed. In other words, a tablet cannot be granted a waiver based on a study done on a capsule and vice versa. Second, the two strengths of the product must be proportionally similar in their active and inactive ingredients. Third, the strength for which the waiver is being requested must meet appropriate in vitro dissolution requirements (13). The General Considerations Draft Guidance gives three ways in which two strengths of a product can be proportionally similar. The first is when the ingredients are present in exactly the same proportions. In this case, a 20 mg formulation would contain exactly twice the amount of all ingredients as a 10 mg formulation. This is called dose proportional. The second case is when the two formulations differ from dose proportionality by no more than the amounts permitted by the postapproval changes guidances up to level II (14). The third case is limited to low-strength drugs. In this case the total weight of the dosage unit stays the same, and the amount of one or more inactive ingredients is decreased by the same amount as the active
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ingredient is increased. The change in the amount of any inactive ingredient may not be more than that permitted by the postapproval changes guidances up to level II. There are several more details that must be controlled and rules that must be followed in order to achieve an acceptable set of biostudies for an ANDA submission. The reader is referred to the appropriate FDA guidance.
5. PREPARE A SUBMISSION The current OGD Guidance for Industry on Organization of an ANDA became official in February 1999 (15) (available on the FDA web site). The Guidance describes how OGD has preferred to receive ANDAs for many years. The text below describes the contents of an ANDA as it has been developed since 1985. However, changes may occur because of an initiative of the International Committee on Harmonization (ICH). The ICH is a joint venture between the drug regulatory authorities and pharmaceutical innovator trade associations of the United States, the European Union, and Japan. As of this writing, the ICH initiative for a common technical document has not had any impact on ANDA preparation, but in January 2003, FDA published a draft guidance for Industry called Drug Product Chemistry, Manufacturing and Controls Information, which incorporates the common technical document approach. The introduction to this guidance states that it will apply to both NDAs and ANDAs. While the information described below is generally also included in the draft guidance, the order is different. The reader is advised to check the FDA web site before commencing preparation of the documentation. 5.1. Cover Letter The first page or two of every ANDA should be a cover letter. This letter must make clear to FDA who is submitting the application and what they are submitting. Regarding who is submitting the application, the letterhead used and signature of the applicant should match the
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corresponding fields on the 356h form described below. All subsequent submissions must use the same letterhead and be from the same firm at the same address. If the name or address of the firm changes, FDA must be provided with adequate documentation. In a merger or sale, the Agency usually wants documentation from both parties and a clear indication of who now owns the application. The person whose signature is on the application cover letter and the 356h form will be the one to whom FDA will address all communications regarding the application. It is most useful for this to be the employee who has the primary responsibility to prepare responses to FDA communications for this application. This is often the director of regulatory affairs. Be sure to provide phone and fax numbers so that FDA communications can be received expeditiously. 5.2. 356 h Form The signed application form goes directly after the cover letter, in the first section of the application. Fill in the Applicant Information section of the form to exactly match the information in the cover letter. If the firm submitting the application is located outside the United States, it is required that the firm appoint an agent with an office in the United States. The information about this agent should be placed in the appropriate box in this section. U.S. firms should leave this box blank or fill it in as not applicable (N/A). The first line of the product description section is left blank for a new ANDA submission. If a previously withdrawn application is being resubmitted, the number of the withdrawn application goes in this box. The generic name of the product goes in the box marked Established Name. If a trade name has been chosen, this name goes in the Proprietary Name box. (Trade names require clearance from FDA in order to try to minimize the chances for errors due to similar names.) The chemical name of the drug goes in the box marked Chemical/Biochemical/Blood Product Name. FDA usually prefers the official Chemical Abstracts name. For example,
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USP lists three names for ibuprofen in the active ingredients monograph: Benzeneacetic acid, -methyl-4-(2-methylpropyl), () ()-p-Isobutylhydratropic acid ()-2-( p-Isobutylphenyl)propionic acid [15687-27-1] The third name is followed by a number in brackets. This is the Chemical Abstracts number, which can be used to search Chemical Abstracts for information about the compound. OGD has traditionally asked that the name before the Chemical Abstracts number be the name used in the labeling and on the 356h form. Dosage form, strengths, and route of administration should be self-evident. The contents of the Indications for Use box should match the indication section of the labeling but may be paraphrased if this section is too long to fit. Be sure not to include any indications protected by exclusivity, unless you are requesting that your approval be made effective after the exclusivity expires. Refer to the Orange Book to be sure. If you include indications protected by patent but not exclusivity, a patent certification regarding them will be required. In the first box in the Application Information section, the box next to Abbreviated New Drug Application (ANDA, 21CFR 314.94) should be checked. The next box is for NDAs only. In the next box, the trade or brand name of the reference listed drug should be entered, as well as the name of the company that owns the NDA for this product. This entry should match the company listed in the FDA Orange Book as the owner of the application, regardless of who actually markets the product. Since we are discussing a new ANDA submission, Original Application should be checked in the Type of Submission box. Partial submissions are not used for ANDAs, so the next box should be left blank. The box labeled If a Supplement is also not applicable to original applications. The reason for submission is Original Application in this case. Proposed Marketing Status must be the same as that of the reference listed drug. Number of Volumes and Paper and/or Electronic should be self-evident.
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For the last two sections on the first page of the 356h, it is almost always necessary to attach one or more continuation sheets. In the Establishment Information section the application must list all sites to be used to manufacture, package, and or test both the bulk active pharmaceutical ingredient and the finished product. Even an outside laboratory used to do one test must be listed here. The address, phone number, and name of a contact for FDA to call must be given. For firms in the United States, the registration (CFN, central file number) number must be included. Just to make things even more complicated, FDA is currently in the process of changing CFNs to FEI numbers. For firms that have Drug Master Files (DMFs), the DMF number must be provided. Finally, for every firm listed, the applicant must state whether the firm is ready to be inspected or, if not, the date on which it will be ready. A DMF is a separate submission made to the FDA in which a firm other than the applicant can disclose information to the FDA that they do not want to disclose to the applicant because it is proprietary or a trade secret. FDA only reviews DMFs in connection with the review of an application; they are not independently reviewed. Do not state that a firm is ready in the hope that it will be ready by the time FDA calls. It is always possible that the firms district FDA office might call to schedule a preapproval inspection shortly after the application is filed by FDA. The last section on the first page of the 356h form is Cross References. For ANDAs, this is a list of all DMFs referenced throughout the application. In addition to the DMFs listed in the previous section, packaging components suppliers and sometimes suppliers of inactive ingredients have DMFs. It is advisable to carefully review the assembled submission to ensure that all DMFs mentioned anywhere in the application are listed here. For every DMF mentioned, the holder of the DMF must send a letter to FDA for filing in the DMF, authorizing the FDA to refer to the DMF on behalf of the ANDA applicant. A copy of each letter must be included in the appropriate section of the application. The second page of the 356h form contains a list of various sections that might be included in an application. An initial
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ANDA submission normally contains item 2, labeling; items 4.A and 4.C, the chemistry section; item 6, the bioequivalence section; item 14, the patent certification section; item 16, the debarment certification; item 17, the field copy certification; and item 19, financial information for those who conducted the biostudies. Items 16 and 17 are briefly discussed in the next section; item 19 is normally provided by those who conduct the biostudies. Make sure that the original 356h with the original signature is placed in the archival copy of the ANDA; this is the copy that is submitted with the blue plastic covers and that contains all sections of the application. Also make sure that the address and telephone number on the second page match those on the first page. 5.3. Organization of Application It is strongly suggested by OGD that the application be organized according to Attachment C of OGD Guidance for Industry on Organization of an ANDA, February 1999. Each volume of the submission must contain a copy of the table of contents. Page numbers in the table of contents are filled in after the entire application has been numbered as required in the Guidance. Section I of the application contains the completed 356h form discussed in the previous section. Section II is called Basis for ANDA Submission. In this section the applicant states that the submission is based on the reference listed drug. This is the same information that is in the third box of the Application Information section of the 356h. Make sure it matches exactly. It is advisable to include a printout from the electronic Orange Book in this section, so there is no doubt as to the status of the reference listed drug chosen. If the application is based on an approved Citizens Petition, this section must make an affirmative declaration to that effect. A copy of the petition and its FDA approval should be included. Section III includes the patent certification and the exclusivity statement. If no patents for the reference listed drug were listed in the Orange Book, then the applicant should
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submit a Paragraph I certification. Suitable language would be Paragraph I Certification: Company X (the applicant) certifies that patent information for product Y has not been submitted to FDA. In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the listed drug referred to in this application or that claim a use of the listed drug. If patents were listed in the Orange Book but they have all expired on the date the submission is sent to FDA, then a Paragraph II Certification is required. For example, Paragraph II Certification: Company X (the applicant) certifies that all patents submitted to FDA for product Y have expired. If there are patents still in force on the day of submission and the applicant does not intend to market their product until they expire, a Paragraph III Certification is appropriate. Typical language would be Paragraph III Certification: Company X (the applicant) certifies that Patent No. ZZZZZ will expire on QQ (date). Applicant requests that final approval of this application be made effective on that date. Paragraph IV certifications are submitted when the applicant is challenging the patent. FDA regulations (21CFRx314.94 (a)(12)(4) give language to be used: I, (name of applicant), certify that Patent No. ZZZZZ (is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of ) (name of proposed drug product) for which this application is submitted. Following the certification must be a statement that the applicant will comply with the requirements under Sec. 314.95(a) with respect to providing a notice to each owner of the patent or their representatives and to the holder of the approved application for the listed drug, and with the requirements under Sec. 314.95(c) with respect to the content of the notice. Section IV of an ANDA, entitled Comparison between Generic Drug and Reference Listed Drug, is usually submitted as a table. (See Table 1 for a guide to preparing this.) With the exception of permitted variations in ingredients, the information for the reference listed drug and that for the proposed generic drug should be the same. Section V contains the proposed labeling for the generic drug. The first pages of this section may be a copy of the reference listed drug labeling or a side-by-side comparison of the
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Table 1
Guide to Preparing Table for Section IV of an ANDA

NDA holders brand name of reference listed drug Applicants name of proposed generic drug e.g., Pain Generic name of active(s) List all ingredients included in proposed product
Conditions of use Active ingredient(s) Inactive ingredients (for products required to have the same inactive ingredients only, such as parenterals) Route of administration Dosage form
e.g., Pain (exactly as in labeling) Generic name of active(s) List all ingredients included in brand labeling
Oral, parenteral, etc. Tablet, capsule, injection, ointment, etc. X mg See Section V
Oral, parenteral, etc. Tablet, capsule, injection, ointment, etc. X mg See Section V.
Strength Labeling
proposed labeling to that of the reference listed drug, both the insert and the container labels. If the reference listed drug labeling is first, a side-by-side comparison is included with the copies of the applicants proposed labeling. In the side-by-side comparison of the proposed labeling to that of the reference listed drug, every difference between the two must be highlighted and explained. In all cases, the brand name in the reference labeling must be changed to the generic name. It is not always easy to decide exactly how to do this, especially when the drug is a salt. The name of the product with its dosage form is used in the description of the product, the Dosage and Administration section of the labeling, and in the How Supplied section. When discussing the drug after it has been absorbed into the circulation, the counterion is not included, since dissociation will have occurred in solution. After the side-by-side comparison, four copies of the proposed labeling in draft must be presented. It is rarely appropriate to
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submit final printed labeling in an initial submission. However, should the applicant choose to do so, 12 copies must be presented. Section VI is quite long for those submissions that require one or more biostudies. Therefore, it is recommended that the order of information not follow that given in the guidance. The beginning of Section VI should contain a summary of the section contents, a list of all biostudies included in the application, any necessary requests for in vivo biostudy waivers, and all dissolution profile data required. Immediately after the dissolution profile data, it is advisable to include a copy of the method used to obtain the results. The reason for placing the method here, even though it will be repeated in Section XV, is that the bioequivalence review copy does not contain Section XV. The bioequivalence reviewer needs to see the method used to obtain the dissolution results. For applications requesting biostudy waivers, a comparison of the formulation for the strengths on which biostudies were performed to the formulations of the strengths for which waivers are requested is required. This comparison should also be in the beginning of Section VI. The comparison is used by the reviewer to determine if the products meet the requirements for proportional similarity of formulations. These requirements are discussed earlier in this chapter. In addition to the items listed in Attachment C of OGD Guidance for Industry on Organization of an ANDA for Section VI, it is advisable to include the actual yields of all batches used for biostudies or dissolution profile testing. While it is true that these data can be found in Section XII in the executed batch records for these batches, Section XII is not a part of the bioequivalence review copy, so this information is not readily available to the bioequivalence reviewer. We have now finished the information that should be in the beginning of Section VI. The remaining information includes the Financial Certification/Disclosure Statements (Forms 3454 or 3455) and the biostudies themselves, together with their protocols. Firms may choose to number these many pages sequentially after the page numbers of the information already included in the Section or may choose to put the
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studies in Appendices, numbering them at the end of the submission or with their own appendix numbers. The former allows the information to remain in the order specified by the OGD Guidance, while the latter is much easier to perform and allows the rest of the pages to be numbered before the biostudy final reports are received. Section VII is entitled the Components and Composition Statements. One would think that this section should be one of the easiest to complete in the entire ANDA, as it is often only one or two pages. Nevertheless, this section garners a disproportionate number of comments from OGD reviewers. There are several pitfalls that one should attempt to avoid. The Components statement is a qualitative list of all the ingredients in the product; the Composition statement includes the same ingredients in a quantitative manner. The amount of each ingredient per dosage unit must be in the Composition statement. Firms often include the amount per batch and/or the relative percentage of each ingredient. These statements must match exactly the equivalent statements in the manufacturing and processing instructions and the executed batch records. A difference of one digit in the last decimal place between these documents and the lists will likely elicit a comment from the OGD reviewer. Manufacturing aids such as solvents that are removed during processing must also be included. They should be annotated to indicate that they are removed during processing. Inactive ingredients that are mixtures, such as commercial tablet coatings, must have their individual ingredients listed. The Components statement must also match the inactive ingredients statement in the labeling, except that those ingredients removed during processing are not included in the labeling and the order of ingredients may differ. Section VIII covers the raw materials used to manufacture the dosage form. The first subsection of this section concerns the active ingredients. Start with a list of each active ingredient and the name and address of the facility at which it will be manufactured. This is often not the address of the administrative office, so research it carefully. Foreign addresses are often less complete than those for American firms, but try to get at least the name of the street on which the factory is
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located, even if there is no equivalent to the American street address. If possible, try to include the facilitys FDA Central File Number (CFN). The CFN is a number used by the FDA Districts and the Foreign Inspections Branch to organize their records. There is a space for the CFN on the FDA 483 form; this is the form where the FDA Investigator reports his or her observations during the inspection to the inspected firm. The CFN is also usually included in the Establishment Investigation Report (EIR) that the investigator writes reporting his or her observations to FDA management. If neither of these sources provides the CFN, a telephone call to the appropriate FDA District Office or the Foreign Inspections Branch should suffice. For most ANDAs the required information about how the active ingredients are produced is contained in the relevant DMFs held by the manufacturers of these materials. Copies of all letters of authorization from the holders of these DMFs should be placed here. If the manufacturer has authorized their U.S. agent and/or supplier to issue DMF authorization letters, a copy of that authorization letter should follow the DMF authorization letter from the agent or supplier. If the product contains more than one active ingredient, an introductory page listing which manufacturer and which supplier are used for each will help the reviewer avoid confusion. It is not a bad idea to do this even when only one active ingredient is involved. If the ANDA applicant is going to synthesize the active ingredients, all the information usually included in a DMF may be included in Section VII of an ANDA. A discussion of this information is outside the scope of this chapter. Those firms that synthesize their own active ingredients should be sophisticated and knowledgeable enough to prepare this information. The next pages of this section are certificates of analysis (CoA) from the manufacturers of the active ingredients. These certificates should contain both the specifications and the test results for all appropriate tests. At times the letterhead of the DMF authorization letter or U.S. agent authorization letter contains a different address than the address on the
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CoA. This may be caused by the headquarters of a manufacturer issuing the letters while the manufacturing site issues the CoA. Be careful to explain any such circumstances to the reviewer. It is usually advisable that this information be for the batches actually used to produce the exhibit or biostudy batches. After the manufacturers CoAs come the CoAs from the firm that will be manufacturing the finished dosage form. Include the same batches as those for which manufacturer CoAs are submitted. Any large discrepancy between the two data sets must be investigated and explained. Following the CoAs, examples of spectra and chromatograms are required. For each test, include both standard and sample examples, clearly labeled so the reviewer can tell which is which. Include the source and lot numbers of the standards. If any standard was not USP, the FDA reviewer will want to know how it was qualified. There is no mention of where to place this information in the OGD Guidance, so many firms put it directly after the spectra and chromatograms. Be sure to include every test that produces a spectrum or a chromatogram, including thin layer chromatography photographs. The last requirement for this subsection is a statement of the retesting period that will be used for the drug substances. If a subset of the original tests will be used for retesting, that subset should be described at this point in the application. The second subsection of Section VIII covers inactive ingredients. For each ingredient the applicant must include the specifications the applicant will apply to the ingredient, a copy of the suppliers CoA with specification and test results, and a discussion of the retesting schedule. It is appropriate to include a general discussion of any reduced testing program used at this point in the application. The applicant would be well advised to compare the contents of this section to the components and composition statements in Section VII. Failure to include all ingredients, especially solvents removed during processing, is a frequent observation made by OGD review chemists. Section IX is much shorter than Section VIII. It starts with a list of every facility used to manufacture, package or test the
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product, including the address and Central File Number (CFN) of each. A brief description of the facility is listed next in the OGD Guidance. Inclusion of this description is voluntary because facility issues are handled by the FDA District Offices and not OGD. The Quality Unit of each facility described in this section must provide a signed certification that FDA Current Good Manufacturing Practice regulations are being followed at the facility. A copy of each certification is placed in Section IX. Section X covers outside firms, including contract testing laboratories. Admittedly, whether a firm is considered outside or not is somewhat arbitrary, particularly for firms that use contract manufacturers or packagers. As long as every firm is listed in either Section IX or X, the reviewer should be satisfied. It is important to make it very clear what each facility or firm will do and how they will be involved in the product that is the subject of the application. Include the CFN of each firm. Each outside firm is also required to provide a signed certification that FDA Current Good Manufacturing Practice regulations are being followed at the firm; copies go in Section X. Section XI covers manufacturing and processing instructions. It starts with a description of the manufacturing process. A flow chart of the process is often a useful tool to assist the reviewer in understanding the methods and procedures used. Each stage should be labeled clearly and in a manner consistent with the manufacturing instructions, which come next. Manufacturing instructions can also be called masters, master batch records, or blank batch records. Whatever they are called, the blank batch records for the largest intended commercial batch size planned are included here. These records are included for each product strength covered by the application. All equipment to be used must be specified. Be aware that if a firm has not yet received the equipment specified in this section of the ANDA at the time of a preapproval inspection, FDA will classify the inspection as firm not ready and will not grant approval. Further scale-up is permitted after approval. It is prudent to restrict the equipment specified to that already in the plant. Do not forget to include blank batch records for the packaging operations.
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For sterile dosage forms, there are some special requirements for Section XI. Microbiological Validation should be included in the description of the manufacturing process, if it is applicable. The applicant should explain whether the product is prepared using aseptic fill techniques or if it is terminally sterilized. If aseptic fill is used, filter validation should be provided. If terminal sterilization will be used, explain the method and its validation. The OGD Guidance lists the reprocessing statement as coming after the blank batch records. Since the blank batch records are long, while the reprocessing statement is short, it is usually advisable to reverse this order. The reprocessing statement is basically an acknowledgment that the applicant is aware that reprocessing procedures require prior approval from FDA. FDA will only grant this approval based on data showing that the reprocessing does not affect the performance or quality of the drug product. If a firm has such data, it is permissible to include the procedure and its supporting data at this point in the application. However, most firms will not do this for fear that such a procedure might delay application approval. Section XII is designated In-Process Information. The primary contents of this section are the executed batch records for the batches on which biostudies or dissolution profile testing were performed. The records must specify the equipment used and the results of yield reconciliation at each stage. Packaging records with label reconciliation must also be included. As a rule, only one batch for each strength of the product is required. However, for antibiotics manufactured by fermentation, three batches are required. Inevitably, there will be some differences between the executed records in Section XII and the blank records in Section XI. Each such difference must be explained. For example, if the equipment used to make the executed batch differs from that planned for the commercial batches, the firm could use the FDA Guidance for Industry SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum (16), to demonstrate that they are equivalent.
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Executed batch records contain information not included in the blank batch records, such as temperature chart recordings, forms from Standard Operating Procedures, and labels that were removed from drums being used. Keep in mind that while these items may seem obvious to those preparing the submission, they will not be so obvious to the reviewer. Careful labeling and explanation of the forms can avoid unnecessary reviewer questions and observations. After the executed batch records there is a subsection for the in-process controls used during manufacturing and packaging. The test procedures, specifications, and data obtained from the exhibit batches must be provided. OGD reviewers often ask for tighter control specifications than those proposed by applicants. They will accept only specifications that can be justified by real data. If the specifications are based on data obtained during product development or on data from batches not included in the submission, a report justifying the specification with the associated data can avoid reviewer comments. Section XIII includes Packaging Materials Controls. Start this section with a summary of the packaging system, usually a list of each package size and the components that go into it. Make sure that this list matches the sizes listed in the product labeling and the information in the packaging records in Sections XI and XII. Include in the list the source of each componentboth the name of the firm and the address where the component is manufactured. After this list include a subsection for each component. Instead of attempting a physical description, an engineering diagram from the component manufacturer is usually included. Provide information about the source of the component, the materials used to manufacture the component, the sources of these materials, and the testing performed to ensure that the component complies with appropriate specifications. For those components, like bottles, that have USP specifications, make sure that there are provisions for ensuring that these requirements are met. GMPs require that a firm perform periodic testing to confirm the acceptability of their vendors; information about how this is done for packaging components must be included in this section. Also include the acceptance
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tests done by the packaging facility when they receive the components and the retest requirements for components that have remained at the facility for some time. Section XIV, entitled Controls for the Finished Dosage Form, contains the test procedures the laboratory will use to test the finished product and the specifications that the product must meet. The results of the testing of the submission batches are also presented in this section. Most firms use preprinted specification and report forms, but these are sometimes not available at the time the testing of the submission batches is performed. Many firms will transcribe the data onto the form for the submission. This is acceptable provided the fact that this is a transcription after the fact is clearly indicated on the form. This transcription must be carefully checked and signed following GMPs. Section XV is for Analytical Methods. There should be two subsections: one for the drug substance (the active pharmaceutical ingredient) and one for the finished product. If the drug substance is listed in USP, it is not necessary to include a copy of the USP monograph. The applicant simply states that testing will be performed as directed in the current USP. No method validation is required for USP monographs that apply to drug substances. If the drug substance is not listed in the USP, a copy of the test procedure and its validation must be included at this point. In many cases, additional tests must be added to a USP monograph for a drug substance to control impurities such as process intermediates, side products, and residual solvents. The Guidance for Industry ANDAs: Impurities in Drug Substances [U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), November 1999] explains that no unidentified impurity may be present in a drug substance at a level greater than 0.1%. The Guidance for Industry, Q3C Impurities: Residual Solvents [U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), ICH, December 1997] gives permitted levels of solvents. These tests must be validated. Recovery and
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limit of quantitation are particularly important for limit tests of this type. The applicant must include the methods for these tests and their validation at this point in the ANDA. The FDA Guidance lists drug substance test specifications and data as being the next item in this section. However, this information has already been included in Section VII under the active ingredients subsection. Some firms choose to repeat the information at this point, while others will include a reference to Section VII. Both approaches have been accepted by OGD. The next subsection concerns the methods for the drug product. The methods themselves are included in Section XIV and need not be repeated in Section XV. Method validation is always required. Even if the drug product is listed in the USP, the applicant must demonstrate that the methods are suitable for the product being submitted. Recovery and specificity studies are the most common ways that suitability is demonstrated. Similarly to the drug substance requirements, the FDA Guidance lists drug product test specifications and data as being the next item in this section. However, this information has already been included in Section XIV Controls for the Finished Dosage Form. Some firms choose to repeat the information at this point, while others will include a reference to Section XIV. Both approaches have been accepted by OGD. If the drug product and/or the drug substance are not USP articles, two separately bound copies of Section XV must be submitted. These are supposed to be sent by the review chemist to the testing laboratory. If Section XV refers to Sections XIV and VII, include the appropriate information from those sections as well. It is prudent to make another copy of this information and include it with the samples when FDA requests them. In the most recent ANDA Checklist for Completeness and Acceptability of an Application, there is no section for Analytical Methods. It is possible that the intent is for the information described above for this section to be included only in the Methods Validation Package. Because of this difference, the numbering of Sections XV and higher is different in the Checklist and in the Guidance. Section XVI covers Stability of the Finished Dosage Form. Five items must be included in this section. First, the applicant
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must include a stability protocol. This document is specific to the product covered by the application, but it may be derived from the firms Stability Standard Operating Procedure. The protocol defines which samples will be included in the stability testing program, how often and when they will be tested, and which tests will be performed. It should also include information about how the data obtained will be used to extend the expiration period of the product, if appropriate. The second item in this section is postapproval commitments. This is a statement by the applicant that the first three postapproval batches and at least one batch per year will be included in the stability testing program and that any batch for which any parameter goes out of specification on stability will be removed from the market. The applicant also promises to notify OGD of any stability recall conducted on the product covered by the application. This commitment is usually signed by the firms director of quality or the employee responsible for ensuring that the commitments are followed. Third on the list of things for the stability section is a statement of the expiration period that the applicant plans to use for the product. If a solid dosage form continues to meet all specifications after testing for 3 months under accelerated conditions (17), the applicant may request a 24-month expiration period. If the product is packed in blisters, an 18-month period may be requested. If the product does not stay within specifications on accelerated stability, at this time OGD requires real-time stability at controlled room temperature up to the requested expiration period and does not accept intermediate condition data as defined in the draft stability guidance. The stability data available at the time of submission are presented next. OGD requires extensive information about the batch to be part of the stability record. For example, the source of the active ingredient and all packaging components, the location where the finished product was manufactured, the batch size, and the formulation must be included. Several commercial computer programs are available that make the task of preparing acceptable stability reports somewhat easier. The last item listed for this section is stabilityindicating test data of samples under various stress conditions. The data
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are almost always included in the method validation report in Section XV. The firm may choose to reproduce the data in this section or include a reference to Section XV. There is no Section XVII. This number is annotated as reserved in the FDA Guidance. Section XVIII covers Samples. Do not submit samples with the application. FDA will send a letter telling you when and where to send them. However, you do need to submit a list of available samples. List the active ingredient lot used to make the exhibit batches and all exhibit batches. If any standards needed to test these samples are not compendial, list those as well. Section XIX is Environmental Considerations. For most ANDAs this section is a claim of a categorical exclusion from the requirements to submit an environmental assessment, because approval of the application will not increase the use of the active moiety. The applicant should refer to 21CFR x25.31(a). Section XX contains information required by the Generic Drug Enforcement Act and U.S. agent letters of authorization. All firms mentioned in Sections IX and X of the application must provide certifications required by the Generic Drug Enforcement Act, often called debarment certifications. In the debarment certification the applicant must certify that no one who was in any way involved with the ANDA being submitted is on the current FDA debarment list. The current list is posted in the Office of Regulatory Affairs section of the FDA web site, under compliance references. In addition, all foreign firms are now required by FDA to appoint a U.S. agent. A copy of the letter from the foreign firm to FDA, usually part of the DMF, which appoints this agent should be included in Section XX. FDA will send all correspondence, such as DMF deficiency letters, to the U.S. agent. Section XXI is a catch-all section for information that is not included in the previous sections. References to previously submitted information and copies of literature publications for which English translations are submitted are included in Section XXI. If some or all of this information is not needed, the applicant should so state. For example, state references to
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previously submitted informationnone. Even though letters of authorization for FDA to refer to a DMF on behalf of an applicant were submitted in various previous sections, two copies of each letter are to be included in Section XXI. The applicant must also certify in Section XXI that a copy of the application is being sent to the FDA District Office responsible for the geographical location in which the applicant is located. This Field Copy is required to contain all sections of the ANDA except the bioequivalence and labeling sections. Section XXII covers Sterilization Assurance for sterile product only. For all other products, Section XXII should say sterilization assurance not applicable. If the application is for a sterile product, the review copy of Section XXII should be bound separately from the chemistry review volumes. This section will be reviewed by the microbiologists. FDA recommends including a copy of the cover letter, package insert labeling, a summary of the manufacturing process including the components and composition statement, and copies of the executed batch record containing holding times, filter integrity testing, and sterilization records. FDA also recommends that the application follow the portions of the Guidance for Industry on Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products that apply to the process in the application. 5.4. Electronic Submissions As of July 15, 2000, one may now submit ANDAs in electronic format in place of paper. OGD placed the ANDA on public docket 92S-0251 as a submission acceptable in electronic format as allowed under 21 CFR Part 11. It should be noted that Part 11 requires that datasets provided in electronic format and used in the review process meet the requirements for archiving, i.e., protection of those records to enable their accurate and ready retrieval throughout the records retention period. It is highly recommended that the applicant discuss the format they plan to use with appropriate OGD staff before making a financial commitment to a given electronic submission system.
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In June 2002 a guidance for industry entitled Providing Regulatory Submissions in Electronic FormatANDAs (18) was implemented by OGD. This guidance indicates that most files should be images in PDF format. It also gives a folder structure that the applicant should use and other important details. The applicant should be aware that electronic datasets, including those accompanying a paper submission, cannot be considered as official and used to support the application if they are submitted in a file format that is not archivable. In the future, as FDA and industry progress in meeting the goals of use of electronic submissions, compliance with electronic submission regulations will be required. Even if the rest of the application is paper, electronic datasets must accompany an ANDA application to support the review of bioequivalence studies. At this time the archival dataset format is SAS Transport. Applicants typically rely on their biostudy contract laboratories to create the electronic datasets in a way that is pleasing to the FDA reviewers. 5.5. Making the Submission User-Friendly An ANDA, even though it is abbreviated in comparison to an NDA, is not a short document. If the applicant makes it easier for the FDA reviewer to find the information in the document, the review will go more smoothly. A table of contents for the entire document is required, a copy of which must be in the front of each volume. Any section that is more than four or five pages long should have its own table of contents. Make liberal use of dividers between sections and colored paper or other markers between subsections. Do not hide short subsections of required information behind longer subsections, even if this means you deviate from the order of section information listed in the FDA Guidance. Make your submission easy to read. Use clear language. All information authored by those whose first language is not English should be carefully reviewed by good editors whose first language is American English. All sections should be reviewed by several editors, as well as those who are responsible for the
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technical contents. Use a clear font and do not make the type size too small. Inevitably, your submission will contain some photocopies of documentation, such as manufacturers certificates of analysis. Make sure that every copy you submit is completely legible. Beware of American copies of European documents. Europeans use paper that is slightly longer, and if copies are not reduced, information on the bottom will be cut off.
6. RESPONSE TO FDA COMMENTS One to 3 months after the OGD receives the ANDA, the applicant can anticipate a letter indicating that the application has been accepted for filing and providing the ANDA number. If there is a relatively small matter preventing OGD from accepting an application, the usual procedure is for the project manager to call the person who signed the application and explain what is needed. A very quick response is required. If the application has a serious flaw or if one does not respond quickly to the telephone call, the applicant will receive a refuse-to-file letter. About 120 days after OGD receives the application, the applicant should anticipate receiving the first FDA bioequivalence comment letter, followed by the chemistry and labeling comment letter at about 180 days. If the applicant has done a good job of preparing a complete and reviewer-friendly submission, and if there are no difficult scientific issues involved, one might anticipate that the bioequivalence letter might say that the Division of Bioequivalence has no comments, while the chemistry and labeling letter will require a minor amendment, rather than a major amendment. In OGD, each reviewer has a computer-controlled work queue. New applications and major amendments go to the bottom of the queue. Minor amendments go after all other minors already in the queue but ahead of majors and new applications. The difference is usually about 4 months in turnaround time.
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How an applicant responds to the FDA reviewers observations is critical to how quickly the application can be approved. Read the observation very carefully. Make sure that your response addresses what the reviewer is asking for. Watch out for observations that require more than one item in response. Include as much supporting data, as attachments or exhibits to your response, as is necessary to prove to the reviewer that your response is correct. Sometimes the reviewer will ask for something that was already in your original submission. The applicant should consider these observations as an indication that the application was not as reviewer friendly as it could have been. Politely point out in your response the page number where the information was located in the original application. It is a good idea to provide another copy as an attachment to the response for the reviewers convenience.
7. APPROVAL At this point the applicant who has prepared a complete and reviewer-friendly application and responded carefully and completely to all FDA requests for additional information can anticipate a speedy approval. As of this writing the median time from submission to approval is 1824 months. When you are close to approval you may inquire with the OGD Project Officers as to the status of the approval package for your submission. This can help in planning scale-up, validation, and commercial marketing. The latter is, of course, the objective of the entire exercise, a commercial product that can produce profits for its sponsor.
REFERENCES
1. Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration, Published yearly and updated monthly.
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2. 3. 4. 5. 6. 7. 8.
The Drug Price Competition and Patent Term Restoration Act of 1984. United States Congress. Food Drug and Cosmetic (FC&D) Act, United States Congress, section 505(3)(D)(ii). United States Code of Federal Regulations, 21CFR 314.95. 21CFR 313.107(b)(3). Federal Register Vol. 67, No. 206, October 24, 2002, pages 6544865465. USP 26NF 21, United States Pharmacopeial Convention, 2002, section <711>. Guidance for Industry; Bioavailability and Bioequivalence for Orally Administered Drug ProductsGeneral Considerations, Draft, U.S. Food and Drug Administration, July 2002. Guidance for Industry; Dissolution Testing of Immediate Release Solid Oral Dosage Forms, U.S. Food and Drug Administration, August 1997. Guidance for Industry; Waiver of the In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, U.S. Food and Drug Administration, August 2000. The Pink Sheet, F-D-C Reports, July 15, 2002 Guidance for Industry; Food-Effect Bioavailability and Fed Bioequivalence Studies: Study Design, Data Analysis, and Labeling, Draft, U.S. Food and Drug Administration, October 2001. 21CFR 320.22. Guidance for Industry; Immediate Release Solid Oral Dosage FormsScale Up and Post Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (SUPAC-IR), U.S. Food and Drug Administration, November1995; and Guidance for Industry; SUPAC-MR: Modified Release Solid Oral Dosage FormsScale Up and Post Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation, U.S. Food and Drug Administration, October 1997.
9.
10.
11. 12.
13. 14.
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15. 16.
Guidance for Industry; Organization of an ANDA, U.S. Food and Drug Administration, February 1999, OGD #1 Revision1. Guidance for Industry; SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum CMC 9, Revision 1, U.S. Food and Drug Administration, January 1999. Guidance for Industry, Stability Testing of Drug Substances and Drug Products, Draft, U.S. Food and Drug Administration, June 1998. Guidance for Industry, Providing Regulatory Submissions in Electronic FormatANDAs, U.S. Food and Drug Administration, June 2002.
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18.
14
Current Good Manufacturing Practice and the Drug Approval Process
NICHOLAS BUHAY Food and Drug Administration Rockville, Maryland, U.S.A.
Employment of current good manufacturing practice (CGMP) and approval of a new drug application (NDA) are two pillars of federal law providing support of manufacturing quality for pharmaceutical drug products offered to American consumers in the United States marketplace. These requirements are established in the Federal Food, Drug and Cosmetic Act (FDCA). In this chapter we will discuss these two requirements and how they interface with each other in the FDA programs designed to execute the mandates of the law.
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The CGMP requirement focuses on manufacturing quality for the purpose of assuring that each pharmaceutical drug product is as safe as the law requires it to be and that it has the identity, strength, quality, and purity characteristics by which it is defined in large part. Under FDCA Section 501(a)(2)(B), activities that amount to manufacture, processing, packing, or holding of a drug must be performed in conformance with this current good manufacturing practice. Very explicitly, the CGMP requirement applies to the methods used in performing the above regulated activities and to the facilities and the controls used for these activities in producing a drug. Pharmaceutical drugs resulting from manufacturing methods, facilities, and controls that are not operated or administered in conformance with CGMP are considered to be adulterated. In essence, their manufacturing quality is not assured to a legally minimum level. They are in violation of the law, and they are subject to regulatory actions by the U.S. Food and Drug Administration (FDA). Section 505(a) of FDCA prohibits in U.S. commerce any new drug unless that product is the subject of a properly filed application with FDA to place it in commerce and an FDA approval of the application is effective. A new drug application (NDA) filed with FDA to meet the requirement to acquire approval may be disapproved if a number of conditions are not met. The full list can be found in Sections 505(d)(3) for new drug applications and 505( j)(4) for abbreviated new drug applications (ANDAs). Both sections contain the conditions for approval that the methods used in, and the facilities and controls used for, the manufacture are adequate to preserve its identity, strength, quality, and purity. It should be noted that this is essentially the same expression as the statement of the CGMP requirement. The CGMP requirement assures that legally acceptable product attributes result from manufacturing operations; all manufacturing-related proposals in the application for the product must maintain these same attributes. A new drug application may not be approved if FDA finds the CGMP to be employed in its production is inadequate. FDA programs for assessment of conformance with the CGMP requirement use an approach that includes a number of
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variations in inspection action. The variations have been devised and put into use to satisfy a number of regulatory purposes as well as management efficiency purposes. There is no such thing as virtual manufacturing of pharmaceutical drugs. They are real products fashioned in a real environment with real resources. It is a fundamental axiom of the regulatory scheme that this environment, both physical and operational, in large part determines the quality, identity, purity, and strength characteristics that have been established for drug products. Conditions and practices in this manufacturing venue are complex, involving many steps, sophisticated equipment, and many people. This complexity provides the potential or the occasion for variation or contamination that raises concern that the desired fundamental characteristics have been put into output products. An inspection operation directed at evaluating the ongoing conditions and practices in the site addresses this concern. Besides the concerns for manufacturing in an environment free from obvious conditions like insanitation, there are additional conditions and practices unique to the industry. Pharmaceutical drug manufacture is a part of the chemical industry; products are applied to the living individual. Most pharmaceutical manufacturing occurs in multiproduct facilities. Manufacturing operations may create conditions resulting in cross-contamination. An example is chemical ingredient dust generated by equipment operations. Many white powders are used to produce different products. Each may have a vastly different toxicity profile and treatment application. Wrong selection of materials and incorporation in a manufacturing process has occurred. Manufacturing processes are complex, employing many steps and ordered activities to realize the object product. Written procedures, preparation of records of actions, and training decrease or eliminate mistakes or variations that have an impact on product attributes. To ensure against manufacturing quality problems resulting from this situation, Congress has recognized the value and importance of inspection and established it as a required operation for the assessment of conformance with the CGMP requirement for manufacture of pharmaceuticals.
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Periodic inspection of a pharmaceutical manufacturing factory is a specific requirement in the Food, Drug, and Cosmetic Act. Section 510(h) requires every such establishment engaged in the manufacture, propagation, compounding or processing of a drug or drugs . . . shall be so inspected at least once in every . . . two-year period. Section 704 of the law discusses some purposes of the inspection and indicates both specific and general items of interest for the inspection. Those items include processes, controls, facilities, equipment, finished and unfinished materials, containers, labeling and records and files. Mandated periodic inspections are performed to assess the conformance of the factory site to the requirement for manufacture within current good manufacturing practice. The inspections are performed according to instructions provided by an FDA operating procedure called the Drug Manufacturing Inspections Compliance Program. This compliance program is one of a set of such programs established and maintained to allocate resources for and to guide the performance of investigative operations for compliance assessment in identified priority regulatory areas. The need for compliance programs is reviewed each year. Compliance programs may be established and retired in response to emerging developments in the regulated industry. Because of the enduring priority of assurance against manufacturing error and of controlled manufacturing practice, the Drug Manufacturing Inspection Compliance Program has been and will continue to be a fixture in the overall drug regulatory program of the Center for Drug Evaluation and Research (CDER). The outcomes of these inspections are available for use in the drug approval decision. Pharmaceutical factory sites found by the inspection to be in acceptable conformance with the CGMP requirement means that manufacturing methods, facilities, and controls are operated or administered satisfactorily in that site. This general conclusion may be applied to the case of a specific new drug application pending approval, recalling that one of the approval requirements is that methods used in, and the facilities and controls used for, the manufacture are adequate to preserve its identity strength, quality, and purity.
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It is evident that some extrapolation is done in applying a CGMP inspection conformance assessment to an approval decision for an application. The inspection observes and assesses conditions and practices at a period in the past; a new drug application proposes future manufacture. The inspection evaluates manufacturing operations for products that are different from the product that is the subject of the application. The proposed product may involve for commercial production some manufacturing technology not yet in operation at the time of the CGMP inspection. Judgments are made, indirect information is considered; a risk management approach is used. Similarities between the manufacturing experience in place and the proposed product manufacturing requirements, the complexity of the manufacturing process and the process controls, the CGMP compliance history of the factory site proposed, the physical and toxicological properties of the materials that may be processed in a site, the completeness of information available supporting a factory site conformance with the CGMP requirementall may be used to decide upon the use and extent of application of a CGMP inspection. Where an existing report of CGMP inspection is judged insufficient for supporting an application approval decision, a special inspection will be scheduled. This is known as the preapproval inspection. As with CGMP conformance assessment inspections, performance of FDA preapproval inspections are organized in a compliance program. This program is called the Preapproval Inspections/Investigations Compliance Program. The program was established in August 1994, largely in response to the discovery that a number of applicant firms provided in new drug applications to the FDA unreliable, misleading, and false information. In an investigation that spanned about 8 years, about 20 companies and 75 individuals were prosecuted for various violations of requirements for submission of invalid, incomplete information related to new drug applications. Such information is essentially worthless for the process of evaluating the safety and efficacy of a proposed new drug before it is introduced to the marketplace. The preapproval inspection (PAI) was designed to provide assurances
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that the data and information submitted in new drug applications are reliable and that actual conditions and practices in a given manufacturing facility were adequate to incorporate the production of a new product. Since FDA does not have the enough inspection resources to perform a PAI for every application received, risk management principles were incorporated into the program rules for selection of facilities for inspection. Considering the products, PAIs are scheduled for applications proposing products with new chemical entities, with narrow therapeutic ranges, with the first generic version of a brand name product, and with generic versions of the most prescribed drug products. Considering producer firms, PAIs are scheduled when the application is the producers first and when the producer has a CGMP compliance history that has been inconsistent, trending down, or noncompliant. Any apparent discrepancy in an application may result in a PAI to investigate the matter thoroughly. Data and information universally required to be included in a new drug application document trial manufacture of the proposed product and summarize results of various tests on samples from the trial manufacture. Trial manufacture may include one or more batches of the proposed product. Tests include those assessing conformance with the product specifications, those assessing the manufacturing process, and those assessing stability of the product in a container-closure presentation. PAIs may be performed at any facility providing manufacturing or control services for and associated data and information on production of the proposed product. These facilities include the site where the dosage form is realized, but also at contract packagers and labelers, contract test laboratories, contract processors like sterilizers or micronizers, and at producers of the active pharmaceutical substance chemical and other ingredient chemicals. A major objective of the PAI was to develop an assurance that application data and information are authentic and accurate. The PAI could include examination of any and all systems and records used to generate the data and information
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submitted to FDA. Trial manufacture is verified. Investigation of the industry has shown that trial manufacture was not done, that it was done on a much smaller scale than reported, or that it was done using different procedures than reported. The PAI will determine if resources were available at the time and place of the manufacture trial reported. The inspection will look for consistent and mutually supportive documentation of the manufacture. Reported test results are verified. The investigation of the industry has shown that reported tests were not done, the tests were not done on approprite samples, or that results were not reported accurately. The PAI determines if test documentation supports the test results reported and if test methods had been developed, validated, and applied correctly. Application data and information from trial manufacture and tests are not all-inclusive; data showing support of the proposed product have been reported, while data not supporting the product have not been included in the application. The PAI inspection determines if development data not submitted was properly excluded. Reports of findings in a PAI are reported to the application review division. PAI findings of data unreliability could cause review of the pending application to be suspended; findings of a pattern or practice of submission of unreliable data by an applicant could result in a broad-scope evaluation of many, or even all, of the applicants approved new drug applications to determine if those also contained unreliable data. Suspension of review of any submission by the applicant could be put in place until the applicant has carried out an adequate corrective action operating plan. Experience has shown that it can take years to clear up the concerns raised by an applicants submission of unreliable data. These regulatory procedures are implemented under FDA Compliance Policy Guide 7150.09 Fraud, Untrue Statements of Material Facts, Bribery and Illegal Gratuities published in the Federal Register on September 10, 1991. Also published with the policy was another document called Points to Consider for Internal Reviews and Corrective Action Operating Plans. This document provides detailed discussion of elements of an adequate plan.
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PAI findings may result in the withholding of approval of a pending application if the findings show that preapproval batches were not made in compliance with current good manufacturing practice or that noncompliance with CGMP may adversely impact the product that is the subject of the pending application. Drug product dosage form units resulting from trial manufacture using the proposed manufacturing procedure are those tested for data and information that will be used to determine if the product is safe and effective. The data and information could be difficult or impossible to interpret if the tests are made on units that are not uniform or that include an unknown contaminant. Manufacture in compliance with CGMP assures the quality, identity, purity, and strength in the products to be tested. Trial manufacturing performed in compliance with CGMP assures that the data and information used to evaluate the safety and efficacy of the proposed product are interpreted scientifically. Likewise, PAI findings that indicate that CGMP would be incorrectly applied to the manufacture of the proposed product after approval would have to be resolved. Again, the approval of the application may be withheld until such resolution is achieved. Manufacture in compliance with CGMP assures quality, identity, purity, and strength in the products to be distributed to the marketplace after approval. Commercial manufacturing performed in compliance with CGMP assures that the untested units of products sold and used in the marketplace perform in an equivalent manner to the products tested and evaluated for approval. The CGMP requirement provides support for reduction of information required to be submitted to FDA in a new drug application. From the earliest days of the use of the new drug application for assuring the safety and efficacy of new drugs, there has been lively debate about the type and amount of data and information needed for FDA to agree with the applicant proposer that the product may be introduced to the marketplace for use by patients. FDA reviewers of applications have before them the need to decide on product questions that will impact the life and health of patients using them, beginning with the very first dosage unit sold. Having no other data
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and information except that before them in an application, an FDA reviewer is encouraged to be sure that all important attributes of the proposed product are supported. The producers of the proposed product have before them as a matter of presence and experience vast amounts of data and information about the conditions, practices, and resources used, available, or planned for the new product. With this as background, they are encouraged to interpret differently the needs for the collection, arrangement, and presentation of data and information they regard as routine or usual. Reducing required data and information in applications has been part of an ongoing FDA process to make the application process and the review of applications as efficient as possible while maintaining the high level of public health protection the drug approval process provides. This process has included recognition of an existing CGMP requirement as adequate regulatory oversight of an issue being considered for an application requirement. In October 1982, FDA proposed a significant revision to the regulations that govern the approval process. A major feature of that revision, finalized in February 1985, eliminated from applications substantial information about manufacturing practices that had been included in the September 1978 revision of the current good manufacturing practice regulations. It was recognized that the updated CGMP regulations set comprehensive standards for drug manufacturing conditions and practices that were enforced by required on-site inspections of manufacturing facilities. The CGMP regulations eliminated the need for application-by-application review of some drug manufacturing information. The same revision cut new drug application recordkeeping requirements for manufacturing and control data resulting from postapproval manufacturing of the application product. This was done because adequate record retention requirements are imposed on manufacturers of drug products under the CGMP regulations. In April 1992, FDA published final regulations detailing requirements for abbreviated new drug applications. During the regulation-writing process there had been a proposal for
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ANDA applicants to obtain samples and to retain them in their stability containers for all lots of a finished generic drug product. This proposal did not need to be accepted because manufacturers are already required to retain samples of each lot by existing CGMP regulations. In March 1987, FDA published final regulations governing the submission and review of investigational new drug applications (INDs). That new regulation allowed a sponsor of a new drug under investigation to perform stability testing concurrently with clinical investigations of the product because concurrent testing was consistent with existing requirements for stability testing in the CGMP regulation. It was noted that permitting concurrent stability testing furthers the FDA objective of speeding up the drug development and approval process. The application reduction program also includes a large effort in publishing guidance documents specifying the format and content of sections of applications and recommending types of data and information that will be useful in an efficient review of chemistry, manufacturing, and control issues. The latter guidances especially serve to inform the expression of CGMP requirements as they are applied to the manufacture of the application product or products using similar manufacturing processes. Most often the application requirement is the same as the CGMP requirement. Where they are different, the differences are usually in extent of use rather than in the nature of the compliance expected. An example would be that more frequent testing might be needed to meet a CGMP requirement than to meet the requirement for submission of data for the application. Application guidances and CGMP guidances are developed using a process that includes cross-program participation. CGMP program representatives sit on work groups developing application guidance documents and attend application review coordinating committee meetings that monitor the development of guidance projects. Draft guidances are distributed to the CGMP program for review and comment at later stages of preparation. The development of CGMP guidances occurs with representatives of the application review program as participants.
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The relationship between the GMP requirement and the application approval process continues to develop. In August 2002, FDA announced a formal management initiative to update the agencys approach to ensuring manufacturing quality. The initiative, titled Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach, will examine closely the currency of both the CGMP program and the premarket review of chemistry and manufacturing issues. With a view toward the industry, goals identified include incorporation of modern concepts of risk-management, quality systems, and advances in electronic technology into pharmaceutical manufacturing control. Specific attention will be given to fashioning a drug regulatory program that will encourage innovation in manufacturing to enhance efficiency and quality management. From the FDA view, coordination of the application review program with the CGMP inspection program is to be sought for effective, efficient, and consistent application of regulatory requirements. The two-year CGMP initiative concluded in September 2004. A full report of findings and goals is published on the FDA/Center for Drug Evaluation and Research web site. Many of the goals provide for closer coordination of the CGMP program operations and application review activities. Under certain conditions, FDCA permits exportation of unapproved drug products ordinarily requiring approval for interstate commerce. One of the conditions to allow unapproved products to be shipped out of the United States is that such products are manufactured, processed, packaged, and stored under conditions and practices substantially in conformance with the current good manufacturing practice requirement. This allows manufacture in U.S. factories of products that do not meet U.S. requirements for approval but meet a foreign countrys requirements. Of course, they must be intended for use only in the identified foreign country. The CGMP provision provides basic protections against low-quality products being distributed from a U.S. base and assists foreign governments in establishing a level of acceptability for the products to be used in their country without conducting expensive regulatory programs and operations of their own.
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Approval of a new drug application does not insulate the product that is the subject of the application from the current good manufacturing practice requirement. When the new drug application requirements were being established, some holders of applications had contended that the approval process and requirements made withdrawal of the application the exclusive method available to FDA for regulating application products. FDA rejected that contention and established a specific regulation explicitly stating the full applicability of the CGMP requirement to products that are the subject of new drug applications. FDA explained that the approval process was a set of additional requirements on the new products in order to make a showing of safety and efficacy. Thousands of drugs in U.S. commerce are not the subject of a new drug application. These drugs are legally marketed because they are not new drugs under the law, and so they are not required to have an approved application covering them. This includes many prescription drugs as well as the vast majority of over-the-counter products. While the application regulatory pillar for assurance of manufacturing quality is not available to the FDA oversight program, the CGMP requirement does apply. CGMP inspections are made to assess methods, facilities, and controls used to make these products to ensure that the consuming public gets the product attributes mandated for all drugs by the law. The CGMP requirement also provides protection against adverse conditions and practices in the distribution of drugs not required to be submitted for approval in new drug applications. In the FDA Modernization Act of 1997 (FDAMA), Congress again linked CGMP with new drug applications in establishing certain procedures for the regulation of the quality of a special category of drugs and in establishing an exemption from the federal regulation of quality. Section 121 recognized the special characteristics of positron emission tomography (PET) drugs. That section directed FDA to establish special procedures for the approval of applications on PET drugs and directed the preparation of a special CGMP requirement for these drugs. The agency has prepared draft rules for meeting these directions and is now conducting a public debate of the
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proposed approaches. The resulting procedures and requirements will be closely coordinated as a result of their concurrent development. A discussion of the regulation of the quality of pharmaceuticals in U.S. commerce would not be complete without a discussion of the approach and role of the official compendia. A compendium is a collection of products recognized, by the inclusion in the collection, as having medical value. Standards for each product are specified in monographs. The three compendia now recognized are the USP, the NF, and the Homeopathic Pharmacopoeia. Section 501(b) of FDCA provides that a compendium drug is adulterated if any sample is tested by the method specified and the result falls outside the acceptance limits. Standards for a new drug established in the FDA application review process enter the compendium monograph upon the products acceptance into the compendium. In the application review process at FDA, standards for new generic drugs are closely coordinated with the existing standards in a compendium monograph. Compendia standards for nonapplication drugs, along with technical information on testing, are accepted as primary guidance in meeting many CGMP requirements, especially in testing procedures.
DISCLAIMER This chapter was written by Mr. Buhay in his private capacity. No official support or endorsement by the Food and Drug Administration is intended or should be inferred.
15
CMC Post-approval Regulatory Affairs: Constantly Managing Change
LEO J. LUCISANO and KEVIN A. MILLER GlaxoSmithKline, Research Triangle Park North Carolina, U.S.A.
1. INTRODUCTION You arrive at work this morning feeling refreshed and unburdened. Last night was the first time in the last 6 months that you had a full and restful sleep. Late yesterday afternoon you finally received the approval letter for the New Drug Application (NDA) for your companys projected blockbuster product, and you are savoring the moment. You casually saunter to the break room for your morning cup of coffee, take a few minutes to celebrate with your coworkers, and return to your
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office, expecting a light day by recent standards. As you wait for your computer to boot up so you can catch up on the seemingly infinite backlog of e-mail, the phone rings. You note on the caller ID display that its the marketing director for the new product. Shes probably calling to congratulate me on the approval letter, you speculate as you reach for the receiver. The tone of her greeting immediately tells you otherwise. New market research data just arrived on her desk that morning indicating that patients preferred a blister package compared to a plastic bottle. She wants to know if a submission is required for a blister package and, if so, how long it will take for preparation and approval. She indicates that time is of the essence to maximize market penetration, as a competitors product is anticipated to be approved imminently. While speaking with the marketing director, you receive an urgent message from your administrative assistant to call the vice-president of manufacturing as soon as possible. You tell the marketing director that you will research the regulatory implications of the proposed packaging change and will call her back with an answer as soon as possible. You phone the vice-president, and he tells you that content uniformity failures have been encountered during process validation of the commercial batch size for the new product. To correct the problem, it appears the blending speed and time for the bulk powder need to be modified. He wants to know if the changes have any regulatory implications and comments that any production downtime will almost certainly delay the launch. You advise that you will research the regulatory implications of the proposed manufacturing change and will call him back with an answer as soon as possible. Well, so much for the light day, you think to yourself as you hang up the phone. What will you do? While the above scenario is fictitious, it is an accurate depiction of the dynamic world of Chemistry, Manufacturing, and Controls (CMC) (referred to by the authors as constantly managing change) Post-approval Regulatory Affairs. This chapter provides an overview of the scope of CMC post-approval regulatory affairs, the recent U.S. history of CMC post-approval regulations and their current status, the different types of
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regulatory submissions to file CMC changes, and the relationship of Current Good Manufacturing Practice (cGMPs) regulations to CMC post-approval activities. Measurements of performance are suggested to gauge the effectiveness of the CMC post-approval regulatory function, and commentary is provided regarding the development of professionals in this field. The chapter concludes with a discussion of the forces affecting the future of this expanding arena of regulatory oversight.
2. CMC POST-APPROVAL REGULATORY AFFAIRS OVERVIEW CMC regulatory affairs is concerned with the technical characteristics of a drug molecule and the dosage form used for its administration. The regulatory affairs professional is responsible for assuring that sufficient CMC knowledge is accumulated about the molecule to permit evaluation by the U.S. Food and Drug Administration (FDA) through the product life cycle. Table 1 depicts a typical list of CMC information required for evaluation. In the pre-approval phase of the product life cycle, CMC information is initially provided to FDA through the application of an Investigational New Drug (IND). Depending on the outcome of clinical trials conducted under the IND, an NDA may be filed with an additional level of CMC information that
Table 1 CMC Database for a New Drug Application
Drug product Components and composition Manufacturers Method of manufacturing and packaging Specications and analytical methods Stability information
Drug substance Physicochemical properties Synthetic process Controls for starting materials, reagents, etc. Process controls for intermediates Specications and analytical methods List of impurities Stability and life to retest
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Table 2
Comparison of CMC Regulatory Environments

Pre-approval Post-approval Supplemental NDAs Annual Reports CMC Commitments Manufacturing Manufacturing product Weeks and months Less dened Approved conditions in NDA
Type of submissions
INDs and NDAs
Internal customer Customer priority Timelines Format of submission Reference base of information
R&D Supporting INDs and NDAs Months and years Well-dened Being developed as part of the NDA
may result in approval of the drug product and its commercialization. The CMC section of the NDA establishes the approved conditions for manufacturing and testing the drug substance and its dosage form(s). In the post-approval phase the regulatory affairs professional is responsible for managing changes to these conditions. Table 2 compares the different environments encountered during the two phases of the product life cycle. Prior to approval of the NDA, the CMC regulatory professional interacts primarily with a research and development (R&D) team that is dedicated to developing the body of information required to gain FDA approval of the drug product. The sequence of steps from the application of the IND to NDA approval takes several years, and the process is well defined. Various initiatives supported by FDA, such as the International Conference on Harmonization, provide a clear roadmap regarding the CMC information and data that need to be accumulated to adequately characterize a new drug product and its active ingredient. (Refer to www.ich.org for additional information.) Following approval of the NDA, the CMC regulatory professional interacts primarily with marketing and manufacturing, whose priority is to maximize the commercial potential and return on the investment of the drug product. These drivers may result in a stream of requested changes to the originally approved CMC conditions in the NDA. Unlike
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R&D, the productivity of the manufacturing environment is measured in weeks and months, and multiple changes to the drug substance and/or drug product often need to be evaluated and implemented in a parallel timeframe. Additionally, the approval of an NDA often results in a number of CMC postapproval commitments that must be fulfilled, including the statutory requirement to file Annual Reports. The regulatory professional supporting these CMC post-approval activities must be diligent in providing regulatory oversight and strategies that ensure that CMC changes are implemented in a reasonable time frame while adhering to appropriate regulations.
3. CMC POST-APPROVAL REGULATIONS AND GUIDANCE In order to make CMC changes to the conditions of approval in the NDA, the drug manufacturer must file the changes with FDA through one of the various types of post-approval submissions described below. An appropriate level of information and data must be included in the submission to demonstrate that the changes do not adversely affect the quality attributes of the drug substance and/or drug product. Prior to 1997 the regulation governing CMC changes to an approved New Drug Application was 21 CFR 314.70 (Supplements and Other Changes to an Approved Application) (1). This statute was established in February 1985 as part of a comprehensive effort to improve the NDA and postapproval application process. It defined three reporting categories for post-approval changes: (a) prior approval supplement, (b) changes being effected supplement, and (c) Annual Report. In practice, the provisions in the original version of 21 CFR 314.70 were vague, and the interpretation and review of CMC changes by different review divisions within FDA were inconsistent. The situation led to increasing criticism by the pharmaceutical industry that the post-approval regulations stifled changes in the manufacturing environment. On November 21, 1997, the Food and Drug Modernization Act was signed into law by the President. Section 116 of the
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Act required that 21 CFR 314.70 be revised to streamline the regulatory process for CMC post-approval changes. Two years later 21 CFR 314.70 expired without an updated version in place. As a result FDA issued an interim guidance document, Guidance for Industry: Changes to an Approved NDA or ANDA (CANA), that has been the current reference for determining the appropriate regulatory submission for CMC post-approval changes (2). In April 2004 the revised 21 CFR 314.70 rule was published, and the CANA Guidance was updated accordingly. The final rule became effective on June 22, 2004. The revised rule and CANA Guidance retained the same reporting categories identified in the original rule but expanded the Changes Being Effected (CBE) Supplement into two types, CBE-30 and CBE-0. They also linked the submission reporting category to the potential for a change to have an adverse effect on the identity, strength, quality, purity, or potency of a product as it relates to the safety or effectiveness of the product. By establishing this link, the revised rule and CANA Guidance integrated the quality and regulatory perspectives in evaluating CMC changes. The revised rule and CANA Guidance provide recommended filing categories for changes to the following: (a) components and composition, (b) manufacturing sites, (c) manufacturing process, (d) specifications, (e) packaging, (f ) labeling, (g) miscellaneous changes, and (h) multiple related changes. However, neither defines the information and data required in the application. Recommendations regarding the appropriate information and data package required to assess the impact of CMC changes are contained within the battery of guidance documents issued by FDA in recent years. The content of information and data packages may also be dependent upon historical precedence with a particular drug substance and/or drug product and FDA review division. Figure 1 depicts a spectrum of guidance documents that the CMC post-approval regulatory professional can consult in determining the appropriate submission category and supporting data and information package to appropriately assess and file changes. FDA issued the first guidance document in 1995 that specifically addressed CMC post-approval changes, namely the
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Figure 1 changes.
Regulations and guidance affecting CMC post-approval
Guidance for Industry: Immediate Release Solid Oral Dosage Forms: Scale-Up And Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence Documentation (3) (commonly known as the SUPAC-IR Guidance). Since that time the FDA Center for Drug Evaluation and Research has issued more than 20 additional guidance documents in draft and final form (425). They range from covering changes to specific dosage forms to addressing relevant scientific and technical topics in assessing change (e.g., equipment design and dissolution testing). Many concepts and the vocabulary introduced in these post-approval documents have now been embedded into the New Drug Application process. Examples include the terminology associated with the design and operating principles of manufacturing equipment, as well as the various approaches to demonstrating dissolution similarity when changes are made to the drug product. 4. CMC POST-APPROVAL REGULATORY SUBMISSIONS Table 3 lists the types of CMC post-approval submissions addressed in the revised rule and CANA Guidance. 4.1. Prior Approval Supplement A Prior Approval Supplement is required for a CMC change that has a substantial (major) potential to have an adverse
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Table 3
Types of CMC Post-approval Submissions

Potential impact on product quality Major (substantial) Moderate Moderate Minor (low) Implementation 46 months following submission 1 month after FDA receipt of submission Immediately upon FDA receipt of submission Immediateled yearly on anniversary date of NDA approval
Submission type Prior Approval Supplement Changes Being Effected Supplement30 Day Changes Being Effected Supplement0 Day Annual Report
effect on the identity, strength, quality, purity or potency of the product as they may relate to its safety or effectiveness. Its title is self-defined, meaning that FDA must approve the change before drug product incorporating the change can be distributed for patient consumption. Occasionally, a Prior Approval Supplement may need to be approved as soon as possible in the interest of the public health (e.g., drug shortage) or if a delay in implementation will cause extraordinary hardship on the drug manufacturer (26,27). When these situations arise, the applicant can request an Expedited Review of the supplement. The supplement should be clearly labeled Prior Approval SupplementExpedited Review Requested, and a justification for the request should be provided in the accompanying cover letter (26). 4.2. Changes Being Effected Supplement A Changes Being Effected Supplement is required for a CMC change that has a moderate potential to adversely affect the drug product as it relates to its safety or effectiveness. The 1999 CANA guidance provided for two types of Changes Being Effected supplements: (1) SupplementChanges Being Effected in 30 Days (CBE-30) and (2) SupplementChanges Being Effected (CBE-0). The revised 21 CFR 314.70 rule and CANA Guidance have retained these filing categories.
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A CBE-30 Supplement requires that an applicant wait at least 30 days following receipt of the submission by FDA before distributing product incorporating the change. This waiting period permits FDA to conduct a cursory review of the supplement to assess if the proposed change has been filed in the proper reporting category and is supported by a sufficient data package to justify its implementation (1,2). Unlike a CBE-30 Supplement, a CBE-0 Supplement does not require a waiting period. Drug substance/product incorporating this category of change can be distributed immediately following receipt of the submission by FDA. 4.3. Annual Report The Annual Report is a periodic, postmarketing submission required by 21 CFR 314.81(2) (other postmarketing reports) (28). From a CMC perspective its purpose is twofold: it provides a reporting mechanism for changes that are considered to have minimal potential to adversely affect the drug product, and it serves as a conduit for providing updates to nonsupplemental post-approval commitments (e.g., stability updates). Unlike changes requiring supplemental applications, annual reportable changes are filed after implementation has already taken place and do not undergo a formal review and approval process. However, FDA has the authority to disagree with a change filed in the Annual Report and require the submission of a supplemental application if the Annual Report filing category is deemed inappropriate for the change or additional information is requested to support the change. 4.4. Impact of Revised 21 CFR 314.70 Rule and CANA Guidance The Food and Drug Modernization Act in 1997 was intended to streamline the regulatory process, and the revised 21 CFR 314.70 rule and CANA Guidance that emerged has accomplished this objective in several areas of CMC changes. For example, a move to a different manufacturing site for a drug substance intermediate can now be reported in an Annual
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Report, where previously it required the submission of a Prior Approval Supplement. However, the revised rule and guidance also increased the regulatory burden for other types of changes. For example, a change in a packaging component that controls the dose delivered to the patient (e.g., the valve of a metered dose inhaler) now requires a Prior Approval Supplement, whereas under the original 21 CFR 314.70 rule it was possible to file this change in an Annual Report. The revised rule and CANA Guidance (Section IV, Assessment of the Effects of the Change) also require that the effects of any CMC changes be assessed by the holder of the application regardless of the submission category required to report the change. Assessment includes evaluation of the postchange product to assure that the changes do not negatively affect the quality attributes of the drug product. This may require additional testing beyond that required by the specifications approved in the NDA. If an assessment concludes that the change has an adverse impact and the applicant still desires to implement the change, then the applicant must file a Prior Approval Supplement for the change, regardless of the recommended filing category for the change being considered. 5. CURRENT GOOD MANUFACTURING PRACTICES AND CMC POST-APPROVAL REGULATORY AFFAIRS The previous sections described the various submission mechanisms and information requirements for supporting CMC post-approval changes. However, the submission process is not conducted in isolation. Many complementary activities occur before, during, and after the submission to comply with cGMPs, and these activities are described below. 5.1. Change Control Change control is required by 21 CFR 211.180(e) (General Requirements) and entails proper review, assessment,
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implementation, and adherence to written procedures for making CMC changes (29). A drug manufacturers change control process is frequently scrutinized by FDA during inspections and is often the subject of objectionable citations in inspection reports. An effective change control system is the foundation for successful management of CMC post-approval changes. In providing the appropriate regulatory perspective to a change control request from manufacturing, four steps are conducted by the CMC post-approval regulatory affairs professional: 1. Define the change: This may require several iterations of discussion with the manufacturing site in order to understand the change(s) being proposed. For example, a change request may specify that the site is considering a batch size change. This type of change may require related changes to equipment and process. The full extent of the changes must be understood in order to provide comprehensive regulatory advice. 2. Establish the regulatory basis for the change: Once the true extent of the changes is elucidated, the change scenario needs to be evaluated against the context of the approved conditions in the NDA file and current FDA guidance. A small change in batch size for an immediate-release solid dosage form, with no additional changes, is categorized as an annual report change in Section VII.D.1 of the CANA Guidance. If multiple changes are required to attain the increase in scale, Section XII (Multiple Related Changes) of the Guidance requires that the filing category be defined for each individual change and the most restrictive filing category applied. If the increase in scale requires adopting equipment of different design and operating principles, a Prior Approval Supplement would be required to implement the sum of the changes.
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3. Determine the data and information required to assess and implement the change: This information can be obtained from the various guidance documents issued by FDA that address specific dosage forms and regulatory topics, as well as prior experience with FDA in implementing related changes. In the above example, the SUPAC IR Guidance would provide the information and data package required to support the changes in scale and equipment (3). The guidance document on dissolution testing addresses the considerations in developing and evaluating comparative dissolution profiles to assess the impact of the changes on the release profile of the drug product (7). 4. Provide the appropriate regulatory advice: Once the above steps have been completed, a recommendation should be prepared that integrates the regulatory, quality, and commercial aspects surrounding the proposed change(s) to the drug product. It may be as straightforward as communicating the required regulatory submission and the associated data package, or it may require that the change not be progressed at this time due to mitigating circumstances. In the example of the batch size increase, the regulatory affairs professional might be aware that an alternate supplier of the drug substance is being considered. Consequently, it may be prudent to advise the manufacturing site to delay the evaluation of the batch size increase and equipment change for the drug product until a supply of the alternate source of the drug substance is available for concomitant evaluation. Occasionally, the filing category cannot be defined until the information and data package required for the submission has been provided for assessment. In this case a two-stage response may be required from the regulatory affairs professional. The initial response describes the submission requirements, regardless of filing category, and includes
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Figure 2
CMC regulatory change controltwo-stage process.
a statement that the reporting category will be determined when the data and information package has been assembled and assessed. Upon completion of the assessment, a second (final) response is provided confirming the appropriate filing category for the proposed change. A flow diagram of a two-stage regulatory response is provided in Figure 2. 5.2. Validation Post-approval CMC changes that pertain to the manufacturing process or analytical method of a drug substance or drug product may have validation implications. cGMPs (21 CFR 211.100 and 211.160) require that manufacturing processes and analytical methods be appropriately validated (30,31). The implementation requirements of a CMC change may include revalidation of the manufacturing process or analytical method, even if the change does not require a submission. Regardless of whether a submission is required, validation documentation should be available for FDA inspection purposes to support the implemented change.
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5.3. FDA Inspections FDA periodically inspects manufacturing and testing facilities for adherence to cGMPs, and inspections may require involvement by the CMC post-approval regulatory professional depending on their purpose. In a general inspection questions about the regulatory advice provided in a change control proposal may arise, and the regulatory professional must be prepared to respond accordingly. Other inspections may be the direct result of a CMC post-approval submission, in which case the regulatory representative is likely to be a member of the core inspection team or possibly even the inspection team leader. In either case the regulatory affairs professional must be thoroughly knowledgeable of relevant regulations and submission information, as well as the systems and processes used by the manufacturing site for managing CMC changes. This overview is required to interact effectively with FDA inspectors and facilitate a successful outcome of the inspection.
6. PERFORMANCE MEASURES FOR CMC POST-APPROVAL REGULATORY AFFAIRS The manufacturing environment that is the primary internal customer of the CMC post-approval regulatory affairs professional is monitored by various measurements such as the number of recalls, batch rejects, cost of goods, and utilization of manufacturing capacity. Similarly, a number of performance measures can be used to gauge the activities within CMC postapproval regulatory affairs. 6.1. PDUFA Goals and First-Time Approvals of sNDAs The Prescription Drug User Fee Act of 1992 (PDUFA) defined FDA review targets for manufacturing supplements. Table 4 provides the action dates for supplements reviewed in the fiscal year 2004. These goals are intended for FDAs Office of Pharmaceutical Sciences and provide a level of predictability regarding the timing of feedback and the acceptability of
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Table 4
FDA Review Goals for Manufacturing Supplements

PDUFA goal FY2004a (Oct. 1, 2003Sept. 30, 2004) 90% reviewed and acted upon within 4 months 90% reviewed and acted upon within 6 months 90% reviewed and acted upon within 6 months
Supplement category Prior Approval Supplement Changes Being Effected Supplement-30 Day Changes Being Effected Supplement-0 Day
a
PDUFAPrescription Drug User Fee Act of 1992 provided FDA additional resources for accelerated drug evaluation without compromising review quality.
changes filed through sNDAs. After review is completed, an action letter is issued indicating that the supplement is approved, approvable upon resolution of deficiencies found in the application, or not approved (32). If an Approvable letter is issued subsequent to the implementation of a change filed through a CBE or CBE-30 Supplement, generally the manufacturer can continue to distribute the post-change product while addressing the deficiencies unless FDA specifically objects (1,2,20). While the PDUFA Goals establish guidelines for timely review, a regulatory affairs group is in the business of obtaining approvals, and goals should be set with respect to achieving approval of supplemental New Drug Applications (sNDAs) within the PDUFA time frame. A low percentage of first-time approvals is an indication that the sNDAs being filed do not provide a sound regulatory justification for the changes or that an insufficient information and data package is provided to support the changes. It may also signal a poor rapport with the particular FDA review division within the Office of Pharmaceutical Sciences that may need to be addressed. 6.2. Submission of Annual Reports Section 21 CFR 314.81(2) requires that Annual Reports be submitted within 60 days of the anniversary date of the approval of the New Drug Application (28). A CMC post-approval group should strive to collaborate with the manufacturing sites to
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compile and submit the CMC section of the Annual Reports on time. A consistent trend of providing late Annual Reports or ones that are lacking in sufficient detail may affect the Agencys review of related supplemental applications. 6.3. CMC Commitments Both NDAs and supplemental applications are often approved with commitments to provide additional data once the manufacturer has gained a greater level of experience with the drug product and related changes. The post-approval CMC function needs to monitor these commitments and assure that the firm appropriately fulfills its obligations according to the deadline specified by the FDA or proposed by the drug manufacturer. 6.4. Continuity of Supply Situations sometimes arise that may prevent the manufacture of the drug product according to the approved conditions of an NDA. For example, an accident at a packaging site may prevent it from continuing operations, or a supplier of a key component (e.g., drug substance or packaging material) may no longer be able to maintain inventory. In these situations the CMC post-approval regulatory affairs professional may be able to negotiate a strategy with the appropriate branch of FDA to quickly restore supply. For example, the review division may grant Expedited Review of a Prior Approval Supplement for an alternate supplier of the drug substance if the currently approved supplier can no longer manufacture the drug substance. Successful negotiations under these circumstances reflect active engagement by the CMC post-approval regulatory affairs professional. 6.5. NDA Conformance Site inspections conducted by FDA may result in observations of nonconformance to the approved conditions in the NDA. The firms quality organization may also conduct internal audits to verify site practice and correct conditions of nonconformance
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to the NDA. These instances typically point to a lapse in communication between the manufacturing site and the CMC regulatory affairs function. A useful measurement of the adequacy of the change control process is to track the number of NDA nonconformance observations resulting from these external and internal audits. 6.6. Due Diligence (Divestments) Pharmaceutical companies seeking to purchase an established product conduct a due diligence exercise prior to purchase to assess the status of the CMC aspects of the NDA file. The buyer seeks to verify that all commitments to the FDA have been met and that there are no regulatory deficiencies that may result in nonconformance or jeopardize supply following the sale. For example, the analytical testing of an older product may not meet current standards such that it may be viewed as a regulatory risk. A product that is well managed by the CMC post-approval regulatory function should facilitate the current application holders efforts to divest the drug product. 6.7. Regulatory Strategies and Cost Savings In a complex supply chain in which multiple sites supply either the drug substance and/or drug product, CMC regulatory affairs may be the only department that has a comprehensive overview of the various changes affecting the NDA. Figure 3 illustrates the number of changes that may be simultaneously affecting a drug product and its active pharmaceutical ingredient in a global supply chain. From this vantage point the regulatory affairs professional has the opportunity and bears the responsibility to recommend that various changes be assessed concurrently or staged in a reasonable manner. The data required to support CMC post-approval changes often cost tens, sometimes hundreds of thousands of dollars, and it may be possible to evaluate several changes in an integrated set of experiments (e.g., reducing the number of stability studies to evaluate multiple changes through a matrix approach) (11).
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Figure 3
Change control in a global supply chain.
7. DEVELOPMENT OF THE CMC POSTAPPROVAL REGULATORY AFFAIRS PROFESSIONAL The competencies required for effectively supporting the CMC post-approval regulatory arena differ somewhat from the CMC pre-approval arena due to differences in customer base and the types of submissions that are filed to the FDA. Figure 4 depicts the steps associated with the development of a post-approval regulatory affairs professional. These steps are described in greater detail below.
Figure 4 affairs.
Career development in CMC post-approval regulatory
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7.1. Change Control Change control is fundamental to CMC post-approval regulatory affairs and is the area in which new personnel should start in order to develop a sound foundation in the field. Addressing change control inquiries from the manufacturing sites requires the regulatory professional to evaluate the change, research the drug product history in the NDA file, and read the pertinent regulations and guidance. This information must then be interpreted and articulated in a succinct, clearly written response to the customer at the manufacturing site. 7.2. CMC Conformance Guides CMC Conformance Guides are a distillation of the conditions approved in the NDA for the drug product and its active ingredient(s). Table 5 is a representative table of contents of a CMC Conformance Guide for a tablet formulation. Compiling a CMC Conformance Guide for a product that has been marketed for several years requires researching the entire NDA file to establish the currently approved CMC conditions. Developing and maintaining CMC Conformance Guides is a worthwhile activity for the regulatory affairs professional. The guides provide a reference tool for both regulatory affairs and the manufacturing sites in determining the regulatory ramifications of proposed changes. 7.3. Annual Reports The compilation of Annual Reports is the next appropriate step for the CMC post-approval regulatory affairs professional. It requires a review of the data and information provided by the manufacturing sites to support the filed changes with a cross check to the change control advice provided earlier for those changes. Annual Reports also contain an updated stability profile of the drug substance/product that requires a critical review by the CMC post-approval regulatory affairs professional. The data reported need to be consistent with approved stability
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Table 5 Contents for CMC Conformance Guide for Tablet Formulation

I. Product description A. B. C. D. E. II. A. Name, dose form NDA numbers List of approved pack congurations with NDC codes Outstanding commitments Approval date Components
Drug product B. Composition C. Specications and analytical methods for inactive-components 1. Inactive components included in the USP/NF 2. Inactive components not included in the USP/NF 3. Quality control of inactive components D. Manufacturers 1. Name and address of manufacturer(s), packager(s), tester(s), and what part is done by each 2. List of DMF references (if any) Method of manufacture and packaging 1. Description of the manufacturing process 2. In-process controls 3. Reprocessing/Rework operations 4. ContainerClosure system a. Bulk product container b. Bottles c. Child-resistant closures d. Blister pack Specications and analytical methods 1. Sampling plan (if any) 2. Specications 3. Description of analytical methods and any alternates Stability information 1. Stability protocols 2. Storage conditions and expiration dating 3. Other a. Commitment for on-going studies b. List of batches for continued monitoring (if applicable) c. Analytical methods used during stability studies
E.
F.
G.
III. Index of approved changes IV. History of changes
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protocols and support the approved retest date/shelf life for the drug substance/product while being reported in a format consistent with current FDA guidance (33). Fulfilling this responsibility may require the CMC post-approval regulatory affairs professional to have several iterations of discussion with the manufacturing sites involved with the Annual Report. 7.4. Simple sNDAs Understanding the process and obligations associated with filing the CMC Section of the Annual Report leads to the ability of the post-approval CMC regulatory affairs professional to compile and submit sNDAs. Working on submissions that address a single change (e.g., change in analytical testing site) and progressing to submissions that combine multiple changes (e.g., change in manufacturing site coupled with changes in packaging and testing) is a logical progression. Starting with the less complex type of CMC submission allows the maturing professional to gain an understanding of the review and approval process for sNDAs. Filing a supplemental NDA requires the post-approval regulatory affairs professional to understand the responsibilities associated with being a responsible agent for the NDA holder and to begin interacting with FDA personnel, such as project managers and members of the CMC review team. 7.5. Complex sNDAs With time and experience the regulatory affairs professional can support very complex supplemental NDAs, such as those requiring a biostudy or biowaiver to gain approval of CMC changes. Examples include reformulation of a drug product or a manufacturing site change associated with a modifiedrelease solid oral dosage form. These complex sNDAs often require meetings with FDA in which the regulatory affairs professional needs to submit a formal meeting request with an accompanying Information Package. The Information Package outlines the issues that need to be resolved and the supporting data that are the basis for discussion at the meeting (34). The regulatory affairs professional is expected to chair the meeting
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with FDA and to appropriately prepare the project team and direct the dialogue during the meeting to achieve the desired outcome. 7.6. FDA/Industry Interactions After gaining proficiency with complex sNDAs and chairing meetings with FDA, the CMC post-approval regulatory affairs professional likely has achieved the experience, confidence level, and stature to participate in FDA/industry interactions. Activities include giving presentations at professional meetings or assisting in workshops that address CMC regulatory issues. It typically takes several years to progress to this level of development.
8. THE CMC POST-APPROVAL REGULATORY PROFESSIONAL AS THE RESPONSIBLE AGENT All regulatory submissions are accompanied by FDA Form 356h signed by the regulatory affairs professional acting as a responsible agent for the drug manufacturer (35). The form includes a number of certification statements that define the scope of responsibility associated with this role. They require that the regulatory professional attest to the veracity of the information provided in the supplement and assure that the application complies with all applicable laws and regulations, including adherence to cGMPs. It also includes a reminder that it is a criminal offense to willfully provide fraudulent information. The role of acting as a responsible agent is what differentiates the CMC regulatory affairs professional from other functional groups involved with compiling and submitting a post-approval application. Although the regulatory affairs professional does not generate the data and information included in a CMC submission, specific measures need to be taken to assure the authenticity of its contents. Such steps may include reviewing source documentation housed at the manufacturing site, which may not be included
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in the application. Examples include internal technical reports, supplier specifications, and batch records. The regulatory affairs professional may also conduct a submission audit at the site as a double check prior to submission. These measures provide the necessary checks and balances to assure that the regulatory affairs professional fulfills the associated requisite obligations of the responsible agent while at the same time becoming familiar with the systems utilized by the site to evaluate and support manufacturing changes.
9. FUTURE OF CMC POST-APPROVAL REGULATORY AFFAIRS The SUPAC-IR guidance issued in November 1995 was the first guidance document that specifically addressed CMC postapproval changes, and it marked the beginning of a transformation in the level of sophistication in this regulatory arena (3). It provided a scientific basis for the evaluation of changes to an approved product and introduced a new vocabulary with which to discuss these changes. The publication of the SUPAC-IR Guidance coincided with a trend toward consolidation of the pharmaceutical industry that spurred a number of mergers and acquisitions. This often resulted in an overabundance of desired manufacturing capacity for an acquiring or postmerger firm requiring the closure of a number of manufacturing sites. Drug substance/ product transfers require active management by the CMC postapproval regulatory affairs function and increase the importance of this role in supporting the manufacturing environment. A number of business and regulatory drivers will likely continue to increase the complexity and demand for specialized CMC post-approval regulatory affairs support. Developing a new medicine takes 1015 years and costs approximately $800 million (3638). Consequently, timelines are constantly being shortened in the NDA pre-approval phase to reduce the time to market. These pressures may result in non-optimized manufacturing processes or analytical specifications that
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require post-approval modification. Advances in manufacturing experience and technology provide opportunities to reduce production costs and increase profitability, while consumer preference is ever-dynamic and satisfying this need will require continual changes in product presentation to maintain market share. The regulatory environment also continues to evolve, and several ongoing initiatives will present new challenges for CMC post-approval regulatory affairs: 9.1. FDA Initiative for Process Analytical Technologies In February 2002 FDA launched a new initiative called Process Analytical Technologies (PAT), a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality (39). (Refer to www.fda.gov/cder/OPS/PAT.htm for additional information.) On September 23, 2003, FDA approved the first PAT submission. It provided for the adoption of rapid microbiological methods for product release using a Comparability Protocol filed as a Prior Approval Supplement (40,41). The regulatory review and approval process for the implementation of PAT is still evolving but holds the promise of having a major impact on the CMC post-approval environment. The initial thrust for PAT will be its application to approved products through the filing of sNDAs with the subsequent application to new products through NDAs occurring after the utility of PAT has been established. 9.2. Globalization of the Regulatory Environment The efforts invested in the International Conference on Harmonization and the Common Technical Dossier continue to make progress in defining global standards for the content and format of regulatory submissions (4244). Although these advances will
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initially have their greatest impact on new applications (INDs and NDAs), they will establish a new reference upon which to evaluate and file the changes made after product approval. 9.3. Electronic Publishing The future may see the electronic filing of all regulatory submissions throughout the product life cycle (45). Although most companies are focusing on applying this technology to the NDA process and clinical sNDAs, it will eventually find its way into CMC post-approval submissions. This will pose a challenge to the CMC post-approval regulatory affairs professional to integrate the requirements for electronic publishing into the manufacturing environment. 10. CONCLUSION Recall that at the beginning of this chapter, the fictional CMC post-approval regulatory affairs professional faced a day of unexpected changes that required urgent attention. Continuing this story, the regulatory affairs professional had to review the CMC section of the NDA files, consult FDA guidance documents, interact with various functional groups within the company, and potentially contact the FDA to address the change scenarios posed by marketing and manufacturing. As the day concluded, the regulatory affairs professional was able to offer a variety of regulatory strategies and timelines to assure timely supply of the drug product and address marketing preferences within the boundaries of the approved conditions of the NDA and current FDA regulations and guidance. Such is a typical day in the career of the CMC post-approval regulatory affairs professionalconstantly managing change. ACKNOWLEDGMENTS The authors are gratefully indebted to Lorien Armour for her meticulous research and Christie Ahlheit for her word processing expertise in completing the manuscript.
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REFERENCES
1. 2. 3. Federal Register, Vol. 69, No. 68, April 8, 2004, Code of Federal Regulations, Title 21, Part 314.70. FDA, Center for Drug Evaluation and Research, Changes to an Approved NDA or ANDA, Guidance Document (April 2004). FDA, Center for Drug Evaluation and Research, Immediate Release Solid Oral Dosage Forms: Scale-Up And Post-approval Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence Documentation, Guidance Document (November 1995). FDA, Center for Drug Evaluation and Research, Sterilization Process Validation in Applications for Human and Veterinary Drug Products, Guidance Document (November 1994). FDA, Center for Drug Evaluation and Research, SUPACIR Questions and Answers, Guidance Document (February 1997). FDA, Center for Drug Evaluation and Research, SUPAC-SS Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation, Guidance Document (June 1997). FDA, Center for Drug Evaluation and Research, Dissolution Testing of Immediate Release Solid Oral Dosage Forms, Guidance Document (August 1997). FDA, Center for Drug Evaluation and Research, Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations, Guidance Document (September 1997). FDA, Center for Drug Evaluation and Research, SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation, Guidance Document (October 1997). FDA, Center for Drug Evaluation and Research, PAC-ALTS: Post-approval Changes-Analytical Testing Laboratory Sites, Guidance Document (April 1998).
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FDA, Center for Drug Evaluation and Research, Stability Testing of Drug Substances and Drug Products, Draft Guidance Document (June 1998). FDA, Center for Drug Evaluation and Research, Metered Dose Inhalers (MDI) and Dry Powder Inhalers (DPI) Drug Products: Chemistry, Manufacturing, and Controls Documentation, Draft Guidance Document (November 1998). FDA, Center for Drug Evaluation and Research, SUPAC-SS: Nonsterile Semisolid Dosage Forms Manufacturing Equipment Addendum, Draft Guidance Document (January 1999). FDA, Center for Drug Evaluation and Research, SUPAC IR/ MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum, Guidance Document (February 1999). FDA, Center for Drug Evaluation and Research, Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action, Draft Guidance Document (June 1999). FDA, Center for Drug Evaluation and Research, Container Closure Systems for Packaging Human Drugs and Biologics, Guidance Document (July 1999). FDA, Center for Drug Evaluation and Research, NDAs: Impurities in Drug Substances, Guidance Document (February 2000). FDA, Center for Drug Evaluation and Research, Analytical Procedures and Methods Validation: Chemistry, Manufacturing, and Controls Documentation Draft Guidance Document (August 2000). FDA, Center for Drug Evaluation and Research, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Guidance Document (August 2000). FDA, Center for Drug Evaluation and Research, Changes to an Approved NDA or ANDA: Questions and Answers, Guidance Document (January 2001). FDA, Center for Drug Evaluation and Research, BACPAC I: Intermediates in Drug Substance Synthesis: Bulk Actives
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Post-approval Changes: Chemistry, Manufacturing, and Controls Documentation, Guidance Document (February 2001). 22. FDA, Center for Drug Evaluation and Research, Statistical Approaches to Establishing Bioequivalence, Guidance Document (February 2001). FDA, Center for Drug Evaluation and Research, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug ProductsChemistry, Manufacturing, and Controls Documentation, Guidance Document (July 2002). FDA, Center for Drug Evaluation and Research, Comparability ProtocolsChemistry, Manufacturing, and Controls Information, Guidance Document (February 2003). FDA, Center for Drug Evaluation and Research, Bioavailability and Bioequivalence Studies for Orally Administered Drug ProductsGeneral Considerations, Guidance Document (March 2003). FDA, Center for Drug Evaluation and Research, Requests for Expedited Review of NDA Chemistry Supplements, Manual of Policies and Procedures MAPP 5310.3 (June 1999). FDA, Center for Drug Evaluation and Research, Drug Shortage Management, Manual of Policies and Procedures MAPP 4730.1 (November 1995). Code of Federal Regulations, Title 21, Part 314.81(2). Other postmarketing reportsAnnual Reports. Code of Federal Regulations, Title 21, Part 211.180. Current good manufacturing practice for finished pharmaceuticals Records and ReportsGeneral Requirements. Code of Federal Regulations, Title 21, Part 211.100. Current good manufacturing practice for finished pharmaceuticals Production and Process ControlsWritten procedures, deviations. Code of Federal Regulations, Title 21, Part 211.160(e). Current good manufacturing practice for finished pharmaceuticals Laboratory ControlsGeneral requirements. Code of Federal Regulations, Title 21, Part 314.3(b). General ProvisionsDefinitions.
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FDA, Center for Drug Evaluation and Research, Format and Content for the CMC Section of an Annual Report, Guidance Document (September 1994). FDA, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Formal Meetings with Sponsors and Applicants for PDUFA Products, Guidance Document (February 2000). Code of Federal Regulations, Title 21, Part 314.50(a)5. Content and format of an applicationApplication form. Pharmaceutical Research and Manufacturers of America, 2002 Industry Profile, PhRMA, Washington, DC, 2003. J.A. DiMasi, R.W. Hansen, and H.G. Grabowski, The Price of Innovation: New Estimates of Drug Development Costs, Health Economics 22 (2003): 151185. H. Grabowski, J. Vernon, and J. DiMasi, Returns on Research and Development for 1990s New Drug Introductions, Pharmacoeconomics 20 (2002): suppl. 3, 1129. FDA, Center for Drug Evaluation and Research, A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, Draft Guidance Document (August 2003). FDA, Center for Drug Evaluation and Research, Comparability ProtocolsChemistry, Manufacturing, and Controls Information, Draft Guidance Document (February 2003). GSK Announces FDA Approval of Their First Submission, AAPS News Magazine (April 2004): 10. PAT
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43. 44. 45.
16
The Influence of the USP on the Drug Approval Process
EDWARD M. COHEN Consultant in Pharmaceutical Sciences Newtown, Connecticut, U.S.A.
1. INTRODUCTION The objective of this chapter is to provide the reader with an overview of the United States Pharmacopoeia/National Formulary (USP/NF) and its formal and legal role in the U.S. Food and Drug Administrations (FDA) drug regulatory process in the United States (1). When considering the history of the USP and NF, once separate drug standards compendia originating from two different sectors of the health-caredelivery system, it is interesting to note in parallel the key milestones of U.S. Food and Drug Law History (2,3). The role of the USP
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(inception 1820) and NF (inception 1888) has always been to establish public standards for purity, quality, and strength for medicinal articles and compounding information. The role of FDA, formally established in 1930, and all of its predecessor organizations, starting with the Bureau of Chemistry of the Department of Agriculture in 1862, has always been involved with the enforcement of purity and potency standards for drug materials, in addition to other stipulated regulatory responsibilities (2,3). The earliest recorded interface between the USP, as a private, nongovernmental drug standards setting organization, and the federal government regarding enforcement of public standards for strength and purity of drugs occurred in 1848. Congress passed the Drug Importation Act in 1848 to prevent the importation of adulterated and spurious drugs and medicines into the United States. The U.S. Customs Service was empowered to test or have tested drugs and determine if they were inferior in strength and purity to the standard established in the United States Pharmacopoeia, and therefore improper, unsafe, or dangerous to be used for medicinal purposes, the articles shall not pass the custom house (4). Currently the USP/NF is recognized in federal statutes as a drug standardssetting body, which in turn mandates that all marketed medicinal articles in the United States that are the subject of USP/NF monographs must be fully compliant with all standards established in the monograph for the medicinal article. Noncompliance of the medicinal article with the USP/NF monograph standards makes the article adulterated. Marketing of adulterated articles is illegal and subjects the marketer to FDA compliance actions. In addition to the formal monographs in USP/NF there are sections termed General Notices and Requirements and General Chapters, which contain information applicable to all drug substances, inactive ingredients (excipients), drug products, and all other official articles (5). Finally, it should be noted that the USP operated as a private, not-for-profit organization without any legal status until 1900, when the United States Pharmacopeial Convention (USPC) incorporated in the District of Columbia, with a formal constitution and by-laws. The USPC has a formal elected
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Board of Trustees, which oversees the overall operations. Currently there is a staff of about 320 and a volunteer force of over 1200 to support USP/NF activities. The volunteers represent practitioners from virtually all sectors of global health-care delivery systems. Volunteers participating in USP activities (including participation at the 5-year cycle conventions of the USPC) include individuals representing accredited schools of medicine and pharmacy, state medical and pharmacy associations, national and international scientific and industry trade associations, consumer organizations, public interest groups, U.S. and international governmental and pharmacopeial agencies, and other sectors of health-caredelivery activities. A very descriptive overview of the current USP can be found in the publication USP, People, Programs, Policies, Procedures (USP PPPP) (6). Included in USP PPPP is a complete breakout of the USP Council of Experts, Expert Committees, Information and Standards Development organization, and a listing of all USP products and services and relationships, as well as explanations of how the reference standards system works and the evolution of compendial changes (1,6).
2. BRIEF HISTORY OF THE USP AND NF The United States Pharmacopoeia traces its origins to 1820. American physicians in the postRevolutionary War period were forced to depend on imported texts for information and counsel on the use, composition, and preparation of medicines. The need for a national pharmacopoeia became apparent to key practicing physicians at the time. A number of independently developed formularies and pharmacopoeias emerged, each servicing regional needs. Dr. Lyman Spalding took the lead and was instrumental in getting the medical establishment to recognize the need for a true national formulary. The process involved bringing together the major medical establishments at a national convention in Washington, DC, in January 1820 to work out the basis for a national formulary. His vision, diligence, and leadership finally resulted in the compilation, preparation, and publication of the first U.S. Pharmacopoeia on
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December 15, 1820, under the auspices of the convention (7). The first edition of USP bears on the title page the statement that the text was issued under the authority of the Medical Societies and Colleges. The pharmacopoeia included a primary list of 221 drugs and a secondary list of 71 drugs. The so-called listing of drugs was referred to as the materia medica and represented what the medical experts of the time determined to be the critical medicines needed to treat the population. Primary objectives of the first USP were to provide the correct Latin and English names for a medicine and a description of the material. This point of nomenclature remains as a critical ongoing activity of USP, through the United States Adopted Names (USAN) Council and the USP Dictionary of USAN and International Drug Names (1). At the beginning of the USP process there were no formal standards or quality specifications included in the compendia for the official articles. Preparations sections gave the reader recipes to prepare specific products. The scope of formulation types included solid, semi-solid, and liquid dosage forms recognized at that time. The end result of the USP would be to help physicians across the country provide defined and standardized medicines to the public without having to depend on importation of the articles from overseas. The listing of a medicinal article in the USP was akin to that named material being an official medicinal agent. As the USP continued to grow in stature and public recognition, a revision process was put in place to assure that the compendia included the most current recognized medicines and that articles no longer in common use would be removed from compendial status. Augmentation of USP monographs with tests for identification and drug quality began in 1840 (4,7). As the USP continued on its path of growth and update, practicing pharmacists founded a national organization, the American Pharmaceutical Association (APhA), in 1852. Their primary concerns centered on dealing with the continuing problem of inferior-quality medicinal articles coming into the United States from Europe. The approach to this problem was to establish quality standards to incorporate into official monographs to augment the USP. There was concern about giving physicians the option to forego ready-made medications
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and write out prescriptions for such articles that could be compounded by practicing pharmacists. Many of the readymade medicines were not included in the USPthus the impetus to establish a formal compendia of unofficial preparations. This activity came under the leadership of Charles Rice and Joseph Remington. The first National Formulary appeared in July 1888. The formal title of the compendium was the National Formulary of Unofficial Preparations, published under the authority of the American Pharmaceutical Association. NF I contained 435 recipes for preparations, covering all of the oral dosage forms recognized at that time. The theme of NF I was that it was not going to be only a repository for USP discards or a proving ground for novelties, but a source of reliable preparation information for established medicines (8). As the USP and NF evolved independently as compendia of medicinal agents, their formats and general content became quite similar. The APhA established a laboratory in 1936 for conducting tests to establish adequate drug standards (9). Prior to that point in time, laboratory testing incidental to the development of NF standards was done voluntarily or supported by an APhA subsidy at outside laboratories. The USP did not have its own testing laboratory in place, but relied on outside laboratories. In 1962 an integrated laboratory servicing the USP, NF, and AMA was put in placethe Drug Standards Laboratory. Key responsibilities of the laboratory were preparation and testing of reference standards (10). The work of the laboratory advanced to investigations of analytical techniques. In 1975 the acquisition of the NF by the USP resulted in the combination of the USP and NF into one compendium, with two separate sections of entry for monographs. The Drug Standards Laboratory became the Drug Research and Testing Laboratory in 1978. The focal point for the laboratory was to qualify reference standards and establish standards for dissolution testing. Currently USP maintains and operates two laboratories. The Reference Standards Laboratory (RSL) is responsible for the validation of testing procedures developed to support the qualification and release of material to serve as USP reference standards. Currently a batch of material targeted to be a lot of a reference standard article is tested in
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two outside laboratories plus the USP RSL. The Research and Development Laboratory (RDL) provides scientific support to the Expert Committees for the evaluation of analytical tests and methods proposed for inclusion in the USP (11). Until 1906 there were no federal or state laws requiring adherence of medicinal articles being produced or sold in the United States that were the subjects of USP and NF monographs, to meet the standards of the USP and NF. In 1906 the Federal Food and Drugs Act clearly and specifically acknowledged that drugs sold in interstate commerce under names mentioned in the USP or NF monographs must comply with the listed standards of strength, quality, or purity for these drugs (4). Noncompliant articles would be considered as misbranded and subject to the legal actions of the Bureau of Chemistry (part of the Department of Agriculture). Products sold under the compendial monograph name that had quality attributes differing from those specified in the USP or NF monographs had then to declare on the product labeling the strength, purity, and quality of the article (4). In 1927 the Bureau of Chemistry was reorganized into two separate entities, one of which was the Food, Drug, and Insecticide Administration. In 1930 the unit was renamed the Food and Drug Administration. The administrative control of FDA was changed from the Department of Agriculture to the Federal Security Agency in 1940. In 1953 the Federal Security Agency became the Department of Health, Education, and Welfare. An excellent summary of the history of FDA and all key milestones in the history of U.S. food and drug laws is provided in Ref. 2. Continuing concerns about the shortfalls of the 1906 federal legislation regarding false therapeutic claims for patent medicines and food adulteration led to efforts to revise the 1906 Food and Drugs Act. The revision efforts were accelerated by the deaths of more than 100 people in 1937 attributed to the ingestion of Massengills Elixir Sulfanilamide, which was formulated with highly toxic diethylene glycol. In June 1938 Congress passed The Federal Food, Drug, and Cosmetic Act, which required manufacturers of drugs to submit a New Drug Application to FDA that included full reports of investigations made to show that the such a drug is safe for use. The section of
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the law dealing with the New Drug Application is Section 505. There was no stipulation to require manufacturers to provide data to support the efficacy of new drugs or new formulations of already marketed drugs. A key element in the legislation was the retention of the recognition of the USP and NF as official public standards for medicines, including packaging and labeling requirements (12). Additionally, the new legislation extended control of the FDA to cosmetics and therapeutic devices. In 1962 the Kefauver-Harris amendments to the 1938 Food, Drug, and Cosmetic Act (Drug Amendments) became U.S. legislation to further strengthen the role of the FDA in controlling prescription drugs, new drugs, and investigational drugs. The public standards role of the USP and NF was not materially affected by the legislation, except for the establishment of the antibiotic certification program. The compendial role in assigning official nomenclature to new drugs was not reduced (13). It is interesting to note that in the 1965 Medicare amendments to the Social Security Act regarding payments for medical and other health services . . . which cannot be selfadministered and which are provided in a physicians office, such as drugs and biologics, must be included or approved for inclusion in the USP or NF (or in hospital formularies for administration in hospitals) to be eligible for Medicare coverage (14). In 1994 the Dietary Supplement Health and Education Act, amendments to the Food, Drug, and Cosmetic Act, named the USP, NF, and the Homeopathic Pharmacopeia as official compendia for dietary supplements. If a USP-NF monograph exists for a dietary supplement and the material in the marketplace represents that it meets USP standards, it is considered as misbranded if it fails to comply with all monograph requirements. The program is voluntary and a nutritional supplement that makes no assertion of compliance to USP cannot be held accountable to the monograph standards (15). In 1997 the Food and Drug Administration Modernization Act was passed, which included in Sections 353 (a) and (c) the allowance for pharmacy compounding of drug products, outside the jurisdiction of the Food, Drug, and Cosmetic Act. The restriction on compounding in the FDAMA legislation was
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that compounding of drug products would not become an unregulated manufacturing sector. The role of the USP/NF in compounding matters is that compounded articles that are the subject of USP/NF monographs must comply with all standards of the compendia (15). Currently, Sections 353 (a) and (c) of the act have been ruled invalid by the U.S. Supreme Court regarding restrictions in the act to publicly advertise certain compounding services. Pharmacy compounding falls under the jurisdiction of State Boards of Pharmacy. There is no change with respect to requirements regarding compliance of compounded articles to USP monograph and general chapter standards dealing with compounding.
3. BRIEF OVERVIEW OF THE CURRENT CONTENTS OF THE USP-NF The USP 27 and NF 22 (USP/NF 2004), combined in one volume, are actually two separate compendia. Each compendium consists of independent monographs for official articles. Supporting information to aid in the conduct of testing requirements included in individual monographs are contained in a section of the USP/NF called General Chapters. Typically, each monograph will have specifications and test procedures relevant to the monograph article. Additionally, there will be references within each monograph to general chapter information for conducting certain tests, as needed. Finally, as a prelude to the individual USP and NF sections of the compendia, there is a general umbrella coverage of information that provides details about USP/NF terminology and clarification of practices provided under the banner of General Notices and Requirements. There is a separate entry of this section just prior to the USP monographs and a second separate entry of this section just prior to the NF monographs (16). Finally, in addition to the formal sections of the compendia identified as USP and NF, there is a section entitled Dietary Supplements. This section contains monographs structured in similar fashion to the USP and NF monographs. Unlike the USP
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and NF sections there is no entry prior to the Dietary Supplement monographs of a General Notices and Requirements section. It should be noted that the Dietary Supplement section monographs can be considered as being included in the USP, but are distinguished from the formal USP monographs. 3.1. Official Monographs An official substance or article is defined in a USP or NF monograph and includes an active drug entity or drug substance, a recognized nutrient ingredient, a recognized dietary supplement ingredient, a pharmaceutic ingredient or excipient or inactive ingredient, or a component of a finished device. An official preparation is a drug product that contains a drug substance or a dietary supplement active ingredient. It is the finished or partially finished product or preparation containing one or more official substances intended for patient use. There are a certain number of compounding monographs that provide detailed instructions for the preparation of the finished product. Currently the USP section has monographs that include virtually all of the above. The NF monograph section is principally devoted to pharmaceutic ingredients or excipients. The NF also has some monographs for botanical articles, including some compounding formulations. There is a monograph and general chapter section between the USP and NF sections dedicated to nutritional supplements. 3.2. Informational Sections of the USP/NF 1. General Notices and Requirements: Applies to all sections of the USP and NF. 2. General Chapter: General requirements for tests and assays for monograph articles. Includes sections dealing with specific chemical, microbiological, biological, physical tests, and a listing of all current USP Reference Standards. Currently about 1400 standards are sold by the USP. These standards are listed in each revision of USP and
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additions in the supplements. Just prior to the formal presentation of all General Chapters, there is a new feature in USP 27/NF 22 identified as Charts/Guide to General Chapters. The charts shown in USP 2004 break out the contents of the USP into all of the categories of articles present and identify which General Chapters and General Information Chapters have relevance for any particular type of article in the compendium. There is also a break out of all General Chapters that have relevance for the entire sector of Drug Product Distribution, broken out by the individual portion of the distribution chain, starting with the drug product manufacturer. 3. General Information Chapters: Not currently mandated in any Compendial monograph but reflect good scientific practices and procedures provided as supplemental information. The General Information chapter listings start at 1000 and proceed upward. There is no scientific rationale for the order of chapters within the section or assignment of chapter numbers. For Dietary Supplements there is a listing of General ChapterGeneral Information chapters, starting as Chapter 2021. Again one must regard these chapters as supplemental, non-binding information, as is the case for General Information chapters covering the USP and NF sections of the compendia. 4. Reagents, Indicators, and Solutions: Covers materials required for all monograph tests and assays. 5. Reference Tables: Covers ancillary information that supplements the monograph content. Included within the reference tables are two very useful chapters about the monograph articles: Description and Solubility and Solubility. Browsing through these general information sections of USP is valuable to assess the extraordinary scope and depth of the information available. For example, there is one breakout section in the beginning of the NF that categorizes the functionality of all USP and NF excipients (17).
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A key initiative at USP is the process of harmonization of monographs and general chapters with the European Pharmacopoeia (EP) and Japanese Pharmacopoeia. Under an umbrella organization called the Pharmacopoeial Discussion Group (PDG) (formed in 1989), the USP, EP, and JP work to identify monograph or general chapter candidates for harmonization. The World Health Organization is present at PDG meetings as an observer. The PDG works in harmony with the International Conference on Harmonization of Technical Requirements (ICH), with a focus on compendial issues. The USP General Information Chapter, Pharmacopeial Harmonization h1191i, which first appeared in Supplement 2 of USP 2003, provides a detailed explanation of the PDG process and the current metrics for the harmonization for excipients and general chapters. To date no active ingredients have been considered for harmonization. Advantages of harmonization relates to global use of an article and the need to have only one compendial standard for testing.
4. REVISION PROCESS FOR USP/NF Both the USP and NF developed publication cycles for revisions, with interim revision announcements. The cycle times were 10 years, then 5 years. In 1975 the USP purchased the NF, and their new title became the USP/NF. In 2002 the USP/ NF became an annual publication with two formal supplements issued in the calendar year. For the current USP, USP 27/NF22, Supplement 1 was published in February 2004 with an official date of April 2004. Supplement 2 was published in June 2004 with an official date of August 2004. Updates of USP/NF are carried out with a publication termed Pharmacopeial Forum (PF). It is published on a bimonthly basis and is the manner in which the USP advises the public about changes being considered for both monograph and nonmonograph content of the USP-NF. Public comment is invited about all content in the PF and USP. A typical PF issue provides
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the reader with potential revisions (Pharmacopeial Previews), proposed revisions (In-Process Revisions), and adopted revisions (Interim Revision Announcement). Additionally, PF encourages public involvement in the revision process, and there is a section devoted to public comments called Stimuli To The Revision Process. Instructions for public comment are provided in the PF (18). Finally, each entry in PF that concerns a proposed change to USP/NF provides the reader with a guide for the future about the revision proposal. There are defined periods for public comment before a subsequent step occurs in the revision process. It is very important for PF readers to understand the cycle time for events so that changes that may be untoward or unclear or possibly even errata may be intercepted by direct communication to the specified USP staff liaison person designated in the PF entry for the item in question. The interim revision announcement provides the reader with the date that the revision will become official. It identifies which subsequent publication of the USP will contain the official change. This could be either a future supplement or a future revision of USP.
5. FORMAL AND INFORMAL LINKAGE OF THE USP AND FDA All official articles (active or inactive ingredients or preparations or drug products) dictate that the user must assure that the articles are fully compliant with all specified USP/ NF monograph requirements and ancillary compendial requirements. The submission of a drug application to the FDA that includes any article covered by a USP/NF monograph directly links the USP to the submission. The drug application sponsor must provide FDA with data and information that demonstrate that the compendial articles or drug preparation included in the drug application are fully compliant with all compendial requirements. Included in the information sections of the compendia are procedures for validation of compendial methods and the conduct of
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virtually all monograph test procedures. The concept of compliancy is that the article or preparation will maintain compliancy to the monograph requirements throughout the labeled expiry date or use period for the article or preparation. Following satisfaction of the FDA drug product review branch with the drug application, the second tier of demonstration of compliance with all USP/NF requirements occurs during field inspections at the sponsors manufacturing site. Typically this could be a preapproval inspection or a cGMP inspection. The drug application sponsor must be prepared to show FDA that all USP/NF requirements were met from use of the appropriate USP reference standards (or qualified house standards), equipment qualification, and assay validation. It is very important to have complete understanding of the content of the general chapters in USP and be prepared to explain any inconsistencies that may be in internal SOPs or Control Documents versus the USP content. As noted above, USP monograph requirements are not just release requirements but expected quality attributes through the defined expiry period for the product. This can only be confirmed by continued stability evaluation of the product. Some of the typical issues that a drug application sponsor has to deal with are continued vigilance to respond to a monograph change(s) that may occur over time. Any change must be a catalyst to upgrade all procedures and documents affecting the drug article due to monograph or general chapter change(s). It is not uncommon for a drug application sponsor to use alternate methods for the monograph article. Any monograph change dictates that a revalidation be implemented to demonstrate that the monograph change does not alter the comparability of the alternate method to the new monograph procedure. Evaluation of proposed monograph or general chapter changes must be made on a critical path to assure that appropriate comments are conveyed to USP in a timely manner to assure that inappropriate changes do not get to the final step of approval in the USP change process.
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6. CURRENT ISSUES: USP INFORMATION VERSUS FDA REQUIREMENTS The USP includes in the general chapters and general information topics that impact on compendial testing. Frequently the same topics are the subject of FDA guidances or ICH guidances. Updates occur, and it is very important to assess the currency of the information in the USP versus updated FDA or ICH guidances. Any inconsistencies or conflicts must be immediately conveyed to the USP. It is critical that stakeholders of USP products and services become cognizant of the USP change control processes. The contact persons for specific issues at USP should be defined and continually monitored. Participation and awareness of USP conferences and workshops can be a very important source of information about changes that USP may be considering that could impact a firms understanding of USP-defined procedures and practices. Updating internal controls and procedures and updating drug product applications based on USP changes is an eternal task that simply cannot be overlooked.
7. FUTURE ROLE OF THE USP IN THE DRUG REGULATORY PROCESS As the USP continues to evolve with the introduction of new analytical technologies into general information chapters, such as near-IR spectrophotometry, the impact may be that USP stakeholders will be encouraged to consider the use of the new analytical technology as a replacement for the current, and possibly outmoded, USP monograph procedure. Such upgrades in analytical technology will find their way into regulatory filings, likely associated with compendial monograph testing changes. The arena of process analytical technology (PAT), which currently has a very strong endorsement by FDA, dictates the need for USP to reengineer its mindset about reference standards to support future drug product monographs, which
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may have two tiers of testing. Tier 1 might be the traditional monograph portfolio of universal tests and specific tests. Universal tests include description, identification, impurities, and assay. Specific tests include uniformity of dosage units, performance tests such as dissolution drug release, pH, etc. For process monitoring and control, where virtually every dosage unit can be expected to be within an acceptance boundary of critical quality attributes, end product testing may need to be totally redefined in Tier 2 testing requirements. What type of reference standards will be needed is currently unknown. With respect to USP monograph developmentboth the preparation of a new monograph and revision of an existing monographthe USP has just completed the preparation of a guideline for monograph development. The guideline goes across all types of articles, active ingredients, excipients, drug products, etc. The guideline is now on the USP website for public purview. Heretofore USP involvement in process development was very limited. With this new horizon of process monitoring/ process control, a new era is upon the USP. The changing testing objectives will have a very important impact on regulatory submissions and routine quality control. PAT, at its ultimate refinement, is perceived to be an on-line/in-line continuous monitoring and control-based operation during routine manufacturing of a drug product (19,20). Every advance in process analytical chemistry and analytical technologies introduced to the pharmaceutical industry will have an impact on compendial testing. In turn, this will impact on regulatory filings.
8. CONCLUSIONS The USP/NF continues to serve the health-caredelivery system by providing public standards for pharmaceuticals and dietary supplements. It is critical for USP actions to assure that monographs and informational (both mandatory and optional) chapters reflect current scientific technology and that the content of USP is in line with EP and JP standards and meets FDA
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expectations. By such practices, the FDA will almost certainly continue to rely on the USP as a reliable bearer of critical quality attributes for pharmaceutical raw materials and finished products and be a benchmark for regulatory submissions pertaining to product description, identification, impurities, assay, and specific tests related to performance. It is critical that the industry maintain strong vigilance and interaction with USP to make sure that the public standards satisfy the needs of stakeholders and the regulatory sector.
ACKNOWLEDGMENT To the dedicated and interactive staff at USP, with whom I am in contact on a frequent basis, thank you for educating me about the USP.
REFERENCES
1. Mission and Preface, United States Pharmacopoeia 27 National Formulary 22 (USP/NF 2004), The United States Pharmacopeial Convention, Rockville, MD, 2004, pp. vxiii. Milestones in U.S. Food and Drug Law History, FDA Backgrounder, http://www.cfsan.fda.gov/mileston.html. Janssen, W.F., The Story of the Laws Behind the Labels, Part I, 1906 Food and Drugs Act, Part II, 1938 The Federal Food, Drug, and Cosmetic Act., Part III, 1962 Drug Amendments, FDA Consumer, June 1981 (available on FDA website; Part 1, http://www.cfsan.fda.gov/lrd/history1.html, Part 2 history1a, Part 3 history1b). L. Anderson and G.J. Higby, The Spirit of Voluntarism, A Legacy of Commitment and Contribution, The United States Pharmacopoeia 18201995, United States Pharmacopeial Convention, 1995, p. 71. General Notices, USP/NF 2004, 2004, pp. 112; General Chapters, USP/NF 2004, 2004, pp. 21082402.
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5.
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USP, People, Programs, Policies, Procedures (USP PPPP), United States Pharmacopoeial Convention, Rockville, MD, 2002. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995, pp. 2527. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995, pp. 155156. History of the National Formulary, The National Formulary, 10th ed. (N.F. X), American Pharmaceutical Association, 1955, pp. xxiixxiii. L, Anderson and G.J. Higby, The Spirit of Voluntarism, 1995, pp. 363365. USP PPPP, 2002, p. 104. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995, p. 281. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995, p. 357. J. G. Valentino, USP Admissions Policy on Approving New Drugs for Inclusion in the United States Pharmacopeia (USP) Is Presented, Pharmacopoeial Forum, Vol. 26(6), Nov.Dec. 2000, p. 1519. Mission and Preface, United States Pharmacopeia 17 National Formulary 22 (USP/NF 2004), The United States Pharmacopeial Convention, Rockville, MD, 2004, pp. xii. General Notices and Requirements, USP 2003, 2003, pp. 112. Excipients, USP/NF 2004, 2004, pp. 28092812. Pharmacopial Forum, USPC, Bimonthly Publication. A. Hussain, FDAs PAT & cGMP Initiative for the 21st Century: Status Update and Challenges to be Addressed, NJPhAST 2003 Symposium, Rutgers University, Piscataway, NJ, 2003. Gary Ritchie, Topic 3, Process Analytical Technology: Near-IR, Analytical Methods and General USP Topics, Philadelphia, 2003.
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10. 11. 12. 13. 14.
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16. 17. 18. 19.
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Ways and Means to U.S. Registration of Foreign Drugs
ALBERTO GRIGNOLO, JILL E. KOMPA, RICHARD J. SCHWEN, and DAVID SKARINSKY PAREXEL International Corporation Waltham, Massachusetts, U.S.A.
1. INTRODUCTION The economics of pharmaceutical development have a significant impact on the strategy for global marketing approval of new drugs. This is particularly true when sponsors develop and register a drug in one country and then seek marketing approval for the new drug product from regulatory bodies in
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a different country or region. Although the drug development process may be similar in different regions, differences due to culture, medical practice, demographics, and other factors can impact how and how rapidly new drugs gain access to different markets. For instance, such differences could complicate the registration process when sponsors seek U.S. Food and Drug Administration (FDA) registration of a pharmaceutical product for the U.S. market based on data gathered outside the United States. A thorough understanding of the issues involved and careful execution of the U.S. regulatory strategy can help make the process manageable. This chapter addresses the following topics: FDA requirements for registration of foreign drugs, including criteria for acceptability of foreign data, as well as the impact of the International Conference on Harmonization (ICH) guidelines. Challenges facing foreign drugs, including chemistry, manufacturing, and control (CMC), clinical and nonclinical issues. Factors that can facilitate FDA approval of foreign drugs, including a comparison of the requirements for the New Drug Application [NDA] and the Common Technical Document (CTD). Practices and behaviors that increase the likelihood of FDA approval of foreign drugs, including communications with the FDA.
2. REGULATORY FRAMEWORK RELEVANT TO U.S. REGISTRATION OF FOREIGN DRUGS Two regulatory entities have impact on the issues surrounding U.S. registration of foreign drugs. FDA plays the major role, as it sets the criteria for acceptance. Additionally, the ICH, under the auspices of the six founding members representing the regulatory bodies and research-based industry in the European Union, Japan, and the United States, has addressed the issue with specific guidances and the CTD.
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2.1. U.S. Food and Drug Administration FDA regulations governing the approval to market a new drug are covered in the Code of Federal Regulations (CFR), Title 21, Part 314. The regulations do allow the approval of an NDA based solely on foreign clinical data, provided that the application meets three criteria outlined in 21 CFR 314.106. The regulation states that an application based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved if: 1. the foreign data are applicable to the U.S. population and U.S. medical practice; 2. the studies have been performed by clinical investigators of recognized competence; and 3. the data may be considered valid without the need for an on-site inspection or, if FDA considers such an inspection to be necessary, FDA is able to validate the data through an on-site inspection or other appropriate means. The FDA will apply this policy in a flexible manner according to the nature of the drug and the data being considered. The regulation also encourages consultation between applicants and the FDA. It specifically suggests a presubmission meeting between applicants and Agency officials when the sponsor intends to seek approval based solely on foreign data. (For more about presubmission meetings, see Sec. 5.) If the Agency feels that the criteria listed above have been met, it may approve the product based on foreign studies. As Table 1 illustrates, FDA has approved approximately 80 drugs based solely or predominantly on clinical data generated outside the United States. 2.2. International Conference on Harmonization Recognizing the need to eliminate redundancies in research while supporting the sovereignty of the respective regulatory bodies, ICH has examined ways to help make clinical data collected in one region acceptable to the regulatory authority of another region. One outcome of this ongoing effort is the
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Table 1
Drugs Approved by FDA on the Basis of Non-U.S. Data

Genotropin Gonal-F Granisetron Halfan Haloperidol Hycamtin Indium IN-111 Isosorbide mononitrate Lamictal Lamivudine Levonorgestrel Lutamide Merrem Mesna Metoprolol Mifepristone Myotrophin Nafareline nasal solution Naropin Nefazodone Neufolie Nimodipine Novantrone Olsalazine Omeprazole Ondansetron Paclitaxel Plavix Posicor Pravachol Prograf Propafenone Prosynap Quinapril Reuden Rilutek Rivizor Salmeterol Seroquel Stromectol Strontium Chloride Sumatriptan Tacrine Tacrolimus Tamoxifen citrate Thalidomide Ticlopidine Tranexamic acid Trovan Venlafaxine Vinorelbine Viramune Zithromax Zoladex
Acutect Albenza Ambisome Anzemet Arimadex Betaxolol Bravavir Buspirone Calcitonin-Salmon Carboplatin Cellcept Crixivan Cysteamine Dalteparin Denavir Desogestrel/ethinyl estradiol Diazepam emulsion Dinoprostone Dostinex Dronabinol Enoxaparin Exelon Femara Finasteride Follistim Gabapentin
ICH Guideline E5, Ethnic Factors in the Acceptability of Foreign Clinical Data. Developed to facilitate registration of medicines within ICH regions, the guideline suggests a framework for evaluating the impact of a wide range of ethnic factorsgenetic and physiological, as well as cultural and environmentalon the safety and efficacy of the drug for which registration is being sought. For sponsors of foreign drugs, ICH Guideline E5 complements the FDA regulations. The ICH guidance notes that all data in the clinical section should meet the standards for study design and conduct and should satisfy the regulatory requirements of the region in which the sponsor seeks approval.
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Once that has been accomplished, the sponsor must be able to extrapolate the study data to the population of the new regionin this case, the United States. If the sponsor or the regulatory agency is concerned that ethnic differences could have a significant impact on the safety or efficacy of the drug in the new population, additional data may be necessary. The core concept of ICH Guideline E5 is the bridging study. ICH defines the bridging study as a study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the population in the new region. A bridging study for efficacy could provide additional pharmacokinetic information in the population of the new region. When no bridging study is needed to provide clinical data for efficacy, a pharmacokinetic study in the new region may be considered as a bridging study. The concept assumes that the need for any new data is based on the drugs level of sensitivity to ethnic differences between the two regions. If the bridging study results in similar data in the new population, the original efficacy and safety data should be sufficient to support approval in the new region. In such cases, the sponsor should not need to replicate the original studies in the new population. On the other hand, if the bridging study fails, the sponsor would generally need to conduct new efficacy and safety study in the population of the target region. In writing Guideline E5, ICH suggested that increasing experience with cross-regional acceptance would diminish the need for bridging studies. To date, that has not been the case. Bridging studies have become much larger than ICH intended, and many fall outside the spirit of Guideline E5. ICH is in the process of reevaluating Guideline E5 in order to make the guidance more practical and useful to sponsors. The impact of Guideline E5 on FDA approval of foreign drugs can be favorable to sponsors if FDA agrees that a bridging study can help satisfy the requirements for approval of a specific new drug, consistent with 21 CFR 314.106. Sponsors should discuss this possibility well in advance with FDA and
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determine if in fact the Agency might require additional, larger Phase 3 confirmatory trials conducted in the United States.
3. POTENTIAL OBSTACLES TO THE REGISTRATION OF FOREIGN DRUGS Sponsors of foreign drugs face a number of challenges when attempting to persuade the FDA that a new drug is approvable. Most of these obstacles are inherent in the drug development process. They are not unique to foreign drugs; however, differences in culture, testing procedures, standard medical practices, demographics and other factors can magnify the challenges. Sponsors must recognize the potential pitfalls and plan ahead in order to minimize the impact of ethnic factors on the approval of an NDA. The issues that sponsors of foreign drugs must address fall into three broad categories: CMC, nonclinical and clinical. 3.1. Chemistry, Manufacturing and Controls Issues FDA requires the same CMC information for foreign drugs as it does for unapproved new domestic drugs. The amount of CMC information required varies, depending on the type of submission. Specific requirements are stipulated in the various FDA guidances relevant to Investigational New Drug (IND) applications, NDAs, Abbreviated New Drug Applications (ANDAs), etc. All drug manufacturers must comply with current Good Manufacturing Practices (cGMPs) for finished pharmaceuticals, as specified in 21 CFR 211. Manufacturers must meet United States Pharmacopoeia (USP) standards for the drug substance, its excipients, or the drug product, if available. If the substance is not listed in the USP, the sponsor may reference other pharmacopoeial standards, such as the British Pharmacopoeia (BP) or European Pharmacopoeia (EP). If no pharmacopoeial standards exist, the sponsor must provide a full characterization of the new ingredient in the NDA.
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As is true with all drugs, sponsors of foreign drugs should follow ICH quality guidelines regarding stability, validation of analytical procedures, acceptable levels of impurities, residual solvents, etc. Sponsors may submit information regarding the chemistry and manufacturing of drug substances, products, excipients or packaging in a Drug Master File (DMF), which can be referenced in ongoing submissions to FDA. A U.S.-based agent acting on behalf of the sponsor must submit foreign DMFs. Foreign sponsors must comply with the same requirements for establishment registration and product listing that apply to U.S.-based manufacturers. Foreign manufacturers must register with FDAs Drug Listing Branch and have a drug establishment number assigned to them. Individual drug products to be imported must also be registered with this FDA branch. In order to import a foreign drug product through U.S. Customs, the importer should provide relevant documentation. This might include an IND number, an approval letter if the drug is a marketed product, and proof that the product has been appropriately listed with the Drug Listing Branch. The import process is often best handled through an experienced import broker who can facilitate a positive outcome and avoid potential delays. Retrospectively, foreign drug establishments often cite delays in the import process as a common occurrence that they might have avoided had they used an experienced broker. Foreign manufacturers must also have a U.S. agent who resides in or maintains a physical place of business in the United States. The agent facilitates communication between FDA and the foreign manufacturer. FDA will contact the U.S. agent in regard to both facility and drug listing issues for the foreign-based manufacturer. FDA may inspect a foreign manufacturing site if, at any time, the Agency determines that an inspection is warranted. Sometimes the initial act of registering an establishment with the Drug Listing Branch may prompt an inspection, particularly if the sponsor intends to import the listed drug in the very near future. FDA is likely to consider an inspection if the facility has not been inspected previously.
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If FDA conducts an inspection and finds problems, the inspector will report his or her observations of the conditions and practices observed at the site on FDA Form 483. The firm is then required to respond to FDAs findings and to indicate the corrective actions that they will take to resolve the issues. Depending on their nature and volume, the overall findings can be the basis of the FDAs determination as to whether the establishment is compliant with cGMPs. If FDA does not consider a facility to be in compliance with cGMPs, it will not approve pending drug applications until the establishment resolves GMP facilityrelated issues. If the findings are significant, the FDA will likely reinspect the facility to ensure adequate resolution of previous concerns. Reinspection often takes time, and the additional lead time required for inspectors to travel to foreign sites can lead to approval delays. It is important to be aware that lack of inspection readiness on the part of the manufacturing site is a common reason why the FDA considers submissions to be nonapprovable. 3.2. Nonclinical Issues FDAs nonclinical testing requirements for foreign drugs are identical to the requirements for unapproved new U.S. drugs. In all cases the data must demonstrate safety for human subjects during clinical trials and for patients when the drug is marketed. The efforts of the ICH have resulted in the harmonization of basic requirements for nonclinical study design; however, specific requirements for nonclinical studies can be very specific to each drug and indication. ICH Guideline M3, Timing of Pre-clinical Studies in Relation to Clinical Trials, addresses general considerations in regard to when nonclinical studies are conducted in a prototypical drug development program. The guideline provides a point of reference, but it is not a substitute for communication with FDA. Consultation with FDA is appropriate at pre-IND, end of phase 2, and pre-NDA conferences in order to clarify specific requirements on a case-by-case basis. However, the sponsor should not necessarily expect FDA
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to provide guidance and direction spontaneously. Rather, it is the responsibility of the sponsor to design and propose the nonclinical testing program for FDAs concurrence and possible modification. A proper toxicology program is designed with consideration for the following: Known safety data on the drug (in vitro animals and humans) Results of an early risk assessment identifying data gaps that need to be addressed Relevant FDA and ICH guidelines Proposed exposure and use/indication of the drug in humans, whether in clinical trials or on the market Direct input from FDA and Sound toxicology advice In order for the foreign nonclinical data to be acceptable to FDA, the testing must be conducted according to Good Laboratory Practices (GLPs, found in 21 CFR 58). FDA may inspect the nonclinical testing facility, the nonclinical data, or both. FDA is most likely to select for closer scrutiny those studies that suggest potential and significant safety issues in humans. In these cases, FDA tries to determine whether the study was designed and conducted properly, that is to say, in accordance with GLPs. (References and guidance for monitoring GLPs are available on the FDA website at www.fda.gov/ora/compliance_ref/bimo/glp/default.htm.) The Agency will also address the significance of the animal data in relation to humans. Although nonclinical investigational studies, such as dose-ranging or pilot studies, are technically exempt from the GLP requirement, safety (toxicology) studies, which are critical for safety assessment, certainly are not. Serious concerns regarding the quality of the data can trigger a for-cause inspection of the animal facility. The drug substance and drug product, or formulation, tested in nonclinical studies should be relevant to the product that the sponsor intends to market in the United States. This requirement is based on the need for the data from safety studies to be relevant to the risk assessment process, particularly
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if the product formulation or quality are different from that to be marketed in humans. Studies of such variants do not necessarily predict response in humans. This relevance is a critical factor in FDAs acceptance of foreign data. As is usually the case in drug development, sequential improvements in the drug substance and/or drug product are made as the development program progresses from preclinical to clinical stages. The sponsor may need to repeat preclinical studies if the earlier studies were conducted with a product that the FDA considers significantly different from the clinical product. While the final safety database should reflect known safety concerns that have been observed in either animals or humans throughout drug development, the actual timing of nonclinical studies should be linked to the drugs stage of development. The nonclinical testing should generate sufficient quantity and quality of data to allow for a reliable risk/benefit analysis prior to each clinical trial in a drug development program The sponsor should address the safety observations made in clinical trials and should work with nonclinical models addressing relevance to humans when appropriate. Dose relationship and reversibility of observed effects are normally required in order to allow for a proper risk assessment in humans. It is important that the sponsor conduct the nonclinical testing in a species whose absorption, distribution, metabolism, and excretion (ADME) are relevant to humans. As human data become available, the sponsor should reevaluate the selected nonclinical testing models in order to assure the programs relevance to humans. In reality, safety models and programs must be revised if the data collected indicate that different, more appropriate, studies are required to make an accurate risk assessment. 3.3. Clinical Issues Regulatory bodies such as FDA are cautious about basing registration solely on foreign data, due to the potential impact of ethnic differences on the product labeling and selection of dose
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and dose regimen. By planning to address intrinsic (i.e., genetic and physiological) and extrinsic (i.e., cultural and environmental) ethnic differences throughout the drug development process, the sponsor of a foreign drug may save time, reduce the need to replicate studies, and build a stronger case for FDA acceptance, including nearly every aspect of clinical development from study design, to patient issues, to investigator selection, to study conduct. 3.3.1. Investigator/Site Selection
In order to evaluate the quality of foreign data, FDA must feel comfortable with the selection of investigators and sites. Selecting academic or high-visibility centers of excellence and providing standardized investigator training can help address concerns about quality of data. However, the reputation of a center is not, in and of itself, an assurance that clinical trials conducted there are GCP compliant or relevant to the U.S. population. Selected investigators must be familiar with conducting controlled clinical trials according to Good Clinical Practice (GCP) guidelines; they must also understand the critical nature of timely safety reporting to support labeling. Selected sites should have sufficient research training and experience in conducting trials that may eventually be audited by FDA. In case of an audit, documentation of adherence to GCPs and timely safety reporting may be a critical determinant of whether the data will be acceptable to FDA for purposes of NDA approval. Qualified investigators and savvy sponsors need to be aware of the differences between local and cross-border standards of diagnosis and patient care. Standardization of diagnostic criteria and treatment measures prior to initiating a foreign study intended for U.S. registration helps minimize variability across sites and provides for validation of the criteria early in the development process. Linking those criteria and measures to analogous ones known to be acceptable in the United States may prove essential to ensuring acceptance of the trial data to the U.S. medical community and to FDA.
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Control of investigational drug product and control over the conduct of the investigation are essential for U.S. registration. If the study is conducted under an IND, FDA requires the investigator to sign FDA Form 1572, the Statement of Investigator. By signing this form, the investigator makes a legally binding commitmentunder the U.S. federal law and with federal penaltiesto conduct the study according to the protocol, to personally conduct and supervise the investigation, and to maintain study records and submit all materials to the Institutional Review Board (IRB) or local ethics committee (EC). No such commitment or enforcement mechanism exists for a non-IND study. Therefore, the sponsor must provide training and carefully document that the investigator has full control over the investigation and understands his or her ultimate responsibility for the quality of the outcome. It is important to realize that it is not necessary to conduct a foreign clinical trial under an IND for it to be acceptable to FDA, nor will its conduct under an IND make it more acceptable to FDA. The key success factors for clinical data acceptance are GCP compliance and relevance of the data to the appropriate U.S. patient population. 3.3.2. Ethics Committee/Institutional Review Board Selection An FDA concern regarding some foreign studies is the lack of local control or inspection of studies by local ethics committees. It is important to be aware of how local ethical standards and review processes differ from the standards followed in the United States and how those differences may affect the credibility of the foreign data. For a successful submission of foreign data, it is critical to select sites governed by ethics committees with membership and rules of conduct that will be acceptable for U.S. registration. One obstacle that is common, particularly in developing countries, is inadequate or biased representation on the ECs. The EC should include sufficient representatives with the appropriate technical expertise and should provide objective evaluation by both the scientist and
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the patient advocate. It is also important to avoid the appearance of bias or conflict by excluding individuals from the voting process who might have a direct interest in the studyfor example, the investigator or the discoverer of the drug. Selection of sites with an ethics committee that will be acceptable in case of an FDA audit may be a potential source of conflict for the sponsor. The sponsor must be careful to balance the needs and customs of the host country and the investigator who will conduct the study against the requirements of GCP. 3.3.3. Consent Process
Inadequate study subject consent, as well as both overt and indirect coercion of patients to participate in the study, can undermine the acceptability of foreign data for U.S. registration. Providing choice of treatment and a comprehensible understanding of risk in the patient consent document is a critical test of adequate consent, governed by the Declaration of Helsinki and GCP guidelines. Lack of adequate consent can be problematic, particularly if FDA finds that the study does not provide medically indicated treatment or conducts coercive trials in locations where sufficient medical care is not available. Additionally, local medical acceptability and cultural differences in patient beliefs may limit therapeutic choices and excessively expand what is acceptable, resulting in a biased informed consent process that may preclude the use of foreign data to support a U.S. application. 3.3.4. Choice of Comparator and Dose
The relevance of foreign clinical data may also be judged by the choice of comparator, as well as relevant dose or dose range for both test and comparator drugs. Active comparators need to be chosen based on whether the drug, dose and dosage are approved by FDA. Demonstrating superiority or non-inferiority versus an active comparator is only meaningful if the comparator, dose, and dosage are labeled in a previously approved U.S. marketing application based on established safety and efficacy trials.
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The choice of dose and dosage of a drug in a pivotal trial used to support a U.S. application should also be carefully considered. Differences in local medical standards of practice, as well as cultural differences, often lead to different risk/ benefit ratio considerations when selecting dose and dosage for marketing. For example, some foreign countries may favor a greater safety margin over additional effectiveness. 3.3.5. Concomitant Medications and DrugDrug Interactions Drugdrug interaction data from foreign studies may have limited utility in the United States. A wide range of factors may complicate the extrapolation of foreign data to support labeling for the U.S. population. These include cultural, economic, genetic, and ethnic differences. Genetic and ethnic difference may lead to differences in absorption, distribution, metabolism, and excretion. Limited availability of pharmaceutical products, cultural bias toward the use of homeopathic remedies, and the wide use of certain co-medications, nutritional supplements, and/or herbal remedies in some locations may play a limiting role in FDAs ability to consider drug-drug interaction data from foreign sources. In such circumstances, the sponsor and ultimately FDA may determine that additional drugdrug interaction trials may be necessary to support U.S. labeling. 3.3.6. Contraception and Reproductive Toxicity Local practice, economic conditions, levels of education, and cultural differences often drive decisions regarding contraceptive methods. FDA is particularly concerned with the safety of a test product for trial participants, as well as with defining an appropriate level of reproductive safety for labeling. FDA requires any study to assure the safety of female and male patients and their offspring. In the United States, animal reproductive toxicity dataincluding gestation and effects on the various stages of fetal developmentdrive inclusion criteria for pivotal trials and labeling. Nonclinical reproductive toxicity data, and the potential effect that such data may have on
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patient selection, the product safety profile and labeling, should be considered prior to initiating pivotal clinical trials. 3.3.7. Patient Issues
Study treatment compliance, or lack thereof, can also be a barrier to acceptance of foreign data. In populations with low levels of education, it can be difficult to assure patient compliance and diary retention. Underreporting of adverse events may also be common due to cultural differences. In some cultures, for example, tolerance for higher degrees of pain or simple reverence for the physician may preclude complete and accurate patient reporting of adverse events. Incomplete reporting of adverse events leads to inadequate reporting of incidence of expected adverse events needed for U.S. labeling. 3.4. Study Design and Controls When designing a study destined for eventual U.S. registration, it is helpful to begin with the intended labeling in mind. Pivotal trials should be designed prospectively. When studies are not conducted under an IND, little opportunity exists to obtain FDA input. In such cases, it is advisable to obtain external, expert consultations regarding regulatory strategy that incorporates consideration of FDAs ability to label safety and activity claims. In the United States, labeling claims principally depend on data derived from two adequate and well-controlled pivotal trials. U.S. labeling claims often are (a) limited to the specific patient population studied, (b) limited to the route of administration, dose, and dosage used in the pivotal trial, and (c) limited to the prospectively stated objectives in the pivotal trials that proved to be statistically significant. A number of common pitfalls in foreign trials may complicate U.S. approval. Outside the United States, medical experts, rather than statisticians, often define sample size based on clinical exposure comfort levels rather than on statistical models that are the basis of appropriate sample-size calculations used to test a hypothesis. Whenever possible, the sponsor should allow an expert U.S. statistical consultant to review the statistical analysis plans in advance of the study.
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Targeted review can help anticipate issues that may be raised by FDA statisticians. When selecting active comparators or permissible concomitant treatment, sponsors should consider using drugs, doses, and dosages that are approved for marketing in the United States. It will be difficult for FDA to interpret safety data or to compare drug activity if the agency is not familiar with the active comparator, dose, route of administration, or dose regimen. Whenever ethically possible, the sponsor should consider placebo control, rather than active control, for pivotal trials. In the United States and the European Union, it is common for regulators and researchers to hold different opinions regarding the ethics of placebo control in clinical trials. Outside the United States, the use of retrospective historical controls and active comparators has been considered to be the more ethical approach. However, FDA still considers placebo-controlled trials to be the gold standard for demonstrating and labeling safety and efficacy. The exception is in the case of specific lifethreatening indications, such as those in the fields of oncology and infectious diseases. In addition to the careful consideration of a control arm, complete blinding of treatment arms is critical to limit bias and gain acceptability of foreign data. One way to achieve complete blinding is through the use of a jury of resemblance, which is a blinded group of individuals who help confirm the integrity of the blinding process. Such a jury will examine packaging and blinded product samples in order to identify matching homogeneous versus heterogeneous treatment samples. Complete blinding is achieved if the jury cannot differentiate between the two blinded treatments. Finally, in order to maximize chances for success and to support labeling efficacy for a particular subset population, it is preferable to stratify patients prospectively based on relevant endpoints. Such endpoints may be diagnostic criteria as well as severity of the disease and/or treatment. Prospective stratification assures appropriate balance of patients in the subset treatment arms and provides results that are easier to interpret. Compared to retrospective analyses conducted after
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the trial has been completed, prospective stratification is more likely to lead to successful identification of activity in a subset population. With retrospective analyses, low numbers in any one treatment arm may prevent achievement of the statistical power to detect a difference. Prospective stratification can be accomplished by using a telephone randomization system or a variety of site-specific randomization schemes that an expert statistician can design. 3.5. Endpoints In addition to study design considerations, an appropriate choice of clinically relevant endpoints is key to help drive labeling and gain FDA acceptability of foreign data. Surrogate markers of activity, expert medical opinion and nonvalidated, nonstandardized endpoints are often unacceptable to support labeling. A life-threatening condition or an orphan drug indication might be an exception, but even in these cases the sponsor has negotiated the strategy in advance with FDA. Clinically relevant endpoints, such as disease activity, patient mobility, symptom control, or survival, are all preferable to endpoints, such as an obscure lab test result without a historical correlation in the clinic, that lack a clear clinical interpretation. The sponsor should avoid choosing endpoints that lack cross-cultural applicability and validation. For example, food intake questionnaires or quality-of-life scales may contain questions that limit their use to support labeling when considered in a different cultural setting. Even for studies with subjective endpoints that require ratings by the investigator or patient, the sponsor should provide adequate training and, whenever possible, define the limits of interrater variability. Interrater variability among a group of investigators can be assessed proactively by presenting patient case scenarios and having each investigator rate the symptoms or diagnose based on a uniform patient case. Variability should be assessed. Raters whose results lie outside of the predefined acceptable range should be provided with additional training or excluded from trial participation.
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3.6. Local Medical Practice, Therapeutic Differences, and Unmet Medical Needs Considering variability in local medical practice is critical to understanding the relevance of the development program and the acceptability of foreign data in the United States. Variability may be based on differences in disease prevalence, diagnostics, test-ordering practices, prescribing practices, treatment options, treatment and medical care reimbursement, and standard treatment guidelines. If differences are identified, the sponsor should address these differences prospectively by planning for culturally relevant locations for conducting trials or retrospectively via a bridging study. Equally important are subtle cultural differences that may prevent a sponsor from identifying the maximal effective dose for U.S. registration. A physicians approach to adequate dosing may be culturally driven. For example, the standard of practice in Japan is often to identify a dose that is associated with fewer adverse drug reactions. In comparison, U.S. researchers might choose a dose based on maximal activity combined with an acceptable safety profile. Additionally, unmet medical needs that are often the target of pharmaceutical development plans may differ from one region of the globe to another. Health needs are often defined by socioeconomic policy, levels of education, and cultural biases. Development plans and trial designs often incorporate local standards of practice, available therapy, and accessible rescue drugs. These local realities may not apply and may preclude the foreign drug sponsors ability to collect data that will be applicable for labeling in the U.S. environment. For example, in Africa and certain parts of Southeast Asia, standard diagnoses and treatment guidelines may be limited by a variety of factors that include the patients (a) level of supplemental insurance and access to testing, (b) education, and (c) ability to read. In some areas of the world, the availability of alternative medicine and/or the reliance on traditional healers may play a role in defining medical need. Finally, in some regions providing early access to study-associated medical care and investigational treatment may be more acceptable,
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and even expected. Prospective planning, a focus on crosscultural acceptability, and use of multinational advisory boards may be the best way to design a single development program that has cross-cultural acceptability. 3.7. Collecting Foreign Clinical Data One issue for sponsors of foreign drugs to consider is whether to collect foreign clinical data under an IND prospectively. Clinical studies conducted outside the United States can be sponsored under an IND, but this is not an FDA requirement. Two common and related misconceptions exist regarding foreign studies and INDs. Many sponsors believe that FDA will give greater weight to studies that are conducted under an IND than to studies that are not. This is not true. Nor is it true that studies conducted under an IND are more compliant with Good Clinical Practices than are non-IND studies. Another common misconception is that by conducting the study under an IND, the sponsor does not need to obtain local country approval to conduct the study. Conducting a foreign study under an IND offers both benefits and drawbacks. Among the benefits is the fact that multinational studies and investigators are documented to the IND, which then becomes a common archive of study information. This approach allows the sponsor to conduct a single, global protocol for a multinational study, rather than conducting separate, though identical, protocols. Although studies conducted under an IND are not automatically more GCP compliant, such compliance is likely to be higher when investigators are aware that FDA may inspect them. In point of fact, FDA will audit investigator sites in pivotal studies regardless of country and regardless of whether the studies were conducted under an IND. Conducting a foreign study under an IND can also have drawbacks. For one, some non-U.S. investigators may object to signing the FDA Form 1572. The concept of an FDA-mandated Investigator Statement may be unpalatable to them.
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Another potential drawback to conducting a foreign study under an IND can occur if FDA places the IND on hold. In that case, all IND studies underway in all countries must stop. After weighing the pros and cons, the sponsor may decide not to conduct the foreign clinical studies under an IND. If that is the case, the studies must nevertheless conform to the regulations in 21 CFR 312.120, which describe the criteria for foreign studies not conducted under an IND: 1. In general, FDA accepts such studies provided they are well designed, well conducted, performed by qualified investigators, and conducted in accordance with ethical principles acceptable to the world community. Studies meeting these criteria may be utilized to support clinical investigations in the United States and/or marketing approval. Marketing approval of a new drug based solely on foreign clinical data is governed by Sec. 314.106. 2. Data submissions: A sponsor who wishes to rely on a foreign clinical study to support an IND or to support an application for marketing approval shall submit to FDA the following information: (a) A description of the investigators qualifications (b) A description of the research facilities (c) A detailed summary of the protocol and results of the study and, should FDA request, case records maintained by the investigator or additional background data such as hospital or other institutional records (d) A description of the drug substance and drug product used in the clinical study, if available (e) If the study is intended to support the effectiveness of a drug product, information showing that the study is adequate and well controlled under Section 314.126 3. Conformance with ethical principles: (a) Foreign clinical research is required to have been conducted in accordance with the ethical
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principles stated in the Declaration of Helsinki or the laws and regulations of the country in which the research was conducted, whichever represents the greater protection of the individual. (b) For each foreign clinical study submitted under this section, the sponsor shall explain how the research conformed to the ethical principles contained in the Declaration of Helsinki or the foreign countrys standards, whichever were used. If the foreign countrys standards were used, the sponsor shall explain in detail how those standards differ from the Declaration of Helsinki and how they offer greater protection. (c) When the research has been approved by an independent review committee, the sponsor shall submit to FDA documentation of such review and approval, including the names and qualifications of the members of the committee. In this regard, a review committee means a committee composed of scientists and, where practicable, individuals who are otherwise qualified (e.g., other health professionals or laymen). The investigator may not vote on any aspect of the review of his or her protocol by a review committee. 3.8. FDA Inspections of Foreign Clinical Investigators As noted above, FDA inspects selected foreign clinical investigator sites for studies considered pivotal for approval. Such FDA inspections of foreign clinical investigators have increased dramatically in recent years (see Fig. 1) due to an increase in the number of sponsors submitting NDAs that contain pivotal foreign clinical data. In addition, some pivotal trials are so large10,00020,000 patients or morethat sufficient patients are not available for enrollment from the United States alone, requiring the inclusion of foreign data.
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Figure 1 FDA inspections of foreign clinical investigators, 19912000. (From A. El-Hage, FDA.)
Figure 2 FDA inspection of European clinical sites reveals most common GCP deficiencies.
The violations that lead FDA to reject foreign studies include nonavailability of source documentation, inadequate record-keeping, failure to follow the protocol, unreported concomitant therapy, and unavailability of patient diaries. It is interesting to note that FDA inspections of clinical investigators uncover similar types and incidence of GCP violations at both U.S. and foreign sites (Fig. 2).
4. THE NEW DRUG APPLICATION AND THE COMMON TECHNICAL DOCUMENT ICH has promulgated a common format for marketing approval applications in the United States, Europe, and Japan.
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Figure 3 Diagrammatic representation of ICH Common Technical Documents. Module 1 contains documents specific to each region, such as application forms and proposed labeling. The other modules are relatively common to all submissions.
This format is called the Common Technical Document (CTD). The CTD follows a logical and highly structured format (see Fig. 3) designed to facilitate the preparation of marketing applications to multiple countries. Its common elements are intended to save time and labor by minimizing the need to reformat documentation or alter the sequence in which data are presented. The CTD format is now compulsory in the European Union and Japan; Australia will make it compulsory in 2004. Currently in the United States and Canada, the CTD is not required, but its use is highly recommended. In the United States, marketing applications submitted in the CTD format are still referred to as NDAs. As FDA receives more applications in CTD format, reviewers are becoming
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familiar with using the format. Neither FDA nor other agencies such as the European Medicines Evaluation Agency (EMEA) report significant difficulties in working with the new format. On the other hand, some sponsors have experienced difficulty in determining where certain information, such as the Integrated Summary of Safety (ISS) and Integrated Summary of Efficacy (ISE), should be placed within the CTD modules. Communications with FDA at presubmission meetings (see below) can help resolve such issues. The CTD benefits foreign drug development by streamlining the documentation process. Sponsors can submit documentation to FDA and other authorities with minor modifications to tailor the submission to local Agency needs. This allows the sponsor to apply more focus on the documents scientific and medical content and less on its format. Ultimately, the need to submit a document that demonstrates quality, safety, and efficacy remains unchanged. Those requirements are driven by both FDA regulations and ICH guidelines. FDA has the same expectations for an NDA regardless of whether the data was collected in the United States or abroad. The submission must present a convincing, datadriven demonstration of quality, safety, and efficacy, and the data must be relevant to the U.S. patient population. In reality, however, FDA may be more skeptical of data from particular unnamed countries. When presented with extensive data from these regions, FDA sends its inspectors to verify compliance with GCP, GLP, and GMP. Whether the NDA is submitted to FDA in the traditional format or in CTD format, the FDA will look for the same standards: Clarity Navigability Reviewer-friendliness Completeness Logical presentation Data that enable FDA to make sound scientific and medical decisions.
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5. COMMUNICATIONS WITH FDA Communication with FDA is of paramount importance in the drug development and approval process. For both foreign and U.S. sponsors, FDA can be an arms-length partner in drug development. The sponsor should keep FDA informed of drug development plans and progress so that the Agency can provide the best advice throughout the process and help the sponsor prevent costly errors. Foreign-based companies must be especially diligent about communicating with FDA throughout the drug development process. Misunderstandings regarding the Agencys expectations for the NDA can destroy a drug development program. The most significant concern is the potential that the foreign clinical data will have limited applicability to the U.S. patient population. If FDA has concerns regarding limited applicability, the sponsor must be aware of these concerns early enough in the process to be able to take appropriate action, such as conducting studies in the United States rather than abroad. Communicating with FDA may differ from communicating with other Agencies. Some methods of communication are more effective than others, and FDA has issued precise guidances regarding communications and meetings with industry. As noted above, foreign companies that wish to communicate with FDA must do so through a U.S.-based agent. Meetings with the FDA take place at several predetermined milestones in the drug development process. 5.1. Pre-IND Meetings The purpose of the pre-IND meeting is to introduce the sponsor and the drug to the FDA. (The introduction may not be necessary if the sponsor is a well-known global pharmaceutical company.) Many FDA divisions will grant pre-IND meetings to sponsors, but some may be reluctant to do so, preferring to review a submitted IND and then provide comments to the sponsor. When granted, a pre-IND meeting can help a sponsor design additional nonclinical data or refine the clinical protocol prior to submitting the IND; in turn, this level of
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communication and preparation can prevent the imposition of an IND clinical hold based on FDA concerns about safety. It is important to note, however, that holding a pre-IND meeting is no guarantee that the FDA will not issue an IND hold on the study. In presenting the drug at the pre-IND meeting, the sponsor generally discusses the characterization of the drug and presents manufacturing and nonclinical data. The presentation should also address the proposed clinical investigational plan in relation to the desired final labeling (prescribing information). At this time the company should identify any foreign clinical studies that it will sponsor and indicate whether they will be conducted under an IND. The sponsor should also present and discuss the initial clinical protocol. In discussions during the pre-IND meeting, it may be possible to agree to the details of the initial clinical protocol. Critical issues will be identified; some may be resolved at the meeting. Examples of such issues include the inclusion and exclusion criteria, the use of concomitant medications or comparators that may not be approved drugs in the United States, or the use of patient populations that are underrepresented in the United State. 5.2. The End-of-Phase 2 meeting Phase 3 of the drug development process represents the final path to the NDA. Phase 3 trials also require significant investment on the part of the sponsor. The end-of-phase 2 meeting gives the sponsor an opportunity to obtain the FDAs commitment on pivotal study designs and key endpoints. It allows the sponsor to make any necessary adjustments to the development plan regarding CMC, toxicology, clinical or labeling claims. End-of-phase 2 meetings are probably the most important meetings that sponsors will have with FDA. End-of-phase 2 meetings are especially critical for foreign sponsors, because the meetings help identify show-stopper issues such as poor applicability of proposed phase 3 studies to the
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U.S. patient population. This will help avoid large investments in misguided trials. Several factors determine when it is most advantageous to hold end-of-phase 2 meetings. By the time the meeting is held, labeling claims should be reasonably well articulated, and the apparent effective dose should have been established in phase 2 studies. The sponsor should be certain that the dose-finding is sound and the pharmacokinetics/pharmacodynamics (PK/PD) work is well advanced. The meeting should take place when the sponsor has designed the phase 3 program, and is ready to present it to FDA and before the company makes the significant investments required for the phase 3 program, since Agency recommendations may drive changes to the trial plans. 5.3. Pre-NDA/BLA Meetings Meetings with FDA prior to submitting the NDA or the Biologics License Application (BLA) can be helpful. These conferences should be held when phase 3 studies near completion usually about 6 months before the planned NDA submission date. One goal of these meetings is to uncover unresolved issues that might stand in the way of approval. Another goal is to identify those studies that are critical for approval and to ensure that they are adequate and well controlled to establish the drugs effectiveness and safety. In the case of a foreign drug, it is necessary to identify which of the critical studies for approval are foreign studies. The meeting is held with the FDA Division responsible for the drugs review. During the meeting, the sponsor should orient the reviewers to the technical content to be submitted in the NDA as well as the best formatting of the data. Proposed analyses and subanalyses of study data to be included in the application should also be discussed. It is critical to understand the FDAs expectations for the NDA. As already noted, misinterpretations can derail a drug development program. Foreign sponsors may find it particularly helpful to discuss in advance the FDAs intentions to
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inspect the foreign studies so as to be able to alert investigators and prepare the clinical sites for FDA inspection. 5.4. Advisory Committee Meetings Advisory Committee meetings may be advantageous to both FDA and the sponsor. FDA initiates these meetings, usually when the Agency needs advice from the medical and patient communities before deciding on the approval of an NDA. These meetings provide an opportunity for FDA to obtain the advice of medical experts regarding the approvability of the NDA. At the same time, Advisory Committee meetings enable the sponsor to present key findings of efficacy and safety to medical experts. The Advisory Committee includes outside experts in the appropriate medical specialty as well as consumer and patient representatives. The meetings are open to the public. Advisory Committee members are primarily interested in the quality and persuasiveness of the data presented and in the relevance of the data to the U.S. patient population. At the end of the meeting, the Advisory Committee votes on recommending approval or disapproval of the NDA. Although the vote is nonbinding, FDA usually follows Advisory Committees advice. Although Advisory Committee meetings offer the sponsor an opportunity to make its case, several unique characteristics can make them especially challenging for sponsors. These formal, structured meetings are governed by the Federal Advisory Committee Act of 1972, which governs all government Advisory Committees, and by regulations outlined in Section 120 of the Food and Drug Administration Modernization Act. Proceedings of these face-to-face meetings are recorded on audio- and video-tape, and the meetings themselves are webcast; written transcripts of each meeting are prepared and published on FDAs web site. The meetings include sponsor and FDA presentations and committee discussions, all of which are open to the public, including financial analysts and competitors of the sponsor. The sponsor may present information that it considers to be trade secrets in a closed portion of the
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meeting. Personal information about clinical subjects may also be presented in the closed portion of the meeting. As noted above, the committees vote is not binding; however, FDA rarely contradicts an Advisory Committee recommendation. As a result, committee recommendations carry great weight, not only with FDA, but also with the financial community and the pharmaceutical industry at large. A negative committee vote can effectively devastate years of development work. Considering the potential impact of the committees recommendation for or against NDA approval, the sponsor must be prepared to make a persuasive presentation to the Advisory Committee members. A successful Advisory Committee meeting demands extensive preparation and infrastructure. Meetings may be scheduled as long as a year in advance, and committee members must be provided with materials for review several weeks prior to the meeting. The sponsors presenters, and any external parties presenting on the sponsors behalf, should be excellent speakers who can clearly present the sponsors case for approval. Presentations should be well rehearsed and supported with audio-visual aids to make the strongest positive impression possible. 5.5. Labeling Meetings Labeling meetings are held with FDA after the sponsor has submitted the NDA. The purpose of labeling meetings is to reach agreement on the exact wording of the package insert for the pending application. The sponsor and FDA may also discuss the need for any revisions to the label that might be required based on new safety information. Reaching agreement on the exact wording for the label may require several rounds of negotiation. In contrast with most other FDA meetings, labeling meetings usually are teleconferences, rather than face-to-face sessions. Teleconferencing allows participants on both sides to take advantage of muted caucusing during the negotiation process. The foreign sponsor may wish to have its U.S. distributor participate in the negotiations regarding labeling language.
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Much is at stake, because the final package insert wording will either facilitate or restrict the promotion and sale of the drug. Ideally, the labeling meeting results in package insert wording that satisfies both the sponsor and FDA. Such an agreement is a critical milestone toward the launch of a safe and effective product.
6. SUMMARY AND CONCLUSIONS In many ways, development of a foreign drug for approval in the U.S. market is similar to the development of U.S. drugs. Regardless of where the drug originates or where data were collected, sponsors must meet the same requirements: adhere to recognized standards, protect patient rights, design studies that support labeling safety and efficacy claims, ensure the quality and integrity of the data, and submit a complete and clear marketing application. The differences that do exist among countries are due to geography, culture, medical practice, local preferences and practices, and level of comfort of regulatory agencies such as FDA with data collected in other countries and patient populations. To minimize the impact of these differences and to reduce the need to conduct duplicate trials in multiple regions, companies that develop foreign drugs must plan carefully and communicate with FDA early and often. Foreign drug sponsors can facilitate the process of obtaining U.S. approval by communicating with the FDA appropriately and frequently. They should look after the details of development work conducted outside the United States to ensure that it is in line with FDA expectations and requirements. Finally, when sufficient data have been collected, the sponsor should make a solid case for approval. Drug development is challenging for pharmaceutical companies everywhere. The foreign element may complicate the process somewhat, but it is not an insurmountable obstacle. Savvy planning and sound execution make obtaining U.S. approval rather manageable.
18
Common Technical Document Quality (M4-Q): One Regulatory Participants Perspective
UBRANI V. VENKATARAM Food and Drug Administration Rockville, Maryland, USA
1. INTRODUCTION The International Conference on Harmonization (ICH) has set itself the laudable goal to harmonize the technical requirements for the approval of medicinal products in the three most prosperous regions of the world: the United States, Japan, and the European Union (EU). Towards this goal, it has published many guidelines, covering such topics as carcinogenicity testing, good clinical practices, stability testing, impurity testing, etc. This author had the unique and exciting opportunity to be involved in the development of the Common
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Technical DocumentQuality (CTD-Q) that is part of one such guideline, the Common Technical Document (CTD). As a member of the CTD-Q Expert Working Group (EWG), this author had the opportunity to learn from fellow EWG members the regulatory processes in Japan, Canada, and the EU. The ICH employs a unique process to manage the development and publication of these guidelines that affords intense discussions/ negotiations between the various parties, but is efficient in producing the guidelines in a timely fashion. In this article the author has attempted to provide his perspective of the CTD-Q based on his experiences as a CTD-Q EWG member and Chemistry Reviewer in the Office of Generic Drugs. This article was written by the author in his private capacity. No official support or endorsement by the Food and Drug Administration (FDA) is intended or should be inferred. The information provided here is also based on many guidances that are published or unpublished draft guidances. The reader should exercise caution in using draft guidances when preparing submissions to FDA as the content of these draft guidances may change before final publication. Additionally, the reader should note that the guidances represent the Agencys current thinking on the topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirement of the applicable statute, regulations, or both.
2. INTERNATIONAL CONFERENCE ON HARMONIZATION Globalization of the pharmaceutical business provided the impetus for the harmonization of the technical requirements for the approval of medicinal products in three regions of the worldthe United States, Japan, and EU where most of the drug discovery and development occurs. Harmonization of technical requirements has led to uniform standards for drug product quality and resulted in considerable cost reduction to
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the regulated industry. It is expected that harmonization would lead to a reduction in research and development (R&D) cost and time in developing safe and efficacious products. 2.1. Purpose The following statement was issued by the ICH Steering Committee in Tokyo, Japan, at the end of the October 1990 meeting: The Parties cosponsoring this Conference, represented at the 2nd Steering Committee Meeting in Tokyo, October 2324, 1990, reaffirmed their commitment to increased international harmonization, aimed at ensuring that good quality, safe, and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans, and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness. This Conference will provide a unique opportunity for regulators and industry to reach consensus on the steps needed to achieve this objective through greater harmonization of technical requirements and to set out practical and realistic targets for harmonizing requirements where significant obstacles to drug development and the regulatory process have been identified. Recognizing the substantial progress which has already been made in achieving harmonization within Europe and through bilateral contacts between Europe, Japan, the United States, and other regions, the Conference will seek to make further progress through a trilateral approach, with clearly defined priorities, methods of work, and recommendations to both industry and regulatory authorities. While the Conference will be an important step forward, it is not seen as an end in itself, but as a stage in a developing process, at a high level, between regulators and industry.
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The Conference, its preparations and follow-up activities, will be conducted in an open and transparent manner, and the presence of observers from other regulatory authorities and WHO is welcomed as a means of ensuring that the benefits of progress towards harmonization can be utilized worldwide. The Conference will not only look at existing issues but will, based on past experience, seek to minimize future divergence of new registration requirements, as a consequence of technical progress.
2.2. Structure and Process ICH is a joint initiative involving both the regulators and industry as equal partners. The six founding members of ICH who also constitute the steering committee are the EU, the European Federation of Pharmaceutical Industries and Associations (EFPIA), the Ministry of Health, Labor and Welfare, Japan (MHLW), the Japan Pharmaceutical Manufacturers Association (JPMA), U.S. FDA, and the Pharmaceutical Research and Manufacturers of America (PhRMA). The steering committee is responsible for the administration of ICH. In addition, there are three observers: the World Health Organization (WHO), the European Free Trade Area (EFTA) represented at ICH by Switzerland, and Canada represented at ICH by Therapeutic Products Directorate, Health Canada. The observers attend the steering committee meeting as nonvoting members. The ICH Secretariat is managed by the International Federation of Pharmaceutical Manufacturers Association (IFPMA). Harmonization proposals for action may come from any interested parties but must be submitted to ICH through one of the six parties to ICH or one of the observers on the steering committee. Such proposals may include new types of medicinal products resulting from advances in technology and techniques for producing medicines, lack of harmonization in current
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technical requirements, further harmonization of existing requirements, transition to technically improved testing procedures, review of an existing ICH guideline, and maintenance of an existing guideline. The sponsoring ICH steering committee member presents the proposal as a concept paper that details the (a) type of proposed harmonization action, (b) statement of problem, (c) issues to be resolved, (d) background to the proposal, and (e) type of EWG. The steering committee evaluates the proposal for sufficient interest by the ICH parties and also whether it can be accommodated within the ICH framework. Proposals that are deemed worthwhile are then presented to the interested parties. Upon selection, the steering committee formalizes the proposal by confirming the objectives and expected outcome, constitute the EWG, and set a timetable (normally not to exceed 2 years) and action plan. The EWG is composed of two technical experts from each of the six member parties and one technical expert from any of the other observer parties, as designated by the steering committee. One of the two technical experts is designated the topic leader for that member party. The role of a rapporteur, nominated by one of the member parties to lead the EWG at the behest of the steering committee, is unique. The rapporteur is not only the technical expert on the topic, but is also responsible for the smooth functioning and success of the EWG. The rapporteur serves to resolve disputes between member parties and acts as the counselor, timekeeper, scribe, and reporter. The EWGs meet during the same time and at the same location as the steering committee. The meetings are held once every 6 months, and the locations are rotated among the member states. The meeting expenses (travel and hotel) are the responsibility of each member party, and each member party also shares expenses for hosting the meeting with the host member. The EWG may request for additional meetings to meet the timetables and goals that were set by the steering committee. All the member parties are required to be present for the EWG to convene, but the EWG may meet in the absence of observer parties. At the end of each meeting, the rapporteur presents a progress report to the steering committee.
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ICH follows a five-step process for developing and issuing technical guidelines. Step 1. Consensus is built among the member parties on the contents of the guideline. The rapporteur prepares an initial draft of a guideline or recommendation, based on the objectives set out in the Concept Paper, and in consultation with experts designated to the EWG. The initial draft and successive revisions are circulated for comment, giving fixed deadlines for receipt of those comments. Interim reports are made to each member of the ICH steering committee. If consensus is reached within the agreed timetable the consensus text with EWG signatures (see below) is submitted to the steering committee for adoption as Step 2 of the ICH process. Where complete consensus has not been achieved within the timetable, a report will be made to the steering committee indicating the extent of agreement reached and highlighting the points on which there are differences between the parties. Experts from all parties represented on the EWG will have the opportunity to explain their position to the steering committee. The Steering Committee may then: Allow an extension of the timetable, on the basis that the EWG can give assurances that consensus could be reached within a short, specified period Decide to suspend or abandon the harmonization project Decide to proceed to Step 2 on the basis of the current draft, notwithstanding absence of complete consensus in the EWG When consensus is reached on the technical issues, all parties represented on an EWG would be invited to sign the document to indicate their agreement to the consensus text,
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which is submitted to the steering committee. Circumstances could be envisaged, however, when not all parties are present or able to sign the consensus text. It would then be for the steering committee to decide whether to proceed to Step 2. Step 2. The Step 1 document is signed-off by each of the six ICH steering committee members when the steering committee agrees, on the basis of the report from the expert working group, that there is sufficient scientific consensus on the technical issues for the draft guideline or recommendation to proceed to the next stage. Step 3. The Step 2 document is now released for regulatory consultation in the three regions. In the United States, this means the document is published in the Federal Register as draft guidance for comments. At the end of the comment period the EWG members representing the regulatory bodies collate the comments from each region and, after consultation, arrive at a single harmonized document. At this stage, the rapporteur is a regulator who is responsible for finalizing the harmonized guideline and obtaining the consent, in the form of signature, from all the EWG member parties. Step 4. The regulatory rapporteur presents the Step 3 harmonized document to the steering committee. It is generally expected that there are no substantial differences between the Step 2 and Step 3 documents. If it is satisfactory to both regulatory and industry parties, then the steering committee adopts the document as a Step 4 document The guideline is now recommended for adoption by the regulatory bodies in the three regions. In the event that one or more parties representing industry have strong objections to the
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adoption of the guideline on the grounds that the revised draft departs substantially from the original consensus or introduces new issues, the regulatory parties may agree that the revised text should be submitted to further consultation. Step 5. The final step of the process is the regulatory implementation of the guideline. Implementation is specific to the region and is the same as other guidelines put forth in each region. The maintenance process is intended to provide a rapid and flexible way of making minor changes and revisions to published ICH guidelines. The process provides for updating the guidelines with new, current, and relevant information. A concept paper is prepared once a maintenance issue has been identified and sent to the ICH Secretariat and the Coordinators for agreement. With their concurrence, the concept paper is circulated among the ICH parties maintenance network. The consultation among the maintenance network parties is quite informal and is accomplished by emails and telephone conferences. If there is an agreement among the parties, then the ICH Secretariat presents the revisions to the steering committee, and with their concurrence the subject guideline is revised and published. If there is no agreement, the steering committee may initiate the Step 2 process for further consultation among the ICH parties. A successful example of maintenance is Guideline Q3C, Impurities: Residual Solvents. The maintenance of this guideline includes identifying new residual solvents and revising existing permitted daily exposure (PDE) levels,* as information on them become available. An interesting example that illustrates the ICH process of consultation and concurrence is the adoption of Guideline Q3A: Impurities in Drug Substances. Q3A provides guidance on limits and qualification of impurities in new drug substances,
*PDE is defined in Q3C as pharmaceutically acceptable intake of residual solvents.
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produced by chemical synthesis. The intent of the guideline is to ensure that a single drug substance specification is developed that is acceptable in all three regions. The guideline was first recommended for adoption at Step 4 of the ICH process on March 30, 1995. However, several inconsistencies relating to language usage and the scientific principle of rounding were discovered in the Step 4 document. Consensus could not be found on several proposals for revision. The guideline reverted to Step 2 of the ICH process on October 7, 1999. A revised guideline was recommended for adoption under Step 4 for the second time on February 7, 2002, by the ICH steering committee. It then reached the implementation stage (Step 5). The revised guidance document, designated Q3A (Revision 1), was published on the FDA website on February 10, 2003. 2.3. Guidelines ICH has been prolific in producing guidelines for harmonizing technical requirements in pharmaceutical applications. According to the ICH web site, the current tally is 45 at the end of ICH 4 (9 active and 36 at Step 4/5). Table 1 provides a list of quality topics and associated guidelines. A complete list of all published guidelines (including the safety and efficacy topics) may be accessed at the ICH web site.* In addition to the safety (S), efficacy (E), and quality (Q) topics described above, ICH is working on four multidisciplinary (M) topics: medical terminology (M1), electronic standards for transmission of regulatory information (ESTRI, M2), timing of preclinical studies in relation to clinical trials (see Safety Topics, M3), and the Common Technical Document (M4). The advantages of harmonized electronic Standards and the Common Technical Document in a global economy are obvious. A harmonized medical terminology document is a necessity in the preparation of CTD. With advances in technology and globalization of pharmaceutical business, the desire
*The number of guidelines (at various stages of development) was 57 as of 1/2003.
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Table 1
ICH Quality Guidelines and Their Status

Topics Status ICH Step 5: Has since been revised see Q1A(R) Step 5 Step 5 Step 5 Step 5 Step 3 Step 3 Step 1 Step 5 Step 5 FDA (date of FR notice) See Q1A(R)
ICH designation Q1
Brief description Stability testing of New Drug Substances and Products
Q1A(R) Q1B Q1C Q1D Q1E Q1F Q1H Q2A Q2B
Stability testing of New Drugs and Products (Revised) Photostability Testing Stability Testing for New Dosage Forms Matrixing and Bracketing Designs for Stability Testing of Drug Substances and Products Evaluation of Stability Data Stability Data Package for Registration in Climatic Zones III and IV Labeling Text on Validation of Analytical Procedures Methodology
FR, Vol. 66, No. 215, 11/07/2001, pp. 563323 FR, Vol. 62, No. 95, 05/16/1997, pp. 2711522 FR, Vol. 62, No. 90, 05/09/1997, pp. 2563435 To be notied FR, Vol. 67, No. 115, 06/14/2002, pp. 4094950 FR, Vol. 67, No. 115, 06/14/2002, pp. 4095152 N/A FR, Vol. 60, No. 94, 03/01/1995, pp. 11260 FR, Vol. 62, No. 96, 05/19/1997, pp. 274637
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Q3A(R)
Q3B(R)
Q3C Q3C(M)-2 Guidelines Q4 Q5A
Impurities in New Drug SubstancesRevised Note: Q3A (Step 4, 03/30/1995) was revised under Step 2 of ICH process and recommended at Step 4 for adoption on 07/02/2002 Q3B (Step 5) is an extension of Q3A, Impurities in Drug Substances (The revised guideline has reached Step 3.) Impurities: Residual Solvents PDE for N-Methylpyrrolidone (NMP) and Tetrahydrofuran (THF) Pharmacopoeia Harmonization Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products Stability of Products (proteins and/or polypetide containing drug products) Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products Specications for New Drug Substances and ProductsChemical Substances; includes a Decision Tree Specications for New Drug Substances and ProductsBiotechnological Substances Good Manufacturing Practices for Active Pharmaceutical Ingredients
Step 5
To be notied
Step 3
FR, Vol. 65, No. 139, 07/19/2000, pp. 4479197 FR, Vol. 62, No. 247, 12/24/1997, p. 67377 To be notied N/A FR, Vol. 63, No. 185, 09/24/1998, p. 51074 FR, Vol. 61, 02/23/1996, p. 7006 FR, Vol. 61, 07/10/1996, p. 36466 FR, Vol. 63, No. 182, 09/21/1998, pp. 5024449 FR, Vol. 65, No. 251, 12/29/2000, pp. 8304163 FR, Vol. 64, 08/18/1999, p. 44928 FR, Vol. 66, No. 186, 09/25/2001, pp. 4902829
Step 5 Step 5 N/A Step 5
Q5B Q5C Q5D
Step 5 Step 5 Step 5
Q6A
Step 5
Q6B Q7A
Step 5 Step 5
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to be able to produce and submit a common regulatory dossier has become urgent. As discussed in the next sections, the goal is reachable within a reasonable time. 2.4. Common Technical DocumentICH Guideline The ICH Guideline, Common Technical Document, is a subtopic in the multidisciplinary topic M and is designated M4. The proposal for development of this guideline came from the regulated industry and was accepted in principle by the steering committee in the summer of 1996. However, the steering committee requested a feasibility study because of the complex and comprehensive characteristics of the proposal. The feasibility study was to evaluate the readiness of the regulators to accept reform in the technical requirements and document presentation of a New Drug Application. A major concern was resources. It was recognized that the traditional EWG structure would be inadequate for accomplishing the task, and a high-level team would be necessary to bring out the harmonized guideline. The work on M4 began in the winter of 1998 at the ICH Meeting in Tysons Corner, Virginia. The CTD itself consists of several subtopics. Table 2 provides the status of these guidelines at the time of publication. Rapporteurs who led the EWGs for each of the subtopics are: EFPIA (quality), JPMA (safety), PhRMA (efficacy), and FDA (eCTD). The CTDQuality EWG was one of the largest ever involved in such an endeavor. Separate groups were formed from within this EWG to work on new molecular entities (NMEs) of chemical origin and NME of biotech origin. The two subgroups generally met separately to develop their respective guidances. There was even discussion regarding issuance of separate guidelines. However, with time it became apparent that the scientific and regulatory issues for the two types of products are similar and that a common document that addressed all the issues pertaining to NMEs of both chemical and biotech origin could be developed. The overall structure of CTD is best represented graphically (Fig. 1). The CTD is composed of five modules designated
Table 2
ICH CTD Guidelines and Their Status

Topics Status Brief description Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use Including the Granularity document that provides guidance on document location and pagination Format of the Quality sections including the Overall Summary section Format of the Safety sections including Non-Clinical Overview and Non-clinical Written and Tabulated Summaries Format of the Efcacy sections including Clinical Overview and Clinical Written and Tabulated Summaries The Electronic Common Technical Document ICH Step 5 FDA (date of FR notice) Earlier version published in FR, Vol. 66, 10/15/2001, pp. 4646465(reedited version to be published) As above As above
ICH designation M4 Organize with Annex: Granularity
M4 Quality M4 Safety
Step 5 Step 5
M4 Efcacy
Step 5
As above
e-CTD
Step 5
To be published
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Figure 1
Common Technical Document Organization.
1 through 5. It is beyond the scope of this article to describe each of these modules in detail. The reader is referred to the draft guidance Guidance for IndustrySubmitting Marketing Applications According to the ICH-CTD FormatGeneral Considerations and the topic-specific CTDs (i.e., CTD-Q, CTD-S, and CTD-E) at http://www.fda.gov/cder/guidance (available in the Acrobat PDF and HTML formats) for complete details. The reader should note that, as of the date of preparation of this article, the guidance is still in draft status and its contents may change with time. The following information is presented to provide an overview of the contents of this guidance. Module 1Administrative and Prescribing Information 1. FDA Form 356h 2. Comprehensive table of contents 3. Administrative documents
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Module 2Common Technical Document Summaries 1. Overall CTD table of contents 2. Introduction to the summary of documents 3. Overviews and summaries Module 3Quality 1. Module 3 table of contents 2. Body of data 3. Literature references Module 4Nonclinical Study Reports 1. Module 4 table of contents 2. Study reports and related information 3. Literature references Module 5Clinical Study Reports 1. Module 5 table of contents 2. Study reports and related information 3. Literature references As illustrated in Fig. 1, Module 1 is not part of the technical documentation required in a New Drug Application. It is reserved for regional administration information such as application forms, labeling, and others. The regional authorities specify the format and content of this module. The harmonized format of the CTD is described in Modules 2 through 5 and forms the basis for submission of the technical documentation. The CTD-Q (Module 2overall summaryand Module 3) is discussed in more detail in the next section. Discussion of the safety and efficacy documents is not in the purview of the authors expertise and is deferred to experts in those topics. 2.5. Future The work on the Common Technical Document was completed at Step 4 and the document was released to the public at ICH 5 in San Diego, California, in November 2002. An implementation group consisting of topic experts and eCTD-EWG and steering committee members (approximately 70 members) has been
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formed. The implementation group has since met three times. The quality implementation group has produced a questionand-answer document that addresses various implementation questions. These implementation questions concern location issues, polymorphism, multiple drug substance sources, combination products, multiple dosage forms, etc. A Federal Register notice announcing the availability in the United States of this guidance document for comment was published on December 30, 2002 (67 FR 79639). The guideline for eCTD has reached Step 5, although FDA has yet to publish this in a Federal Register Notice seeking public comments. The question-andanswer guideline related to eCTD has reached Step 4. Preparing and submitting a single dossier to the regulatory authorities in the three ICH regions for approval to market drug products may be years away. For the CTD Quality subtopic, some of the issues pertain to harmonization of the pharmacopoeia, lack of guidelines pertaining to manufacturing of the drug substance and drug product, packaging, use of drug master file for submission of proprietary information, and differences in GMP and filing requirements. Harmonization in these topics is essential before the goal of a single dossier may be realized. In addition to the ongoing work on implementation of the CTD, ICH has identified many new areas where harmonization of technical requirements would provide great benefit to the public and the regulated industry. One such topic is gene therapy. ICH has held workshops to develop this topic. Information on all future ICH activities is available at the official website at http://www.ich.org/.
3. COMMON TECHNICAL DOCUMENT QUALITY 3.1. Scope One of the first tasks the CTD-Q EWG set upon working was to define the scope of this guideline. Two aspects of defining the scope of the document were (a) the type of drug products that will be covered by this guideline and (b) whether the
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guideline would address both the format and content requirements of the quality section of a dossier. Agreement on the first aspect was easy to achieve. It was agreed that the drug products that will be covered by this guideline would be the same as those covered by Q6A and Q6B. However, much discussion ensued regarding the second aspect. It was realized that much work was needed to harmonize the content of the quality section of a dossier, and it may not be achievable within the time frame proposed for this guideline. The task of harmonizing the content was made onerous by the lack of ICH guidelines on such key quality topics as manufacturing of drug substances and drug products and container closure systems (packaging). Additionally, progress in harmonization of the pharmacopoeia was slow. The differences in regional requirements, such as the requirement for executed batch records, method validation packages, etc., in the United States, and the Process Validation Scheme for the Drug Product in the EU, Drug Master Files (DMF), complicated the issue. Although the initial draft proposed used the term illustrative examples, it was argued that the language may be construed as defining the content. Hence, clarification such as not all-inclusive was sought to be included in the scope. The finalized scope statement is as follows:
This section of the document is intended to provide guidance on the format of a registration application for drug substances and their corresponding drug products as defined in the scope of ICH Guidelines Q6A New Chemical Entities (NCE) and Q6B Biological/Biotechnological (Biotech). This format may also be appropriate for certain other categories of products. To determine the applicability of this format for a particular type of product, applicants should consult with the appropriate regulatory authorities. The text following the section titles is intended to be explanatory and illustrative only. The content of these sections should include relevant information described in existing ICH guidelines, but harmonized content is not available for all sections. The Body of Data section in this guidance merely indicates where the information should be located. Neither the type nor extent of specific supporting data has been addressed in this guidance, and both may depend on regional guidance.
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The section titles listed in the Regional Information section (3.2.R) represent examples of typical topics of information that are not common to all ICH regions. Hence, the information to be provided in these sections should be based on the relevant regional guideline.
In the United States, it is intended that the respective guidances on Drug Substance, Drug Product, Stability, Container Closure Systems, Validation of Analytical Procedures, Impurities, DMF, etc., will describe the content of the registration application. The reader is directed to the following web site for a complete list of the available guidances: http:// www.fda.gov/cder/guidance/index.htm. Many of these guidances are being revised to be instructive about the use of the CTD-Q format. The draft guidances are also available at the same web site. 3.2. Process The concept of one internationally acceptable registration application had been discussed at various avenues. The Basic International Registration Dossier (BIRD) was developed by a group of farsighted industrialists and regulators with the aim of providing a common format and structure to the quality sections of a registration application. During the diagnostic phase of evaluating the feasibility of a Common Technical Document, the industry sponsors color-coded the BIRD document to identify areas of commonality among the three ICH regions. Table 3 provides a summary of that analysis. Green indicated that the requirements in the three regions were already harmonized. Yellow-coded areas indicated differing requirements but that harmonization was thought possible. The red-coded areas were of the most concern, and harmonization was thought not to be possible. The CTD-Q EWG consisted of members well versed in the submission of dossiers for NMEs of both chemical origin and biological origin. This large group was split into two subgroups: one to develop the guideline for NMEs of chemical origin and a second group for NMEs of biological origin. There
Table 3
Summary of Analysis of BIRD Document

Color code Nomenclature Manufacture Controls Green Green for EU and Japan; red for United States Green for most controls; red for test methods and reference standard Comments Requirements same in all 3 regions More detail required in United States Compendial harmonization required for test methods; United States has denitive requirement for reference standard United States has higher requirement United States has the requirement for site-specic stability data Minor differences between the 3 regions United States requires greater detail and executed batch records; EU requires site-specic validation data Compendial harmonization required Compendial harmonization required
Review item Drug substance
Container closure Stability
Green for United States and Japan; red for United States Green for stability conclusion and postapproval protocol; stability dataRed for United States Yellow for the 3 regions Green or yellow for EU and Japan; generally Red for United States Red for all 3 regions Red for all 3 regions; green for justication of specication and validation Red for all 3 regions Green for all 3 regions except stability data, which is Red for all 3 regions
Drug product
Composition/Master Production formula Manufacture
Excipients Controls for nished product Container closure Stability
United States requires site-specic data 565
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was some thought during this guideline development phase that separate guidelines should be issued. However, a single guideline was formulated when it became apparent that the review process was similar for the two different types of NMEs. Technical staff from the respective Centers served as topic leaders for discussions regarding NMEs of chemical origin and NMEs of biological origin, supported by review staff from several review divisions. The FDA team also regularly consulted with the Technical Committees and the Chemistry, Manufacturing and Controls Coordination Committee of the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) committees for evaluation of the draft guideline. Unlike other ICH guidelines, the CTD-Q guideline was issued twice at Step 2. This became necessary when it became apparent that the EWG would be unable to complete work on the illustrative examples that explained to the applicant the purpose of each section and subsection heading in a timely fashion. It was desired that public comments be elicited on the Format, i.e., the section and subsection headings, and hence the first of the Step 2 document was released in September 1999. The completed guideline with illustrative examples was released at Step 2 again in the spring of 2000. The Step 4 document was signed-off by the ICH Steering Committee in November 2000 and is currently at Step 5. 3.3. FDA Guidance The Agency has published three draft guidances with regard to the CTD. The FDA Draft Guidance M2 - Electronic Common Technical Document Specifications provides details for the preparation of CTD in electronic format. It provides information on the media (preparing the media, media transport, and security), file formats (XML, PDF, SVG files), instructions for amendments, supplements or variations, etc. The FDA Draft Guidance Submitting Marketing Applications According to the ICH/CTD Format: General Considerations is a procedural guidance . It is the Agency version of the ICH document M4: Organization of the CTD, and is
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intended to describe how to organize New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biological License Applications (BLAs) for submission in the United States. It is intended to be used with other CTD Guidances CTD-Q, CTD-E, and CTD-S, and when finalized it will supersede the previous Agency guidelines Guidelines on Formatting, Assembling, and Submitting of New Drug and Antibiotic Applications (February 1987) and Guidance for Industry: Organization of an ANDA (February 1998). The draft General Considerations guidance discusses requirements for both paper (size, margins, fonts, binding volumes, volume numbering and identification, pagination, cross referencing documents, packing carton, and sending in the submission) and electronic submission. Information is provided on the nontechnical, region-specific Module 1, including form 356h, comprehensive table of contents, and other administrative documents. It also describes Agency recommendation for submission of amendments and supplements, number of copies to be submitted, etc. The FDA Draft Guidance M4 Common Technical DocumentQuality: Questions and Answers/Location Issues (Posted December 30, 2002) provides clarification on the issues of location of content in the CTD-Q. To date the Agency has received few NDAs in the CTD format but many inquiries from interested A/NDA and BLA applicants. The Agency is gearing itself to review the A/NDAs and BLAs when submitted in the CTD format by revising the review template to conform to the CTD format. Many of the quality guidances are being revised to provide information on the use of the CTD-Q format. While a true CTD submission that is acceptable to regulatory authorities around the world may take many more years, the first steps being taken are encouraging and foretell a bright future for CTD. 3.4. Format of an A/NDA The basic structure of a Common Technical Document was described in Sec. 2.4. and Fig. 1. The focus in the following sections will be on CTD-Q. The guidance M4: The CTD-Quality
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is available at the following website: http://www.fda.gov/cder/ guidance/4539Q.htm. It should be consulted when perusing this document. The quality technical information required to gain approval to market a drug product in the United States is described in 21 CFR 314.50 (d) and 314.94. The Chemistry, Manufacturing, and Controls (CMC) section should describe composition, manufacture, and specification of the drug substance and the drug product including environmental impact assessment (per 21 CFR 25.30, or 25.31, or 25.40). The CTD-Q, in general, follows this regulatory requirement by separating the drug substance and drug product information into two separate sections. The environmental impact information is included as part of Module 1. The CMC information, when submitted in the CTD format, will appear in Modules 2 and 3. In Module 2, the Quality Overall Summary, the applicant is expected to present a comprehensive summary of the CMC information that is included in Module 3. Module 2 Quality Overall Summary follows the same format as Body of Data in Module 3. The same section headings and subheadings as in Module 3 are to be used. In Module 2 the applicant is not expected to provide any new CMC information, data analysis, and/or conclusions not already described in Module 3. The inclusion of Quality Overall Summary in Module 2 was much debated in the EWG. 21 CFR 314.50 (c) requires that an application contain a summary of the application in enough detail that the reader may gain a good general understanding of the data and information in the application, including an understanding of the quantitative aspects of the data. A stated purpose of such summary is that it could be furnished to FDA advisory committee members and agency officials whose duties require an understanding of the application. Yet the February 1987 Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application did not provide for submission of a well-prepared summary. The safety and efficacy reviewers extensively use the summary documents pertaining to their review disciplines. The chemistry review process, however, is such that the CMC reviewers conduct their own
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data analysis without depending on the summary provided by the applicant. It should be noted that summary documents are also used in EU (Expert Reports) as part of their review process. After many debates, the EWG agreed to provide for a summary document as part of Module 2. It was agreed that the Quality Overall Summary (QOS) should be concise and not include any information that is not already present in the Body of Data. The QOS may include justification for deviations; for example, it may include justification for not following particular guidances. It is most useful when QOS synthesizes information from other modules that is pertinent to CMC review. The Module 3 format clearly distinguishes between the drug substance and drug product information. The drug substance and/or product information is supplemented with information in the Appendices, Regional Information, and Literature Reference sections. In writing this format document a conscious decision was made by the EWG to leave out the Good Manufacturing Practices (GMP) issues and focus instead only on those issues that are reviewed by the regulatory scientific personnel. 3.5. Content of an A/NDA In this authors perspective, the CMC content requirement for an A/NDA will not change with the forthcoming adoption of the CTD-Q format document. The exception is the introduction of the Pharmaceutical Development (CTD-Q designation 3.2.P.2) section as part of the drug product section. Current and draft guidance documents describe the content for submission to FDA. Many of the guidances are being revised to provide information on the use of the CTD-Q format. The guidances have been revised to clearly delineate the placement of content in each section and/or subsection identified in the CTDQ format document. The discussion below provides illustrative examples of the use of the guidance documents in developing the content for an A/NDA to be submitted in the CTD-Q format. The revised guidances will be published as draft documents for public comment in the near future. The author is grateful to the CDER management for permission to refer to the
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unpublished guidances in this article. The reader is cautioned that the content of these unpublished draft guidances may change before final publication. The reader should also note that the guidances represent FDAs current thinking on that topic. They do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations. In the United States, the regulations (21 CFR 314.50(a) (1), 314.50(g)(1), and 314.420) also provide for referencing pertinent information in other applications and/or Drug Master Files (DMFs). This is especially true of ANDAs, where the applicants rely on outside sources for the drug substance. These outside sources furnish the drug substance information to FDA in a Type II DMF. By reviewing the DMF independent of the application, FDA is able to maintain the confidentiality pertaining to manufacture and controls of the drug substance. The reader is referred to the above-cited regulations for additional information. It may be useful for the format of Type II DMFs to be the same as the Drug Substance section of CTD-Q (i.e., 3.2.S) and the content that is recommended in the forthcoming Drug Substance Guidance. The content of QOS in Module 2 should follow closely that in Module 3 and will not be discussed separately. The discussion on Module 3 here will focus on the format and content of those topics that differ from past practice and do not have an ICH guideline. What follows is one regulatory participants perspective on CMC technical content of an A/NDA. Although the following discussion addresses some technical content topics related to CDER guidances, the discussion is not intended to represent CDER recommendation on submission content for these topics. Instead, when preparing an A/NDA, applicants should refer to current Agency guidances for recommendations. 3.5.1. Drug Substance Manufacture (CTD Designation3.2.S.2) This CTD section includes six subsections: Manufacturers (3.2.S.2.1), Description of the Manufacturing Process and
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Process Controls (3.2.S.2.2), Control of Materials (3.2.S.2.3), Controls of Critical Steps and Intermediates (3.2.S.2.4), Process Validation and/or Evaluation (3.2.S.2.5), and Manufacturing Process Development (3.2.S.2.6). In Section 3.2.S.2.1, it is recommended that the applicant provide the name, address, and manufacturing and/or testing responsibility for each firm and each site involved in the manufacture and/or testing of the drug substance. The description of the drug substance manufacturing process and process controls in Section 3.2.S.2.2 represents the applicants commitment for the manufacture of the drug substance. Inclusion of a flow diagram would provide lucidity to the description of the manufacturing process. This detailed flow diagram would include each manufacturing step, showing where materials (starting materials, intermediates, reagents, solvents, and auxiliary materials) enter the process, operating parameters (reaction conditions such as temperature, pH, pressure), and identification of critical steps and controls. Inclusion of chemical structures reflecting stereochemistry, where applicable, of starting materials, intermediates, reagents, and the drug substance will assist the reviewing chemist in understanding and evaluating the reaction sequence. A wellconstructed flow diagram will facilitate discussion of possible synthetic impurities and controls thereof. The description of the manufacturing process and process controls should also include a narrative description of the manufacturing process. This narrative description is expected to be more detailed than the flow diagram and should identify the scale of production. All process controls should be identified, and the associated ranges, limits, or acceptance criteria should be specified. Critical process controls should be identified. Additional information such as storage and transportation conditions for biological starting materials, preparation procedures, isolation process, holding times and storage conditions during manufacture, and procedures used to maintain traceability of all intermediates and drug substance batches to the starting material is recommended for drug substance that is derived from natural source or for a semisynthetic drug substance. For ANDAs, a copy of the executed production
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record may be provided in the Regional Information section (3.2.R) of the application or the Type II DMF. 1. An important consideration in describing the manufacturing process is the selection of the starting material. It should be noted that more than one starting material may be used in a synthetic sequence (convergent synthesis). In the United States, the starting material marks the beginning of the manufacturing process as described in an application. For NDAs, the starting material may be identified during phase 2 consultations. However, this consultation may not be available to Type II DMF holders who may have to rely on the review process. Our EWG wrestled with the definition of the starting material and also consulted with the Q7 EWG repeatedly. However, an acceptable definition was difficult to fashion. The draft drug substance guidance intends to address the starting material issues comprehensively and provide to applicants guidance on justifying their proposed starting materials. 2. Another important consideration in preparing the Description of the Manufacturing Process and Process Controls section is the selection of critical process controls. This author has heard a wide spectrum of opinions on what constitute process controls. Even the regulations have different language when it comes to describing the requirements for drug substance and drug product manufacture (21 CFR 314.50 (d)). The Description of the Manufacturing Process is a document that contains cGMP information as well as scientific information and is evaluated by both the field inspectors and the reviewing chemists at the Center for Drug Evaluation and Research. The intention in the CTD-Q was to create placeholders that allow the applicants to separate the Center reviewed process controls from those subject to field oversight. It is recommended that the applicant include complete manufacturing information in Section
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Figure 2
Manufacturing process information distribution.
3.2.S.2.2. However, the applicant should identify and justify those process controls that are critical to the manufacturing process (reviewed by Center chemists) in Section 3.2.S.2.4. This section should also include information on the intermediates isolated during the process. Figure 2 illustrates the information distribution. 3. The regulations at 21 CFR 211.115 provide for reprocessing of materials (intermediates and finished drug substance). The Guideline Q7 describes reprocessing as follows: introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process and is not reprocessing. The CTD-Q recommends that applicants identify and
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justify reprocessing steps in Section 3.2.S.2.2 and the justification data in Section 3.2.S.2.5. It is recognized that different approaches (types of processes) may be utilized to bring failed material into compliance. The applicant may subject the failed material to one or more of the already described process steps. However, in some instances process steps that have not been described in Section 3.2.S.2.2 may be necessary to bring the failed material into compliance. The different operations may be described as follows: ReprocessingRepetition of one or more of the process steps is generally performed prior to completion of the manufacturing process and quality control release of the material. Examples of reprocessing steps are crystallization, distillation, filtration, chromatography, milling, etc. ReworkingSubjecting the failed material to one or more manufacturing process steps that are different from that described in the application. Reworking is a nonroutine event and may occur mostly during post-approval phase. RecoveryRecovering solvents during drug substance manufacturing for reuse in the manufacturing process is both economical and environmentally sound. Filtrates (mother liquors) are recovered with the purpose of recovering a second crop of the intermediate or drug substance. The impurity levels in the recovered material (solvents, intermediates, drug substance, etc.) should be closely monitored. The physical form of the drug substance that is recovered from the more concentrated filtrates may differ from the desired form. The applicant should provide data to demonstrate that the quality of the drug substance is unaltered by the use of recovered material. RegenerationColumn resins and catalysts may be regenerated and used in the manufacturing process. The regeneration steps should be described in
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Section 3.2.S.2.2 but controls should be included in Section 3.2.S.2.3. SalvagingThe drug substance may be recovered from aged material (past expiration dating) or from drug product. Salvaging is also expected to be nonroutine and may occur mostly during the postapproval phase. In all these instances it is recommended that the applicants describe the process and provide justification in Section 3.2.S.2.2 and specifications in Section 3.2.S.2.3. 3.5.2. Drug Substance CTD-Q Sections 3.2.S.2.3 to 3.2.S.2.7 There are few differences in the content requirements of these sections from past practice. ICH guidelines and Agency guidances are available on such topics as analytical methods validation, impurities in drug substances, container closure systems, and stability. One issue that generated some discussion is the location of the data from stress studies required for demonstrating that the analytical method is stability indicating. The author recommends that stress studies data should be included in Section 3.2.S.7. 3.5.3. Drug Product (CTD-Q Designation 3.2.P) The Center for Drug Evaluation and Research is in the process of revising the 1987 Drug Product Guideline Submitting Documentation for the Manufacture of and Controls for Drug Products. The new draft guidance Guidance for Industry, Drug Products: Format and Content for Submission of New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) is also based on the CTD-Q format. As a result of this, the draft guidance features some significant differences from the 1987 Guideline. One such difference is the addition of the section on Pharmaceutical Development (3.2.P.2 section in CTD-Q). Section 3.2.P.2 is modeled after the Development Pharmaceutics section of the EU dossier.
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Introduction of this section as part of an A/NDA submission in the United States was discussed in the EWG at length. European regulators made special presentations to convince the U.S. industry and regulators of the need for inclusion of this section in the CTD-Q. The draft guidance also provides detailed instructions on the content of Section 3.2.P.3.3: Description of the Manufacturing Process and Process Controls. An attempt has been made to separate the cGMP issues from the CDER-reviewed content. 3.5.4. Pharmaceutical Development (CTD-Q Designation 3.2.P.2) The content in this section provides an overview of development studies that rationalizes the choice of dosage form, formulation, manufacturing process, container closure system, microbiological attributes, and labeling. It may be pertinent to describe and discuss in this section drug substance characteristics that may or may not have influence on the choice of drug product formulation, manufacturing process, stability, bioavailability, and other quality issues. An example of one such drug substance characteristic may be its ability to form various polymorphic forms. Results of studies that demonstrate that the choice of a particular drug substance polymorphic form was dictated by its effect on the drug product dissolution profile and possibly on the drug product bioavailability should be included in this section. Section 3.2.P.2 comprises six subsections that provide for a chronology of the drug product development process. In this authors opinion, the content of Section 3.2.P.2, except for the content of subsections 3.2.P.2.2.1 (Formulation Development), 3.2.P.2.2.3 (Physicochemical and Biological Properties), and 3.2.P.2.3 (Manufacturing Process Development), is similar to that expected in a current A/NDA submission. For example, at the present time the information on the suitability of the container closure system is submitted under the container closure section. In the CTD-Q format, this information will be submitted in Section 3.2.P.2.4. Another example is the compatibility of an injectable drug product with reconstitution diluents or
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dosage devices. This information will be presented in Section 3.2.P.2.6 in an A/NDA submitted in the CTD-Q format, whereas at the present time it may be submitted with the stability data. 3.5.5. Description of Manufacturing Process and Process Controls (CTD-Q Designation 3.2.P.3.3) The description of the drug product manufacturing process and process controls in Section 3.2.P.3.3 represents the applicants commitment for the manufacture of the drug product. To provide an overview of the manufacturing process, a flow diagram that includes the manufacturing steps and showing where materials enter the process, equipment used, and sampling points is recommended. A brief description of the sampling process identifying number of samples taken should also be included. For NDAs, a detailed description of the manufacturing process may be included in place of an actual Master Production and Control Record (MPCR) (see 21 CFR 314.50(d) (1)(ii)(c) and Section 3.2.R of CTD-Q). However, for ANDAs it is recommended that the applicant always submit a MPCR. The description of the manufacturing process and process controls should also include a narrative description of the manufacturing process. This narrative description is expected to be more detailed than the flow diagram and should identify scale of production and equipment to be used, including those for packaging operations. All process controls should be identified, and the associated ranges, limits, or acceptance criteria should be specified. Critical process controls should be identified in this section, but details should be provided in Section 3.2.P.3.4. The discussion pertaining to reprocessing, reworking, and salvaging in the drug substance section is also pertinent here. However, a drug product that includes many components in its formulation is more complex than a drug substance itself. In a proposal to perform any of these operations, the applicant is urged to consider the impact of the operation on drug product quality and submit appropriate data to the Center. The distribution of information between Sections 3.2.P.3.3 and 3.2.P.3.4 for the drug product is similar to that
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for a drug substance. In-process tests are generally used to establish the completion of a manufacturing process step or the suitability of an intermediate for the next process step. Examples of in-process tests performed during critical manufacturing steps include, but are not limited to, pH, blend uniformity, viscosity, particle size analysis, bioburden, etc. Information on these tests, including analytical procedures and acceptance criteria should be included in Section 3.2.P.3.4. When a certain in-process specification is not met, it is conceivable that the applicant may repeat the process step to bring it into compliance. However, for other in-process tests such as individual tablet weight, hardness, and thickness only machine adjustment may be needed. Such process controls should not be reported in Section 3.2.P.3.4. 3.5.6. Control of Excipients (CTD-Q Designation 3.2.P.4) A variety of excipients are used in the formulation of drug products. A careful consideration of the excipient properties may prevent future manufacturing and drug product quality problems. Development data describing the choice of the excipients is presented in Section 3.2.P.2. The extent of documentation for controls of the excipients is dependent upon the following: For excipients that have monographs in USP/NF compendium, only additional specifications should be described in detail. The USP/NF specifications may be referenced. Noncompendial excipients may be proprietary mixtures of compendial components or noncompendial components that have been used in CDER-approved drug products. It is recommended that the applicant include all the specifications that would form the basis for lot acceptance, including, at minimum, an identification test to be performed by the applicant. Novel excipients are those that are used in a drug product formulation for the first time or by a new route of
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administration. Documentation is similar to that of a drug substance and should include details of manufacture, characterization, and controls. Cross-references to safety data should be provided. In recent years there has been much concern that the marketplace is inundated with counterfeit drug products. Tracers or markers have been used to identify authentic products. The draft drug product and other guidances under revision have made provisions for reporting inclusion of these tracers or markers in the drug product formulation. The chief concern is one of safety and the applicant should submit appropriate information for Agencys safety assessment. 3.5.7. Control of Drug Product (CTD-Q Designation 3.2.P.5) The ICH Guideline Q6A defines specification as a list of tests, analytical procedures, and acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. Specifications are critical quality standards that confirm the quality of the drug product and should be selected based on their relevance to safety and efficacy of the drug product. The purpose of the following discussion is to highlight some new concepts that have been introduced in the draft drug product guidance in response to CTD-Q and Q6A documents. These new concepts will help to ease the regulatory burden on the pharmaceutical industry. Periodic or Skip Testing: The performance of specified tests at release on pre-selected batches and/or at predetermined intervals, rather than on a batch-to-batch basis, may be acceptable. The batches that were not tested should still conform to all the specifications. The applicant should justify such testing schedule and implement it with Agency approval. Setting of Specifications: An applicant may justify its choice of specifications based on available development data.
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Reevaluation of the Acceptance Criteria: Limited data are available at the time of approval to set meaningful drug product acceptance criteria. An example is the dissolution specifications for extended-release products. In the Office of Generic Drugs, the dissolution acceptance criteria for an extended-release drug product may be approved with data from one batch of 100,000 dosage units. Manufacturing efficiencies realized during scale-up to commercial production batches may necessitate adjustments to the dissolution acceptance criteria. The Office of Generic Drugs, as a condition of approval, requires ANDA applicants to submit data from the first three validation batches and finalize the dissolution acceptance criteria. However, reevaluation of the acceptance criteria for impurities and/or degradants should be treated with caution. An applicant should consider safety implications when revising acceptance criteria for impurities and/or degradants. Parametric Release: An example of parametric release is sterility testing of terminally sterilized drug products. The terminal sterilization process parameters, such as temperature, pressure, and time, are accurately controlled and are more reliable in predicting sterility assurance than the end product sterility testing. It is recommended that an applicant obtain Agency approval before using parametric release testing as an alternative to routine testing. Alternative Procedures: It is expected that drug products that have monographs in the compendium should meet compendial specifications. However, applicants are encouraged to assess and adapt alternate methods that are superior to compendial methods. Drug Substance Specifications: It is not necessary to include in the drug product specifications those specifications that are unique to the drug substance. An example is the acceptance criteria for synthetic impurities present in drug substances. It is not necessary to include this specification in those for a drug product also.
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3.5.8. Drug Product CTD-Q Sections 3.2.P.6, 3.2.P.7, and 3.2.P.8 Section 3.2.P.6 includes information about reference standards or reference materials used for testing of the drug product. If these reference standards and reference materials are the same as those used in the testing of drug substance, then Section 3.2.S.5 should be cross-referenced. Section 3.2.P.7 is the placeholder for the routine controls information that is submitted in support of the container closure system used in packaging the drug product. Data that demonstrate the suitability of the proposed container closure system is included in the 3.2.P.2 section. ICH has published many guidelines that cover various aspects of drug product stability. A draft Stability Guidance is in preparation at CDER. It is recommended that an applicant consult the CDER guidance document when it becomes official to develop content for Section 3.2.P.8. 3.5.9. Appendices (CTD-Q Section 3.2.A), Regional Information (Section 3.2.R), and Literature References (Section 3.3) Information on facilities and equipment, adventitious agents safety evaluation, as they relate to biotech products, are included in Sections 3.2.A.1 and 3.2.A.2. As noted earlier, novel excipients require extensive documentation, similar to a drug substance. This information is included in Section 3.2.A.3. The content to be included in the Regional Information section 3.2.R is diverse. For the United States they include executed batch records, methods validation package, and comparability protocol. Process validation scheme for the drug product is required for EU only. Key literature referenced in the application should be provided. 3.6. What Is New and Different? An A /NDA submitted in the format of the CTD-Q will look different from that based on the 1987 guideline. An application
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based on the CTD-Q format and the revised Drug Substance Guidance and Drug Product Guidance will provide a logical story of the drug product development. Information pertinent to cGMP will be clearly delineated. Inclusion of the Pharmaceutical Development section (Section 3.2.P.2) will help the reviewing chemist to understand the implications of the drug substance and drug product characteristics on the choice of drug product formulation, manufacturing process and packaging. It will help the regulators in the three regions to come to common rational conclusions regarding the drug product.
4. FUTURE The future of CTD lies with eCTD. With its vast capabilities such as multimedia presentation, hyperlinking various sections and/or documents, and others, an eCTD will offer the applicant many creative avenues to communicate with the reviewers. The reviewer will have the ability to search and compare information, copy and paste information, and in general produce better documentation more efficiently. Adopting single submission standards will allow the applicant to communicate better with the various regulatory bodies. It will help the regulators in the three regions to come to common rational conclusions regarding the drug product. ICH has already begun the process of developing a common dictionary for medical terms. Such an effort is needed for CMC sections. With time, both the regulated industry and the regulators will gain experience to fine-tune an already useful guideline.
ACKNOWLEDGMENTS I wish to acknowledge the help and encouragement of the following individuals during my tenure in the EWG and in the preparation of this manuscript: Frank Holcombe, Florence Fang, Chuck Hoiberg, Don Klein, and the Packaging Technical Committee members.
19
21 CFR Part 11 Compliance and Beyond
RICHARD L. BURCHAM BPI Technologies Arlington, Texas, U.S.A.
1. INTRODUCTION TO FDA 21 CFR PART 11 1.1. What Is 21 CFR Part 11 and What Is It Not? 21 CFR Part 11 is FDAs ruling on the requirements for the acceptability of records recorded and signed electronically. It covers nearly everything that is created and stored in an electronic form, and it applies to all businesses regulated by the FDAnot just pharmaceuticals. Part 11 was first introduced in 1997 and is part of FDAs attempt to modernize the regulation and compliance
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of industries under their auspices. It is widely viewed by FDA as an opportunity for industry to improve business processes as opposed to just another regulatory burden. In February 2003 FDA issued its current thinking on the topic and withdrew the draft guidance for industry, 21 CFR Part 11, because it wanted to avoid loss of time spent by industry in an effort to review and comment on the draft guidance when that guidance may no longer be representative of FDAs approach under the new current good manufacturing practice (CGMP) initiative. These regulations, which apply to all FDA program areas, are intended to permit the widest possible use of electronic technology, compatible with FDAs responsibility to promote and protect public health. The use of electronic records as well as their submission to FDA is voluntary. The agency intends to exercise enforcement discretion with regard to legacy systems that otherwise met predicate rule requirements prior to August 20, 1997, the effective date of Part 11. This means that the agency will not normally take regulatory action to enforce compliance with any Part 11 requirements. However, all systems must comply with all applicable predicate rule requirements and should be fit for their intended use (1). In short, 21 CFR Part 11 is not a mandate to replace paper or manual record-keeping systems. If a record is not generated or stored electronically, the ruling does not cover it. Whats more, Part 11 is not just another IT exercise and is not solvable with vendor-supplied software alone. Compliance also requires planning, resource, and process change. Compliance with Part 11 will require investment in time and capital. It is estimated that the worldwide cost of compliance will range from $1 to $5 billion. The wide range is further evidence that FDA must strive for clearer definition of the principles and practices of Part 11. Do not make the mistake of assuming that this is another unenforceable government regulation. FDA is very serious about implementation and compliance. Expect more warning letters as 2004 continues.
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1.2. Background In 1991, members of the pharmaceutical industry met with the agency to determine how they could accommodate paperless record systems under the CGMP regulations in parts 210 and 211 (21 CFR parts 210 and 211). FDA created a Task Force on Electronic Identification/Signatures to develop a uniform approach by which the agency could accept electronic signatures and records in all program areas. In a February 24, 1992, report, a task force subgroup, the Electronic Identification/Signature Working Group, recommended publication of an advance notice of proposed rule making (ANPRM) to obtain public comment on the issues involved. FDA received 49 comments on the proposed rule. Those commenting represented a broad spectrum of interested parties: human and veterinary pharmaceutical companies as well as biological products, medical device, and food interest groups, including 11 trade associations, 25 manufacturers, and one federal agency (2). 1.3. Highlights of the Final Rule The final rule provides criteria under which FDA will consider electronic records to be equivalent to paper records and electronic signatures equivalent to traditional handwritten signatures. Part 11 (21 CFR part 11) applies to any paper records required by statute or agency regulations and supersedes any existing paper record requirements by providing that electronic records may be used in lieu of paper records. Electronic signatures that meet the requirements of the rule will be considered to be equivalent to full handwritten signatures, initials, and other general signings required by agency regulations (2). Section 11.2 provides that records may be maintained in electronic form and electronic signatures may be used in lieu of traditional signatures. Records and signatures submitted to the agency may be presented in an electronic form provided the requirements of Part 11 are met and the records have been identified in a public docket as the type of submission
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the agency accepts in an electronic form. Unless records are identified in this docket as appropriate for electronic submission, only paper records will be regarded as official submissions. Section 11.3 defines terms used in Part 11, including the terms biometrics, closed system, open system, digital signature, electronic record, electronic signature, and handwritten signature. Section 11.10 describes controls for closed systems systems to which access is controlled by persons responsible for the content of electronic records on that system. These controls include measures designed to ensure the integrity of system operations and information stored in the system. Such measures include validation, the ability to generate accurate and complete copies of records, archival protection of records, use of computer-generated, time-stamped audit trails, use of appropriate controls over systems documentation, and a determination that persons who develop, maintain, or use electronic records and signature systems have the education, training, and experience to perform their assigned tasks. Section 11.10 also addresses the security of closed systems and requires that (a) system access be limited to authorized individuals, (b) operational system checks be used to enforce permitted sequencing of steps and events as appropriate, (c) authority checks be used to ensure that only authorized individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record, or perform operations, (d) device (e.g., terminal) checks be used to determine the validity of the source of data input or operation instruction, and (e) written policies be established and adhered to, holding individuals accountable and responsible for actions initiated under their electronic signatures, so as to deter record and signature falsification. Section 11.30 sets forth controls for open systems, including the controls required for closed systems in x 11.10 and additional measures such as document encryption and use of appropriate digital signature standards to ensure record authenticity, integrity, and confidentiality.
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Section 11.50 requires signature manifestations to contain information associated with the signing of electronic records. This information must include the printed name of the signer, the date and time when the signature was executed, and the meaning (such as review, approval, responsibility, and authorship) associated with the signature. In addition, this information is subject to the same controls as for electronic records and must be included in any human readable forms of the electronic record (such as electronic display or printout). Under x 11.70, electronic signatures and handwritten signatures executed to electronic records must be linked to their respective records so that signatures cannot be excised, copied, or otherwise transferred to falsify an electronic record by ordinary means. Under the general requirements for electronic signatures, at x 11.100, each electronic signature must be unique to one individual and must not be reused by, or reassigned to, anyone else. Before an organization establishes, assigns, certifies, or otherwise sanctions an individuals electronic signature, the organization shall verify the identity of the individual. Section 11.200 provides that electronic signatures not based on biometrics must employ at least two distinct identification components such as an identification code and password. In addition, when an individual executes a series of signings during a single period of controlled system access, the first signing must be executed using all electronic signature components and the subsequent signings must be executed using at least one component designed to be used only by that individual. When an individual executes one or more signings not performed during a single period of controlled system access, each signing must be executed using all of the electronic signature components. Electronic signatures not based on biometrics are also required to be used only by their genuine owners and administered and executed to ensure that attempted use of an individuals electronic signature by anyone else requires the collaboration of two or more individuals. This would make it more difficult for anyone to forge an electronic signature. Electronic signatures based upon biometrics must be designed
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to ensure that such signatures cannot be used by anyone other than the genuine owners. Under x 11.300, electronic signatures based upon use of identification codes in combination with passwords must employ controls to ensure security and integrity. The controls must include the following provisions: 1. The uniqueness of each combined identification code and password must be maintained in such a way that no two individuals have the same combination of identification code and password. Persons using identification codes and/or passwords must ensure that they are periodically recalled or revised. Loss management procedures must be followed to deauthorize lost, stolen, missing, or otherwise potentially compromised tokens, cards, and other devices that bear or generate identification codes or password information. Transaction safeguards must be used to prevent unauthorized use of passwords and/or identification codes and to detect and report any attempt to misuse such codes. Devices that bear or generate identification codes or password information, such as tokens or cards, must be tested initially and periodically to ensure that they function properly and have not been altered in an unauthorized manner.
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1.4. Goals and Expectations FDA has released a Part 11 draft guidance on electronic copies that outlines seven key principles and practices that the agency advises industry to followand its inspectors to scrutinize: 1. Electronic copies of e-records provided to FDA should be accurate and complete, but they do not necessarily have to be in the same file format and in the same media as the original e-records.
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The process of making an electronic copy of an e-record in a file format that differs from the original should be validated. Copies of hyperlinked records incorporated by reference should be included with the electronic copy of the electronic record. Electronic copies of database queries should be included with electronic copies of electronic records when appropriate. Electronic copies of electronic records should include, or be appended with, an authentication value. Electronic copies of electronic records should be in a file format and on media that enable FDA to read and process record data. If the original electronic records were signed electronically, electronic copies of the original electronic records should have electronic signatures that are capable of being authenticated.
FDA has done this to prevent and detect data falsification in order to ensure that electronic records are reliable. The purpose is to enable data reconstruction that can be checked and verified. Confidence in the data integrity is foremost. As a result, records must be under control of the company, not the individuals. While FDAs reexamination of Part 11 is underway, it plans to narrowly interpret the scope of Part 11. Whats more, FDA intends to exercise enforcement discretion with respect to certain Part 11 requirements. FDA will not normally take regulatory action to enforce compliance with the validation, audit trail, record retention, and record copying requirements of Part 11 while it is under review. However, records must still be maintained or submitted in accordance with the underlying predicate rules (1). 1.5. Implications for Regulated Businesses FDA recognizes that it will take time for existing systems to attain compliance. This is a major undertaking for regulated
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industries because all systems generating GxP records are covered in the ruling. For noncompliance situations FDA will consider the following factors when deciding appropriate corrective action: Extent of deviations Impact on product quality and data integrity Timeliness of planned corrective measures Compliance history of establishment The extent of remediation will be determined by FDA on a case-by-case basis and may include: Acceptance of corrective action plan Delay of product approval Halt product shipments FDA warning letters (a.k.a Form 483) relative to electronic records are actively being issued today. Many cite computer systems validation and security, and a growing number cite Part 11 specifically. These warning letters, of course, are and will continue to be public record. They can be accessed at www.fda.gov/foi/warning.htm. PhRMAs response to Part 11 guidance asks for more time or a phased approach over 510 years. It also requests prioritized remediation based on risk and availability of compliant software. Unfortunately, FDA disagrees strongly and will continue to aggressively issue warnings. The risk grows at each stage of the process where computer systems are used to manage the production process for regulated industries. An illustration of this for process manufacturing is shown in Fig. 1. Given the potential for escalating risk, most companies are scrambling to hire expertise to get systems running in the short run. In the long run they are developing in-house expertise. Companies must change their processes and learn to think like a regulator while keeping in mind that compliance is a continuous process. Whats more, companies must demonstrate to the FDA that they have control over all changes.
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Figure 1
Risk escalation. (From Ref. 4.)
2. UNDERSTANDING THE PART 11 RULING 2.1. Archiving Data and Part 11 Compliance As previously discussed, Subpart B of Part 11 is broken down into three major sections: 1. 2. 3. 11.10 Controls for Closed Systems 11.50 Signature Manifestations 11.70 Signature/Record Linking
Each of these sections will be discussed in detail, but first a few common definitions are needed. 2.2. Definitions There are several terms used in the Part 11 ruling that need to be defined and understood in order to interpret compliance requirements. Interpretation of Part 11 centers on the following terms: DefinitionElectronic Record (ER): Any combination of text, graphics, data, audio, pictorial or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system (2). DefinitionElectronic Signature (ES): A computer data compilation of any symbol or series of symbols,
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executed, adopted, or authorized by an individual to be the legally binding equivalent of the individuals handwritten signature (2). DefinitionBiometrics and digital signatures: Biometrics: A method of verifying an individuals identity based on the individuals physical feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable; Digital Signature: An electronic method of signing electronic records based on cryptographic techniques of authentication that enables the verification of the identity of the signer and the integrity of the electronic record (2). DefinitionClosed system: An environment in which system access is controlled by persons who are responsible for the content of the electronic records on the system. DefinitionOpen System: An environment in which system access is not controlled by persons who are responsible for the content of the electronic records on the system (2).
2.3. Understanding Section 11.10 Controls for Closed Systems According to the ruling, Persons who use closed systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and to ensure that the signer cannot readily repudiate the signed record as not genuine. Section 11.10 goes on to define what types of controls need to be in place for closed loop systems: 1. 2. 3. Systems must be validated. Copies of records must be provided to the FDA. Protection of records must be done throughout the retention period.
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4. Limited access to the electronic records must exist. 5. All audit trails must be recorded. 6. There must be operational system checks. 7. Controls must be in place for user authority. 8. Device source controls must be in use. 9. Users must be trained on requirements. 10. Policies must exist for electronic signatures. 11. There must be controlled access to documentation. The closed loop system must have the ability to generate and complete copies of records in both human readable and electronic form. Whats more, it must be suitable for inspection, review, and copying by the agency. Records must be protected to enable their accurate and ready retrieval throughout the records retention period. The agency agrees that providing exact copies of electronic records in the strictest meaning of the word true may not always be feasible. FDA nonetheless believes it is vital that copies of electronic records provided to the agency be accurate and complete. Accordingly, in 11.10(b) the original language true has been replaced with accurate and complete. The agency expects that this revision should obviate the potential problems noted in the draft comments. The revision should also reduce the costs of providing copies by making clear that firms need not maintain obsolete equipment in order to make copies that are true with respect to format and computer system. How we store data is just as important as the information it contains. As an example, consider the 1986 BBC Doomsday Project. Text, pictures, documents, video, audio, etc. were all recorded on state of the art laser disks. One would expect that this would pass FDA Part 11 compliance. Unfortunately, 15 years later these electronic records are now unreadable. Whats more, who has a laser disk reader? The lesson learned is that organizations must look forward as much as possible when deciding on how they are going to manage electronic records. Obviously, the ability to perform migration as technology changes is a fundamental requirement (3). The question arises as to just how long a lifetime does the FDA expect an electronic record to have? Relative to regulatory
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Table 1
Data Types
Rich data types Chemical structures/reactions MOL SDF PDB Etc. Instrument applications Vendor equipment specic Oce applications Documents Spreadsheets Etc.
Common data types Images: JPEG GIF Etc. ASCII text: CSV Etc. Web pages: HTML
compliance, is the time frame equal to the lifetime of the product x years? Or is it the statue of limitations on intellectual property: 17 years, legal statute of limitations? These are issues that still need to be clearly defined. Also clouding the lifetime issue is the fact that there are many different types of electronic data. So, should the lifetime be different for each data type? Again, no clear answer. Table 1 shows some of the many different types of electronic data. In particular, rich data types present an archiving problem because storage formats are often proprietary. Consequently, data are only accessible via specialized software applications and may be platform specific, including proprietary operating systems, databases, and software versions. There are also concerns with application integration. That is, is it practical and/or possible to broadly distribute specialized applications software for accessing the data? Lastly, rich data types have more finite lifetimes than common data typese.g., will the specialized applications still be available, supported, and operational throughout the lifetime of the data? Fortunately FDA realizes that it must provide guidance on these issues. In a September 5, 2002 statement, FDA provided
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additional guidance for maintenance of electronic records. FDA defined two acceptable practices: 1. Time Capsule Approach: a. Preserve exact computing environment hardware and software. b. FDA admits that this is only viable as a shortterm solution. 2. Data Migration Approach: a. Translate and migrate data forward as computer technology changes. b. Viable long-term strategy. c. In the migration approach, the new computer system should enable organizations to search, sort, and process information in the migrated electronic record at least at the same level as what could be attained in the old system, even though the new system may employ different hardware and software. Another major requirement of Section 11.10 relates to Security and Authentication. Section 11.10 requires limited system access to authorized individuals only. Authority checks must be used to ensure that only authorized individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record, or perform the operation at hand. All individuals must have a unique identifier for access to, creation of, and modification of electronic records (2). Many individual data systems already have security capabilities. However, organizations must keep in mind that data archive systems are generally independent of other systems and there likely will be a need to integrate multiple authentication mechanisms. An example would be the need to integrate Oracle/database, MS, Networking, MS Active Directory PKI, and LDAP. A common misconception about archives and audit trails is that a compliant system can make noncompliant instruments
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and applications compliant by adding security and audit trail capabilities to the process. The reality is that archiving systems can only audit trail changes made to their own data. Whats more, archiving systems cannot track/approve specific changes made to rich data types with native applications. Reprocessing, method alteration, and data manipulations are key considerations. FDAs guidance on archives and audit trails is to use secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records. In short, record changes shall not obscure previously recorded information. Moreover, audit trail documentation shall be retained for a period of at least as long as that required for the subject electronic records and shall be available for agency review and copying. 2.4. Understanding Sections 11.50, Signature Manifestations, and 11.70, Signature/Record Linking Section 11.50 provides guidance on signed electronic records in that such records must clearly indicate: 1. 2. 3. The printed name of the signer The date and time when the signature was executed The meaning (such as review, approval, responsibility, or authorship)
The above items are subject to the same controls as for electronic records. Furthermore, Part 11.70 requires that electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective electronic records to ensure that the signatures cannot be excised, copied, or otherwise transferred to falsify an electronic record by ordinary means. According to FDA, compliance can be ensured with closedloop systems where signatures and data can be linked via specific implementations. Unfortunately, current implementations are generally proprietary and there is a lack of industry
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standards in this area. Also, migration will be difficult with large volume of data. However, this is where we are today.
3. ACHIEVING COMPLIANCECOMPLIANCE ENABLING TECHNOLOGIES 3.1. Compliance and Flexibility Electronic records and/or signatures must meet several conditions in order to be acceptable as an alternative to a paper record or handwritten signature. These conditions are necessary to permit the agency to protect and promote the public health. For example, FDA must retain the ability to audit records to detect unauthorized modifications, simple errors, and to deter falsification. Whereas there are many scientific techniques to show changes in paper records (e.g., analysis of the paper, signs of erasures, and handwriting analysis), these methods do not apply to electronic records. For electronic records and submissions to have the same integrity as paper records, they must be developed, maintained, and used under circumstances that make it difficult for them to be inappropriately modified. Without these assurances, FDAs objective of enabling electronic records and signatures to have standing equal to paper records and handwritten signatures, and to satisfy the requirements of existing statutes and regulations, cannot be met. Within these constraints, FDA has attempted to select alternatives that provide as much flexibility as practicable without endangering the integrity of the electronic records. The agency decided not to make the required extent and stringency of controls dependent on the type of record or transactions, so that firms can decide for themselves what level of controls is worthwhile in each case. For example, FDA chose to give firms maximum flexibility in determining (a) the circumstances under which management would have to be notified of security problems, (b) the means by which firms achieve the required link between an electronic signature and an electronic record,
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(c) the circumstances under which extra security and authentication measures are warranted in open systems, (d) when to use operational system checks to ensure proper event sequencing, and (e) when to use terminal checks to ensure that data and instructions originate from a valid source. As a rule of thumb, for records required to be maintained but not submitted to the agency, persons may use electronic records in lieu of paper records or electronic signatures in lieu of traditional signatures, in whole or in part, provided that the requirements of Part 11 are met. For records submitted to the agency, persons may use electronic records in lieu of paper records or electronic signatures in lieu of traditional signatures, in whole or in part, provided that (a) the requirements of Part 11 are met, and (b) the document or parts of a document to be submitted have been identified in public docket no. 92S-0251 as being the type of submission the agency accepts in electronic form. This docket will identify specifically what types of documents or parts of documents are acceptable for submission in electronic form without paper records and the agency receiving unit(s) (e.g., specific center, office, division, branch) to which such submissions may be made. Documents to agency receiving unit(s) not specified in the public docket will not be considered as official if they are submitted in electronic form; paper forms of such documents will be considered as official and must accompany any electronic records. Persons are expected to consult with the intended agency receiving unit for details on how (e.g., method of transmission, media, file formats, and technical protocols) and whether to proceed with the electronic submission (2).
4. STRATEGIES FOR IMPLEMENTATION We have discussed the rules and guidelines of the Part 11 ruling, but the question remains: How do organizations comply? Most technologies, as previously mentioned, are proprietary, nonglobal, and lack universal standards to be an effective means for Part 11 compliance. However, XML, or
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Extensible Markup Language, is one exception in that industry, and governments worldwide have embraced it as a means of compliance. 4.1. What Is XML and What Is Its Role? XML is a standardized representation for data content. It is used for text, instrumentation data, and application integration. Whats more, it is not proprietary and was developed and is supported by the W3C, a nonprofit consortium. There are several standards developed by the W3C that relate to XML, including schema definition, style sheet and transformation, and search capabilitiesall of which make it easier to comply with Part 11. XML is global in scope and according to a December 2000 survey; over 75% of life sciences executives responding said that they are currently planning to deploy XML as part of their R&D strategy. As depicted in Fig. 2, nearly all expected to be employing XML by 2003 (4). Whats more, XML has the support of FDA and, according to SQA CVIC meeting 6/10/97 with Paul Motise (FDA): The problem of system obsolescence can be solved by careful migration from one electronic file format and platform to another. E-commerce and e-government are moving toward, not away from, common e-record
Figure 2
XML in life sciences. (From Ref. 5.)
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formats that are interoperable on many different platforms. Consider the rise of XML, for example. XML can be used to represent any type of data, and it is specifically designed for strong typing of rich datathereby solving some of the rich data problems discussed earlier in this chapter. Furthermore, XML is platform independent, which simplifies distribution and forward migration to avoid obsolescence. XML is extensible, a requirement to support future data types, and it is a public domain standard. Perhaps most importantly, it allows data models to be made available to anyone, but be closed to interpretationa key Part 11 requirement. XML can satisfy electronic data collection requirements of Part 11 as well. XML schemas exist for all instrument data types, and different archiving systems may be implemented for different data types such as: 1. Analytical and lab instruments 2. Chemical structures/reactions 3. Clinical trials/studies 4. Documents Application integration, internal or external to your organization, can be accomplished through the exchange of data and transaction instructions as XML. This has wide industry support in the life sciences as well as with application vendors. Practically everyone and everything is involved with web services making application integration, for the purposes of Part 11 compliance, both feasible and achievable (3). All of the major application and database vendors are committed to XML and web support, including IBM, Hewlett-Packard, Sun Microsystems, Oracle, Microsoft, SAP, etc. The languages supported include Java, C, C, Python, Perl, and Microsoft languages (VB, C#, etc.) Supporting platforms include .NET, J2EE, Apache, Zope, etc., and operating systems include Unix (Solaris, Linux, etc.), Windows, MacOS X, etc. In short, companies have a wide selection of technologies utilizing XML with which to achieve ongoing Part 11 compliance.
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4.2
Example of Part 11 Compliance
Discussed below is an example of how Part 11 compliance can be achieved even when two separate companies are working together on a common project but with different systems and technologies. In this example, a CRO is collaborating with a pharmaceutical company to research a new product (4). Assumptions: 1. A CRO based in the United Kingdom is working on a research project with a pharmaceutical company in the United States. 2. The CRO uses Lotus Notes ELN authoring application. 3. The pharmaceutical company uses Thermo LabSystems Nautilus LIMS and eRecordManager. 4. The companies worked separately over the web to develop system interfaces. Transaction process: Step 1: ELN user at CRO in the UK logs in and creates a sample request in the LIMS of the Pharmaceutical Company. This is done directly from the ELN and the user has no awareness that the request was sent to the LIMS. Step 2: LIMS user logs in, sees the request and processes the sample request. Analysis results are entered directly into LIMS, and eRM automatically captures the chromatogram. The LIMS user has no idea that the sample request came from the CROs ELN. Step 3: The ELN user at the CRO refreshes his screen/ page and the analysis results and chromatogram automatically appears. The chromatogram can be zoomed using an XML enabled plug-in and data are pulled from LIMS and eRM systems using XML. The set of transactions is illustrated in Fig. 3. The only thing that needs to be added to this set of transactions for Part 11 compliance is electronic signaturesi.e., the electronic record criteria of Part 11 has been satisfied.
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Figure 3
Example of Part 11 compliance. (From Ref. 4.)
Two criteria must be added to the electronic record of this transaction in order to be compliant with electronic signatures: (a) identifying information for the individual and date/time and (b) connective links to the information that was signed. Implementation of the first criterion requires authentication of the individual. This can be satisfied in a variety of ways, including passwords and digital codes of identification plus the printed name of the signer, the date and time that the signature was executed, and the meaning such as review, approval, responsibility, or authorship. Implementation of the second criterion requires encrypting hash calculation of data and signature, strong encryption algorithm (i.e., SHA), and, at a minimum, a private digital key. Public/private key mechanisms can also be used. The technologies available for electronic signatures are largely application specific in that many Part 11 applications have internal signature-data linking. However, the proprietary nature of these applications makes forward migration of data and signature difficult, if not impossible. There are also commercial packages available including Verisign, Entrust, ValiCert, Microsoft (Passport), and Liberty Alliance. However, perhaps the best solution for all of the reasons previously discussed is to use the public domain, that is, XML Signature Encryption.
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The final step to make the above example Part 11 compliant is to archive the transaction. Archiving systems must be implemented as closed systems. To this end, FDA guidance requires the following: Record validity must not be challenged. Inseparability of data, audit trail, e-signatures, etc. Must be maintained when moving from applicationspecific implementations to more open technologies (e.g., XML Signature). With respect to infrastructure, the FDA focus is on system security, not application security. Specifically, they are interested in whether or not the records are stored so that only the system has accessno back doorsand that tampering can be detected.
5. BENEFITS OF 21 CFR PART 11 TO ORGANIZATIONS Because the Part 11 affects such a broad range of industries, no data currently exist to estimate precisely the total number of entities that will potentially benefit from the rule, but the number is substantial. For example, within the medical devices industry alone, the Small Business Administration (SBA) estimates that over 3221 firms are small businesses (i.e., have fewer than 500 employees). SBA also estimates that 504 pharmaceutical firms are small businesses with fewer than 500 employees. Of the approximately 2204 registered blood and plasma establishments that are neither government-owned nor part of the American Red Cross, most are nonprofit establishments that are not nationally dominant and thus may be small entities as defined by the Regulatory Flexibility Act (2). Not all submissions to FDA will immediately be acceptable electronically, even if the submission and the electronic record conform to the criteria set forth in this rule. A particular required submission will be acceptable in electronic form only after it has been identified to this effect in public docket
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92S-0251. (The agency unit that can receive that electronic submission will also be identified in the docket.) Thus, although all entities subject to FDA regulations are potentially affected by this rule, the rule will actually only benefit those that (a) are required to submit records or other documents that have been identified in the public docket as acceptable if submitted electronically and (b) choose this method of submission, instead of traditional paper record submissions. The potential range of submissions includes such records as new drug applications, medical device premarket notifications, food additive petitions, and medicated feed applications. FDA will consider these, and all other required submissions, as candidates for optional electronic format. Although the benefits of making electronic submissions to FDA will be phased in over time, as the agency accepts more submissions in electronic form, firms can, upon the rules effective date, immediately benefit from using electronic records/signatures for records they are required to keep, but not submit to FDA. Such records include, but are not limited to pharmaceutical and medical device batch production records, complaint records, and food-processing records. Whats more, as stated earlier in this chapter, the activities regulated by this rule are voluntaryno entity is required by this rule to maintain or submit records electronically if it does not wish to do so. Presumably, no firm (or other regulated entity) will implement electronic record keeping unless the benefits to that firm are expected to exceed any costs (including capital and maintenance costs). Thus, the industry will incur no net costs as a result of this rule. Ultimately, the rule will permit regulated industry and FDA to operate with greater flexibility, in ways that will improve both the efficiency and the speed of industrys operations and the regulatory process. At the same time, it ensures that individuals will assign the same level of importance to affixing an electronic signature, and the records to which that signature attests, as they currently do to a handwritten signature.
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For any firm choosing to convert to electronic record keeping, the direct benefits are expected to include (2,4): 1. Improved ability for the firm to analyze trends, problems, etc., enhancing internal evaluation and quality control Reduced data entry errors, due to automated checks Reduced costs of storage space Reduced shipping costs for data transmission to FDA More efficient FDA reviews and approvals of FDAregulated products More efficient data mining and analysis
2. 3. 4. 5. 6.
There may be some small organizations that currently submit records on paper, but that archives records electronically. These entities will need to ensure that their existing electronic systems conform to the requirements for electronic record keeping described in this rule. Once they have done so, however, they may also take advantage of all the other benefits of electronic record keeping. Therefore, no individual small entity is expected to experience direct costs that exceed benefits as a result of this rule. Furthermore, because almost all of the rules provisions reflect contemporary security measures and controls that respondents to the ANPRM identified, most firms should have to make few, if any, modifications to their systems. For entities that do choose electronic record keeping, the magnitude of the costs associated with doing so will depend on several factors, such as the level of appropriate computer hardware and software already in place in a given firm, the types of conforming technologies selected, and the size and dispersion of the firm. For example, biometric signature technologies may be more expensive than nonbiometric technologies; firms that choose the former technology may encounter relatively higher costs. Large, geographically dispersed firms may need some institutional security procedures that smaller firms, with fewer persons in more geographically concentrated areas, may not need.
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Firms that require wholesale technology replacements in order to adopt electronic record/signature technology may face much higher costs than those that require only minor modifications (e.g., because they already have similar technology for internal security and quality control purposes). Among the firms that must undertake major changes to implement electronic record keeping, costs will be lower for those able to undertake these changes simultaneously with other planned computer and security upgrades. New firms entering the market may have a slight advantage in implementing technologies that conform to this rule, because the technologies and associated procedures can be put in place as part of the general startup. There is an additional cost often overlooked that will be incurred as part of complianceprofessional skills. If a firm elects electronic record keeping and submissions, it must take steps to ensure that all persons involved in developing, maintaining, and using electronic records and electronic signature systems have the education, training, and experience to perform the tasks involved. The level of training and experience that will be required depends on the tasks that the person performs. For example, an individual whose sole involvement with electronic records is infrequent might only need sufficient training to understand and use the required procedures. On the other hand, an individual involved in developing an electronic record system for a firm wishing to convert from a paper record-keeping system would probably need more education or training in computer systems and software design and implementation. In addition, FDA expects that such a person would also have specific on-the-job training and experience related to the particular type of records kept by that firm. The relevant education, training, and experience of each individual involved in developing, maintaining, or using electronic records/submissions must be documented. However, no specific examinations or credentials for these individuals are required by the rule.
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REFERENCES
1. Guidance for Industry, Part 11, Electronic Records; Electronic SignaturesScope and Application. Food and Drug Administration, February 2003. Fed. Reg., Department of Health and Human Services, 21 CFR Part 11. Institute of Validation Technology, conference proceedings, Process Analytical Technology, October 2002. BPI Research Centre, Validation, compliance and beyond, November 2002. XML in the life sciences, Sillico Research Limited, 2001.
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20
Marketing and Advertising/ Promotion: The Impact of Government Regulations
DANIEL GLASSMAN, PHILIP W. McGINN, Jr., and GENE GOLDBERG Bradley Pharmaceuticals Inc. Fairfield, New Jersy, U.S.A.
1. INTRODUCTION Prior to 1900, the pharmaceutical industry was initially relatively small and fragmented. Expenses for marketing and advertising/promotion were rather modest. Products were generally produced, promoted, and sold with a minimum of regulation or scrutiny. Today, the pharmaceutical industry spends billions of dollars in marketing and advertising/promotion activities and
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does so under rather rigid regulations by the U.S. Food and Drug Administration (FDA). The industry is heavily regulated by FDA concerning proof of the effectiveness and safety of its products and the manner in which it promotes its therapeutics. To understand how this dramatic change in regulation has affected the industrys overall promotional activities, it is important to review the evolution of the governments involvement in this important area of the pharmaceutical business.
2. EVOLUTION OF GOVERNMENT DRUG ADVERTISING/PROMOTION REGULATIONS Several minor efforts were directed towards the classification of medicines in the 1800s. However, the regulation of drug promotion started in 1905 when the American Medical Association (AMA), through the Council on Pharmacy and Chemistry, initiated a voluntary drug approval program that forced pharmaceutical companies to submit evidence on their respective drugs for review by the AMA Council and outside experts in order to earn the right to advertise in AMA and related journals (1). This AMA program lasted until 1955. In addition, in 1906 Congress passed the original Pure Food and Drug Act, which was designed to provide safe drugs to patients. Though well intentioned, this Act did not prevent false promotional claims for drugs. It was not until 1912 that Congress enacted the Shirley Amendment, which prohibited the labeling of medicines with false therapeutic claims. Throughout the following years, it was repeatedly demonstrated that the original 1906 Pure Food and Drug Act was obsolete and ineffective for the regulation of promotional claims. However, it was not until 1938 that Congress passed and President Franklin Roosevelt signed the new broad-based Federal Food, Drug and Cosmetic Act into law. This Act required that new drugs be tested for safety prior to marketing and that new drugs have adequate labeling for safe use. At that time, all drug advertising regulation was assigned to the Federal Trade Commission (FTC) (2,3).
Government Regulations of Marketing and Advertisement
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But, much more was to happen in the efforts to provide safe and effective drugs for the nations public and to regulate promotion to accurately reflect and restrict claims to the boundaries of the approved prescription information/labeling. During the next 20 years, the strength and scope of the FDA was substantially increased, due to safety problems related to a variety of drugs tested, produced, and prescribed in the United States. Drug safety and related promotion had become a major issue for FDA. The year 1960 marked dramatic steps designed to further strengthen and expand FDAs powers. Senate hearings on strengthening the drug provisions of the 1938 Act were chaired in June 1960 by Senator Estes Kefauver, who had an established reputation as a crime investigator. During the course of the Senate pharmaceutical hearings, FDA received a request from a pharmaceutical company for the approval, via a New Drug Application (NDA), of the sedative drug thalidomide, which was found to have caused birth defects in thousands of babies in Western Europe. Though pressure had been exerted by the U.S. manufacturer hoping to introduce the product, FDA medical officer Dr. Frances Kelsey refused to allow the NDA to be approved, thus avoiding what would have been a substantial tragedy in the United States. This striking event gave impetus to Senator Kefauver to submit a bill tightening the regulation of all drugs in the U.S., which was approved and signed into law (4). Basically, the 1962 Kefauver amendments to the original 1938 Federal Food, Drug and Cosmetic Act required drug manufacturers to prove that their products were both effective and safe prior to marketing and that all antibiotics had to be certified, and, most important from the perspective of promotional regulation, FDA was given control over all prescription drug advertising. Though the various divisions of FDA were becoming more comprehensive and sophisticated in nature, concern about the safety of Americas drug supply continued. This concern would lead to greater FDA oversight of drug marketing and advertising/promotion.
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Pressure from FDA on drug marketing and advertising/ promotion escalated in the 1970s. In the early 1970s FDA started two new forums in order to increase drug communication with the public. One result was the production of the FDA Bulletin (1971) by the Bureau of Drugs, which alerted physicians and pharmacists to changes in drug use and labeling requirements (5). The other result was the National Drug Experience Reporting System (1971), which allowed FDA to collect expanded data on drug adverse reactions, drug abuse, and drug interactions and provided a mechanism for FDA to take the lead in creating and maintaining the system for health professionals. In the 1980s, in order to render its operations more efficient, the FDA made a number of changes, one of which was the change of the Division of Drug Advertising to that of the Division of Drug Advertising and Labeling in order to increase the publics assurance of pharmaceutical promotional adherence to approved drug safety and efficacy. By this time, drug advertising in professional journals and direct mail and promotion through pharmaceutical sales representatives, were well-accepted practices. However, the first direct-to-consumer television advertising of prescription drugs occurred in 1983, via Boots Pharmaceuticals, and encountered resistance from FDA. Action was taken by FDA because of concern that the consumer could not possibly read the long list of side effects flashing across the screen. This was promptly addressed (6) via an accurate but simpler listing of potential side effects.
3. REORGANIZATION OF THE FOOD AND DRUG ADMINISTRATION The various divisions of FDA were reorganized in the 1980s to improve its overall efficiency relative to the regulation of drug approval, distribution, and advertising/promotion. The reporting requirements for drug adverse reactions were also strengthened.
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Although the primary agency that had jurisdiction over the advertising of drugs was the FTC, the Federal Food, Drug and Cosmetic Act (FD&C Act), as amended in 1962, gave FDA primary jurisdiction over the regulation of prescription drug advertising (7), which continues to this date. To understand how FDA regulates pharmaceutical marketing and advertising/promotion, it is important to first understand how FDA is organized.
4. FDA ORGANIZATION It is within the Office of the FDA Commissioner that the FDA-wide policies are established, and the various Centers within the FDA set the policies applicable to the products they regulate. Figure 1 illustrates the five FDA Centers that regulate a specific area of health-related products. Each Center monitors marketing and advertising/promotion in several ways, namely: 1. 2. Review product materials submitted by companies Review medical journals, trade publications, medical exhibits, and publicly available documents that are issued by various firms 3. Review complaints received from competitors, or others, about marketing and advertising/promotional materials used by companies 4. Review materials supplied by the product review divisions The Center for Drug Evaluation and Research (CDER) is the focus of this review of FDAs regulation of pharmaceutical drugs.
5. CENTER FOR DRUG EVALUATION AND RESEARCH The CDER represents the largest staff Center within the FDA that regulates marketing and advertising/promotion. When the
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Figure 1
FDA centers.
CDER was established in 1987, it consisted of few offices and staff. By 1994, it consisted of six office buildings, which formed the largest headquarters component of FDA and encompassed nearly 1500 people. Drug reviews had become very complex
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Figure 2
DDMAC organization as of September 1999.
and challenging as the sophistication of drug design and manufacturing increased (8). The CDER Division responsible for the regulation of pharmaceutical marketing and advertising/promotion is the Division of Drug Marketing, Advertising and Communication (DDMAC). Figure 2 illustrates the manner in which DDMAC is organized. The staff of DDMAC monitors drug marketing and advertising/promotion from a variety of sources. They have the power to identify volatile and incorrect practices and implement corrective action directly with the pharmaceutical companies concerned (9). Members of the DDMAC staff regularly consult with CDER medical reviewers relative to specific product labeling issues and claims and also coordinate with the review divisions when companies request preclearance of product launch materials for newly approved drugs. Other DDMAC responsibilities include conducting research on marketing, advertising, and labeling activities.
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6. MARKETING AND ADVERTISING/ PROMOTION REGULATIONS FDA regulates the marketing and advertising/promotion of prescription medicines, biological products, restricted devices and prescription animal products. On the other hand, the FTC regulates, with scientific input from FDA, the marketing and advertising/promotion of foods, over-the-counter (OTC) drugs, nonrestricted devices, and cosmetics and nutritional products, i.e., vitamins. The focus of FDAs enforcement of advertising and labeling laws has centered on prescription drugs, primarily because it has been actively regulating in this area the longestsince 1962. However, FDA has broadened its regulatory scope to encompass virtually any information issued by a medical products manufacturer of drugs, biologics, veterinary medicines, or medical devices. What is considered to be the FDAs true crackdown on the enforcement of marketing and advertising/promotion activities began in the late 1980s. This was not a result of congressional legislation but, rather, FDAs expansion of its authority was based on their interpreted powers, resulting from concerns of a number of sources that the Agencys enforcement was not vigorous enough. Public sentiment was that FDA was not establishing rules (regulations) to keep pace with the new methods of advertising/promotion of medical products in the industry. This so-called crackdown originally focused on the marketing and advertising/promotion of prescription drugs (especially nontraditional forms of promotion) and has now been shown to have far-reaching implications for all medical product marketing and advertising/promotion. This crackdown really began in the 1960s and accelerated in the 1980s, a result of a string of ground-breaking, aggressive commissioners. This aggressive approach resulted in antagonism between FDA, pharmaceutical companies, and representatives of the pharmaceutical industry, including the Pharmaceutical Manufacturers Association (PMA), led for many years by the powerful association leader C. Joseph Stetler (Pharma, Executive Vice
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President and General Council from 1963 to 1965 and President from 1965 to 1979 and 1984 to 1985).
7. FDAS AUTHORITY OVER MARKETING AND ADVERTISING/PROMOTION The authority for FDAs regulations emanates from the Federal Food, Drug and Cosmetic Act of 1962, which established FDAs control over the marketing and advertising/ promotion of prescription drugs, restricted medical devices, prescription veterinary medicine, and biological products. Through the authority granted, FDA has issued extensive regulations on marketing and advertising/promotion of prescription drugs. From the overall standpoint of prescription drug marketing and advertising/promotion, 1962 was a key legislative year because, until that year, Congress had exempted drug advertising from FDA control. However, as a result of the 1962 Kefauver hearings (previously discussed), it was required that all drugs be demonstrated not only to be safe, as was the prior requirement, but also to be effective. As a result, marketing and advertising/promotion became one of the more important aspects of FDA control. It should be noted, again, that FDAs regulations on drug promotion were written at the time in which journal advertising, direct mail, and detailing were the most common ways in which prescription drugs were promoted to the medical profession. As the years progressed, the following communication media were added to the traditional forms of product promotion: manufacturers press releases, medical symposia and other medical education programs, electronic advertising, directto-consumer (DTC) advertising, therapeutic monographs, dinner meetings, and verbal communications between physicians and company staff or consultant representatives (10). Much has changed regarding the FDAs regulation of prescription medicine marketing and advertising/promotion. After years of initial combat between the industry and the
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FDA expansion of regulatory power, companies and industry representatives, through experience with the FDA, have become reluctant to challenge FDA jurisdiction. The expanded role of informal rules that FDA applies to various product communications mechanisms has made it difficult to predict what the FDA will deem as acceptable. It should be noted that although members of the FDA are not law officers, their Warning and Regulatory Letters to companies have nearly the same effect as issued laws.
8. EXTERNAL PRESSURES ON FDA REGULATION OF MARKETING AND ADVERTISING/PROMOTION This new intensity of regulatory enforcement, in the late 1980s, was due to the fact that the FDA staff recognized that new methods of communicating product information were becoming prevalent and were being extensively and intensely utilized by pharmaceutical companies. Also, concern had been expressed by external observers concerning the FDAs level of enforcement of misleading advertisements by the drug industry. This new FDA initiative coincided with increased external pressures on FDA to increase its activities in regulating the marketing and advertising/promotion not only of prescription drugs but also of other medicinal products. In 1990, FDAs activities were further intensified by the arrival of Dr. David A. Kessler as the new Commissioner. He increased the staff in the CDER, as well as other Centers, and began the process of setting forth written guidelines for certain marketing and advertising/promotional activities (11).
9. COMPLAINTS BY COMPETITORS Two methods are used by FDA to identify potential company violations in marketing and advertising/promotion practices.
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The first is through FDAs monitoring activities, which, with significant additions in staff, have increased substantially. The second method of FDA scrutiny involves complaints received from competitive firms who monitor the activities of their competition, including marketing and advertising/promotion. In fact, in the late 1980s, competitive complaints formed the basis of half of the regulatory actions taken by DDMAC within CDER. In addition, pressures on FDA can emanate from Congress, the Office of the Inspector General, public press, and others.
10. IMPACT OF THE U.S. CONGRESS A significant and continuing influence over FDA policies and enforcement activities is exerted by the U.S. Congress (i.e., via Senators and members of the House of Representatives) who, periodically, send letters to FDA (receiving priority attention), hold congressional hearings with FDA officials invited to testify, and conduct staff investigations and issue subsequent reports. A major focus of these congressional issues is the amount of money that the pharmaceutical industry spends on marketing, including marketing and advertising/promotion (12). This is a continual area of contention between Congress and the pharmaceutical industry.
11. INSPECTOR GENERAL OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) The Office of Inspector General (OIG) operates as a politically independent office that conducts investigations, frequently as the result of a complaint or external request concerning what are deemed to be illegal activities. Reports by the OIG are considered significant because of their presumed objectivity and are regarded as credible. As a result, OIG reports usually
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result in publicity with resultant pressure on FDA to take some form of regulatory action. During the period from 1981 through 1992, OIG focused strongly on FDA regulatory matters, such as the generic drug scandal, prescription drug advertising, and gifts or payments by firms to physicians. The OIG report noted that many of the gifts to physicians are regarded under the AMA Guidelines on Gifts to Physicians as inappropriate. This led to the recommendation that FDA should finalize guidelines that defined what was considered to be promotional activity, including gifts, and what was considered scientific exchange. The recommendation was issued in the November 27, 1992 publication concerning proposed policy on scientific exchange and continuing medical education.
12. IMPACT OF CONSUMER ADVOCACY GROUPS Consumer advocacy groups provide an important source of external pressure on the FDA in a number of areas. The most prominent consumer advocacy group is the Health Research Group (HRG), founded by Ralph Nader in 1971 and headed by Dr. Sidney Wolfe. HRG has a special interest in pharmaceutical marketing and advertising/promotion and is known for its opposition to certain marketing and advertising/promotion practices. Though the HRG has no policy paper or quantifying data on the subject, it claims, as an empirical observation, that the medical products industries spend too much on marketing and advertising/promotion and that much of this marketing and advertising/promotion is misleading. Therefore, HRG, relying heavily on the media, attempts to pressure FDA to monitor the marketplace more closely and to take more aggressive enforcement actions (13). HRG and other advocacy groups have enjoyed significant success in their endeavors to pressure the FDA to action.
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13. AUTHORITY OF THE FTC OVER MARKETING AND ADVERTISING/ PROMOTION OF FDA-REGULATED PRODUCTS A relationship pertaining to the regulation of product advertising/promotion that is often not understood is the interaction of FDA and the FTC: Under the Federal Food, Drug, and Cosmetic Act (FD&C), the FDA regulates the safety, efficacy, functionality (when appropriate) and labeling of foods (except meat and poultry), prescription and over-the-counter drugs, biologics, veterinary medicine, cosmetics, and prescription and non-restricted medical devices (14). In 1938, the FTC received the authority from Congress to regulate the advertising of foods, drugs, and cosmetics. In 1962 this authority was altered by Congress to give FDA jurisdiction over most aspects of the advertising/promotion of prescription drugs but not OTC drugs. With the passage of the Medical Device Amendments in 1976, FDA also received jurisdiction over the regulation of advertising/promotion for restricted devices, while the FTC retained primary responsibility for the advertising/promotion of nonrestricted devices. Moreover, over the years, FDA has adopted a very broad interpretation of marketing and advertising/promotion. While advertising is commonly considered to be paid advertising, FDA considers promotion to apply to any materials issued by or on behalf of a company or any event that is sponsored by or on behalf of a company that mentions one or more products. Because of their complex working relationship over the regulation of labeling and advertising/promotion of identical products, FDA and FTC entered into what is known as the Memorandum of Understanding (MOU) in 1971, which established the working relationship and division of responsibility between FDA and FTC. As a result of this understanding, FDA and the FTC work closely on many issues that involve advertising/promotion. FDA retains full responsibility for all aspects of prescription drug labeling and promotion plus the labeling of OTC products, whose advertising the FTC regulates.
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14. FDA REGULATION OF MARKETING AND ADVERTISING/PROMOTION OF PRESCRIPTION DRUGS BASIC REGULATIONS AND POLICIES The CDER is responsible for most of the regulations and broad policies that apply to the marketing and advertising/promotion of FDA-regulated products, with the marketing and advertising/promotion of prescription medicinal products, being the most carefully monitored product communications. Within CDER, the DDMAC division is responsible for these regulatory activities. FDA subjects to regulation any advertising or promotional piece issued by a drug company for a specific product. The following general requirements apply to prescription marketing and advertising/promotion: 1. There should be no claims made for a product other than those that are FDA approved and are included in the products labeling. 2. There must be fair balance* in the products advertising and promotion so that the physician, other health professionals, or consumers will have a clear understanding of the product. 3. When an advertisement contains both the name of the drug and its indications, it must also include an abbreviated summary of the package insert.y This requirement applies to any advertisement that is direct-to-consumer, as well as directed to physicians. Concerning electronic advertising, there must be a
* This is an evolved interpretation by FDA and refers to FDAs requirement that risks associated with the products use should be clearly identified, relative to the products benefits for the patient.
The product package insert contains all of the essential information about the product, including: pharmacology, clinical studies, indications and usage, contraindications, precautions, dosage, and administration. This information is often also included in the Physicians Desk Reference. Abbreviated Patient Inserts were briefly prepared for some products but were not successful.
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4. 5.
6. 7.
8.
provision for physician easy access to the product package insert. It is illegal to make safety or efficacy claims for a product prior to its approval. The fact that an advertisement or promotional item may be completely accurate in terms of information is not an adequate defense if any of the specific rules are violated (15). The product must be accurately represented in the advertisement, even in its graphics. When FDA finds an advertisement or promotional piece in violation, the corrective measures it will utilize will vary as to the potential impact on public health. Relative to company-sponsored meetings that mention specific products, FDA then regards every aspect of the meeting as within its jurisdiction, such as the location of the meeting, those attending it, who is speaking and what is said, and the relationship that exists between the company and the organization that conducts the meeting.
15. FDA DEFINITIONS OF LABEL, LABELING, MISBRANDING, AND ADVERTISEMENTS/ PROMOTION Though the Federal Food, Drug and Cosmetic Act does not define advertising and promotion, FDA has chosen to define those terms in the broadest sense possible. This is especially true of promotion, which FDA considers to be any materials that are issued on behalf of a company or any event that is sponsored by or on behalf of a company that mentions one or more products. The key to these regulations begins with labeling and extends through policies on the advertisement and promotion of drugs. According to the FD&C Act, a label is defined as a display of written, printed, or graphic material upon the immediate container of any article. Any word, statement, or other
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information that also appears on the label shall not be considered as in compliance unless such word, statement, or other information also appears on the outside wrapper (if there is any) of the retail package of such article, or is easily legible through the outside wrapper or container (16). As far as labeling is concerned, the same law refers to all labels and written, printed, or graphic matter that appears in any article, container or wrapper, or accompanies such article. FDA has interpreted the matter of labeling to include: brochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogs, house organs, letters, motion picture films, videos, CDs, sound recordings, exhibits, literature, reprints and similar pieces of printed, audio or visual matter description of a drug and references published for use by medical practitioners, pharmacists or nurses, containing drug information supplied by the manufacturer, packer, or distributor which are disseminated by or on behalf of its manufacturer packer, or distributor (17). Misbranding of a product is considered when the labeling or advertising/promotion is alleged to be misleading. To determine this status, FDA takes into account the representations made (or suggested) by the statement, word, design, device, or any combination of the aforementioned. The FDA also considers the extent to which the labeling or the advertising/promotion fails to reveal facts that are material in light of such representations or material with respect to the consequences that could result from the use of the article to which the labeling or advertising/promotion relates under the conditions of use prescribed in the labeling and advertising/promotion or under such conditions of use as are customary or usual.
16. GENERAL FDA POLICIES FOR ADVERTISING AND PROMOTING DRUGS FDA has made it clear to pharmaceutical firms that all advertising and some promotional materials to be used for prescription drugs must be submitted routinely at the time of first
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use. The materials concerned include advertisements, detailing pieces, product brochures, price lists, audio-visual materials, and all other materials that fall into the category of advertising or promotional labeling. These requirements apply to the standard forms of marketing and advertising/promotion as well as newer methods, such as electronic advertising. When these submissions occur, the company concerned must use FDA Form 2253, entitled Transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human Use, and the name, title, and signature of the submitting official must be included. All such materials must be submitted to CDERs Division of Drug Marketing, Advertising and Communications. In order to expedite the review process, companies are required to submit referenced materials with all promotional materials in which the references are cited. DDMAC has issued notice of violation letters when firms batch several promotions for collectivesubmission after some or all of the materials have been disseminated.
17. PRECLEARANCE OF ADVERTISING AND LAUNCH MATERIALS Normally the routine submission of advertising/promotion of the drug is not required in advance of its being used. This applies as well to all direct-to-consumer advertising. However, FDA does specify that if information on the product is not widely known, if the medicine may cause fatalities or serious danger to patients, or if the company has been notified by CDER of a need to publicize such information and has not yet satisfactorily complied, then FDA requires prior approval of the advertising/promotion. In addition, there are two other situations in which preclearance of marketing and advertising/ promotion materials is required or strongly advisable, namely: 1. When it is believed that there has been a serious or repeated violation of FDA regulations 2. When a major new product is being introduced, in which case FDA generally requests that the initial
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marketing and advertising/promotion materials be submitted voluntarily
18. ITEMS FOR PRECLEARANCE FDA requests that, as preclearance items, the company concerned submit only those core materials that are representative of the launch campaign, i.e., the primary detail aid, the primary journal advertisement, introductory letters, and press releases. These should be submitted in their most final and complete form. It is recommended that the launch submission be forwarded to FDA when the labeling for the product is in the final or near-final state. FDA also requests that the submissions be accompanied by hard copies of all references cited and annotated and that the company concerned highlight the specific text supporting various elements of the promotional materials submitted for review. The review of launch materials is considered a high priority by FDA, and DDMACs review of the launch materials is considered a high priority. They are reviewed on a firstin, first-out basis, within 23 weeks of submission. It should be noted that DDMAC will accommodate requests for a rapid approval of certain time-sensitive advertising/promotion materials.
19. FAIR BALANCE Every advertisement must meet FDAs Fair Balance requirements (18), which means that FDA has mandated, through administrative authority, that interpretative risks associated with a product must be clearly identified to offset the benefits. This applies to all promotional materials, including advertisements (printed and electronic), detailing units, and public relations materials. In April 1994 CDER indicated that fair balance applies equally to the content and the format of promotional materials. It will consider both the representations that are made for the
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product as well as the extent to which the labeling or advertising/promotion fails to reveal material facts about potential consequences resulting from the products use. In other words, the plus (positive) aspects of the product must be in balance with the negative (adverse) aspects of its use. A companys compliance with this FDA fair balance provision varies depending on the nature (type) of promotional material. It also seems to ebb and flow in the extent of negative balance needed, dependent on FDA pressure. For example, the inclusion of the product package insert or the brief product summary meets some of the requirements of fair balance and is often used as fair balance, especially if the data or all of the products side effects and contraindications have a prominence and readability that is comparable to the effectiveness-related information that is presented. However, DDMAC has indicated that risk information that is placed in the footnotes and not in the body of the text of a promotional unit does not meet the requirements for fair balance if the benefit information is included in the main body of a promotional piece. The following are examples of situations in which fair balance is not followed: 1. Claims made comparing the product with another product without specific proof 2. Making claims that the product is safer or more effective than the labeling indicates 3. Misrepresenting a study or other information pertaining to the clinical data as it pertains to the product 4. Using product graphics in a misleading manner Examples of situations in which the promotional materials may be violative are: 1. 2. 3. 4. Using a study that is badly (poorly) designed Misrepresenting the statistical data Misusing the graphics for the product material Misrepresenting what is accepted as the products mechanism of action
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5.
Failing to provide a balanced emphasis of product side effects and contraindications 6. When appearing on multiple pages, failing to clarify where the products side effects and contraindications information appears 7. In the case of a multiple page advertisement, failing to refer readers to the products side effects and contraindications information if located on a different page
20. BRIEF SUMMARY OF PRODUCT INFORMATION When FDA required product information (PI) for all promotional material, the practical matter of cost to include the full PI in journal advertising became an issue. Journal advertising space is sold by the page. The need to add a one-, two-, or three-page PI to a one-page promotional message obviously would double, triple, or quadruple the cost of promoting a product by advertising in medical journals. Therefore, a practical solution was agreed upon. FDA found that the labeling contained in a journal ad would be in compliance if it contained an abbreviated product information summary. This usually could be contained in a column or a page encompassing a true (correct) statement of information that relates to the products side effects, warnings, precautions, contraindications and adverse reactions from the approved product package insert (19). 20.1. Wrap-Around Advertisements DDMAC further clarified in April 1994 that wrap-around advertisements, those presenting advertising copy in the front of a publication with the brief summary in the back, were not in compliance with brief summary requirements. It stated that the brief summary must appear adjacent to the advertisement (20) and that an ad appearing in the front and a brief summary in the back that is separated by the entire contents of the publication is not in compliance.
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20.2.
Electronic Advertisements
The above requirement also applies to electronic advertisements. Such ads or commercials must include major side effects and contraindications in either the audio or the audio and video portions of the presentation. A number of company violations have occurred in the establishment of rules for electronic advertisements. The companies concerned were issued a violation warning with a complete explanation of the extent to which FDA considered that the matter of fair balance was violated. The companies concerned then complied with the FDAs request to change or modify the advertisement/commercial. 20.3. Reference to the Product Generic Name
In the 1960s FDA regulated that the generic name of each product must be referenced in advertising/promotion for brand name drugs. The generic name must be cited, for example, the first time, or with the most prominent placement, on each page each time the brand name is featured. Also, the type size of the generic name, except where there are combinations of ingredients, must be at least half the type size of the brand name and must have prominence compared with that of the brand name. Many in the industry consider this matter to be more political than regulatory, especially in light of the efforts that have, and are continuing to be made to drive physician prescriptions and pharmacy dispensing to the usage of generic versus trademark drugs. 20.4. Reminder and Other Advertisements Exempt from the Brief Summary Requirement FDA has indicated that some advertisementsgenerally, prelaunch and reminder adsare exempt from the brief summary requirement. The ads are designed to call attention to the drug but do not include the product indications, dosage recommendations, or beneficial claims. But it should be noted that these ads are not permitted for products that carry any Black Box Warnings, which are imposed by FDA to highlight a particular major health issue involved in prescribing or using the product.
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Reminder advertisements in the past were commonly used for a product with a well-established brand name. These ads, like the prelaunch ads, are designed to call attention to the product name but cannot include product indications, if the product name is used, dosage recommendations, or beneficial claims. These FDA restrictions today make the use of reminder promotion virtually impossible. However, reminder ads for generic drugs that include representations of the bioequivalence of the products as compared to the brand name products are not considered reminder ads and must contain full disclosure information. Advertisements that focus exclusively on price are technically reminders and thus exempt from the brief summary requirements. Help-seeking advertisements are designed to inform the consumer of the symptoms of a particular condition, encouraging the consumer to see a health-care professional in order to discuss an appropriate treatment. This type of promotion is exempt from the brief summary requirement. However, such ads must not refer to a particular prescription product, imply that the product is the preferred treatment for the condition featured, or discuss any unique properties of the drug that allow for its identification. Bulk-sale drugs are exempt from carrying the brief summary if they are intended to be processed, manufactured, labeled, or repackaged in substantial quantities. Also, they must not contain any claims of safety or efficacy. Drugs sold to pharmacists for compounding are exempt from the brief summary requirement as long as they make no safety or efficacy claims.7
21. ADVERTISING/PROMOTION OF PRESCRIPTION DRUGS FOUND LESS THAN EFFECTIVE IN THE DRUG EFFICACY STUDY A major effort to require that all drugs be proven not only safe (as required under the 1938 law) but also effective was
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put into action when Congress in 1962 amended the FD&C Act to this effect. Based on this amendment, FDA decided that all drugs approved between 1938 and 1962 on the basis of safety alone should be evaluated on the basis of efficacy claims. This massive study was initially performed by panels of experts under the aegis of the National Academy of Sciences/ National Research Council (NAS/NRC). It became known as the Drug Efficacy Study, which placed indications for all reviewed drugs into one of the following six categories: 1. 2. 3. 4. 5. 6. Effective Probably effective Possibly effective Ineffective Ineffective as a fixed combination Effective but
As a result of this extensive review, hundreds of older medicine formulations were removed from the marketplace. Also, claims that were unproven were eliminated from drug labeling. The FDA regulations provide for disclosure in both labeling and advertising of the status of those drugs and indications that were found to be less than fully effective. The labeling for those drugs with indications found to be less than fully effective should carry a box statement as to this fact. Because there are relatively few medicines remaining with probably effective or possibly effective indications, this section of the regulations is seldom applied.
22. FDA ISSUES CONCERNING COMPANY EFFORTS TO PROMOTE PRESCRIPTION DRUGS There are a substantial number of issues concerning the FDA regulations for company advertising/promotion of prescription products, including company efforts regarding comparative advertising, price advertising, promotion of unapproved
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product indications, advertising for investigational and orphan products, and promoting to formularies. In order to understand these issues, each will be reviewed separately. 22.1. Comparative Advertising/Promotion and Claims of Superiority In general, FDA tends to discourage company marketing and advertising/promotion that compares specific products or makes claim of superiority of one product over another. However, in April 1994 CDER released a statement that set standards for claims that represent, suggest or imply that their products safety or effectiveness is comparable or superior to that of a competing product or products (21). But, with this proviso appeared the statement that such claims were then considered to be subject to the same standards of review as for efficacy and safety claims in a products approved labeling. A company that makes such claims must support them with substantial evidence or substantial clinical experience that supports the claims presented. CDER further stipulated that such a comparison must be derived from a well-controlled study that compares the products, head to head. The CDER statement indicated that effectiveness claims should be based on at least two adequate, well-controlled studies. Safety claims normally require direct comparisons between the products being compared. Also, there should be statistical clinical therapeutic significance between the products in the comparison. Another significant guideline in the CDERs statement is that both drugs being compared must have been approved for at least the same indications being compared and that the dosage regimens being compared must be consistent with the dosage recommendations in the approved labeling and in the same part of the dose range. Before the claim can be used in company advertising/ promotion, CDER prefers that the studies be reviewed by its medical reviewers. But CDER indicated that the data also can be submitted after the advertising/promotion claim appears. The matter of comparative advertising/promotion has thus been made quite clear from the FDAs regulatory perspective.
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22.2.
Price Advertising/Promotion
This is an area of product advertising/promotion that is not always well understood. Thus, the FDA has certain rules that set the conditions for a company using this marketing approach, namely: 1. 2. 3. That the only purpose of the promotion is to advertise price That the promotion states nothing about the products safety or efficacy That both the brand and generic names of the drug be contained in the promotion as well as its dosage strength for each ingredient That the promotion explains the charge for a specific product, strength, dosage form, and quantity That all product charges are included in the promoted price
4. 5.
This type of promotion also may include other information, such as the identification of professional services provided by the pharmacy or pharmaceutical company, as long as it is not false or misleading. If some pharmaceutical manufacturers advertise nationally that their drugs are less expensive than competing or similar products, but no specific price is indicated, the promotion is not considered to be traditional price advertising. 22.3. Promotion of Unapproved Product Indications The main concern of the FDA regarding marketing and advertising/promotion is the promotion of unapproved uses for marketed drugs. It is the agencys contention that such promotion has the greatest potential to damage public health because it encourages patients to seek, and doctors to prescribe, products for indications that have not been approved by FDA. Another major concern to FDA is the promotion of products during the preapproval stage. This is a period during which opinions are being formed by clinicians as to the potential range of
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usefulness (i.e., the extent of indications for the product) for the product being evaluated. Once this product is approved, it becomes difficult for physicians to limit their prescribing of the product only for approved indications if, in fact, they are under the impression that the drug is useful for other purposes due to the preapproval promotion for the product. The FDA has indicated that an unapproved product or use can be promoted at independent scientific symposia and scientific exhibits. But the materials developed from the symposia may not be used in preapproval promotion campaigns. 22.4. Advertising for Investigational Products FDA specifically prohibits any claims of safety or efficacy for the product being researched, or any claims that the product is equivalent or superior to anothersuch claims would violate FDA regulations concerning promotion of investigational drugs (22). An FDA policy on the subject explains that Institutional Review Boards (IRBs) are responsible for reviewing how research subjects are selected. It also indicates that the clinical investigators may use advertising to attract research subjects, but an IRB should approve such advertising. FDA considers the IRB review to be necessary in order to ensure that the request for participants is not misleading to subjects, especially in those circumstances in which a study will involve persons with acute or severe physical or mental illness or persons who are economically or educationally disadvantaged. 22.5. Promoting to Formularies Due to the industrys increasing promotion to managed care groups, hospitals, and formularies, FDA presented a guidance concerning the promotion of products to drug formularies. FDA indicated that it considers all formulary informational material or kits to be promotional labeling. As such, the formulary informational kits are considered by FDA to be any materials prepared for review by pharmaceutic and therapeutic committees, etc., that review a regulated product and are prepared for and disseminated to hospitals, managed health-care
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organizations, buying groups, and other institutions. However, formulary informational material kits are exempt from the FDA submission requirement if they are prepared in response to unsolicited requests for information. In addition, Under the FDA Modernization Act of 1997, pharmacoeconomic information provided to a formulary committee will not be considered false or misleading if the information directly relates to an approved indication for the drug and is based on competent and reliable scientific evidence (23).
23.
DIRECT-TO-CONSUMER ADVERTISING
Direct-to-consumer (DTC) advertising has had an immense impact on the increased prescription of drugs. Many consider DTC advertising to be a prime mover in increasing the volume of drugs used in the United States. In a study conducted by the National Institute for Health Care Management, it was reported that the increases in sales for the 50 drugs that were most heavily advertised to consumers accounted for almost half of the multibillion dollar increase in drug spending (24). DTC advertising seems almost like the genie that regulatory groups find a need to contain. FDA has been opposed to DTC advertising of prescription drugs since its inception but DTC advertising remains legal as long as it fully complies with all of the FDA regulations applicable to prescription drug advertising and any relevant laws or regulations enforced by other federal authorities, such as the FTC. According to FDA, DTC advertising consists of any materials that are intended by the manufacturer to be seen or used by a consumer, such as traditional product print and electronic advertisements, computer e-mails or websites, videotapes, cassettes, pamphlets, brochures, and other printed materials. Because of FDAs earlier negative attitude to DTC advertising, it was not expected that this promotional medium would thrive. However, the future of DTC advertising was changed in 1982 when FDA Commissioner Albert Hull Hayes, Jr. predicted that this country may be on the brink of the exponential
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growth . . . of direct-to-consumer promotion of prescription products (25). After seeking a voluntary moratorium on DTC advertising in 1983, the moratorium was lifted by FDA in 1985. Though it did not encourage DTC advertising, FDA permitted such advertising as long as it met all the requirements of the labeling and advertising requirements. Of interest is the fact that the initial results from an FDA 2002 consumer survey, released at the April 2002 DTC National Conference in Boston, appear to justify continued FDA support for DTC advertising. Eighty-one percent of the consumers surveyed by FDA indicated that they had seen a drug ad in the past 3 months (26). Even former FDA Commissioner David Kessler, who spent years at the FDA rejecting staff requests that he allow regulations to be changed to permit DTC advertising, admitted that he was wrong in adhering to that position (27). However, U.S. physicians continue to indicate that they do not like DTC advertising by pharmaceutical companies. More than 46% of the physicians surveyed stated that DTC advertising negatively affects their impression of the drug companies that sponsor this promotion. Contrary to these findings, the sixth biennial Scott-Levin Pharmaceutical Company Image 2002 study showed that DTC-promoting companies enjoy high esteem by physicians (28).
24. FDA POLICY ON DTC ADVERTISING The following provides general guidelines to DTC advertising as provided by FDA: 1. Those DTC ads that meet the requirements of reminder and/or help-seeking promotions can be sponsored by pharmaceutical companies. But such ads should be designed to be educational rather than promotional and deliver the basic message to see your doctor. 2. Those ads that mention specific products are allowed, but must meet every condition that applies to
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3.
4.
5.
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prescription drug advertising directed at physicians. This includes the appearance of information that is contained in the product package insert. A fair balance of product information is expected. Those DTC ads that have been defined to include materials, such as product brochures, that may also be regarded as labeling may be voluntarily submitted to FDA for clearance in advance of their use. Though FDA may clear a voluntarily submitted DTC advertisement, the agency may take regulatory action following the ads appearance if it considers it to be misleading in some manner. DTC ads or other promotional materials must not indicate that only physicians can prescribe prescription drugs, because there are many instances in which nurse practitioners and physician assistants may also prescribe such drugs. The FDA, whose officers continue to object to DTC advertising in principle, expresses concern over broadcast DTC ads. Those broadcast advertisements that include a major statement of the drugs critical risk information, present all of the products indications and contraindications in consumerfriendly language, and are not false or misleading may fulfill the FDAs adequate provision requirements (29).
What the FDA guidance outlines is a single method of adequate information provision, namely: 1. A toll-free telephone number. This should provide the consumer with several options, such as: the full package insert mailed to them, the full package labeling sent over Internet electronic media. Each should be provided to the consumer in a timely manner. 2. Reference to a print ad or brochures that are publicly available. 3. A statement that indicates that physicians and/or pharmacists may serve as another source of information.
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4.
An address on the Internet that directs consumers to the approved package labeling.
The FDA mechanisms described will satisfy this adequate information provision requirement, but pharmaceutical companies may use an alternative approach if it satisfies the regulatory requirements.
25. ADVERTISING ON THE INTERNET The growth of consumer interest in health-care information on the Internet has been phenomenal. Even a few years ago, some 70 million Americans searched the web for information on such subjects as diseases, nutrition, pharmaceuticals, and related topics, and this use is growing (30). Now consumers can obtain more information from the Internet about drugs than they can get from their health providers. As a result, pharmaceutical companies have substantially increased their use of the Internet as a vehicle for marketing to consumers and the medical profession. The interest of physicians in health information on the Internet seems to be moving hand-in-hand with that of consumers who view their respective physicians as the most valuable source of this information. A recent study indicates that physician demand for e-detailing is significant and growing: Eighty-one percent of the physicians surveyed think its a good idea to have access to this type of information when and where it is convenient (31). It must also be pointed out that many companies provide physician monetary honorariums for the time spent by physicians during e-detailing. Because of the extremely rapid growth of consumer and physician interest in health information on the Internet plus the growing use of this vehicle for marketing promotion by the pharmaceutical industry, DDMAC has been designated to serve as an agency-wide working group to draft policy on marketing and advertising/promotion on the Internet (32). Thus, FDA will issue a document that provides the drug companies with this guidance in the near future.
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26.
NONTRADITIONAL PROMOTIONFDA POLICIES
For a substantial number of years, pharmaceutical firms advertised and promoted their products primarily through journal advertising, direct mail, detailing by sales representatives sampling, and hospital exhibits. However, due to the advent of newer communications technologies, an increased level of consumers of health care, and greater competition within the industry, many new ways to promote products have been considered and adopted (33). These newer methods of product promotion include: medical symposia, public relations techniques, greater use of single-sponsor publications, an increased use of electronic media, plus responses to unsolicited requests for promotional information. As a result, FDA has adapted existing, traditional policies to cover these new communications vehicles. Such FDA policies on nontraditional promotion are not written in a single document but, rather, are learned and understood by the regulated industry through various means, such as Warning Letters, policy announcements, the issuance of guidance documents, or by similar means. Fairness in dealing with these issues has been the FDA policy. These policies are briefly explored in the following. 26.1. Educational and Scientific Events
FDAs final guidance on industry-sponsored scientific and educational activities was issued in December 1997. This applies to all FDA-regulated medical products, including prescription medicines. Essentially, this FDA policy states that all such activities that are controlled or substantially influenced by companies must meet all of the traditional FDA requirements for marketing and advertising/promotion labeling, such as full disclosure and fair balance (34). What has concerned the FDA about company-sponsored activities is that the companies may influence the content of educational programs by being involved in the selection of speakers and the direction of the content of the activities.
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FDA also indicated that it would focus intense scrutiny on any discussion of unapproved uses of marketed products. In an earlier guidance, DDMAC stated that materials developed from symposia could not be used in preapproval promotion campaigns. DDMAC also noted that, in conducting scientific exhibits, the information about unapproved drugs can be displayed if the exhibit is clearly separated from commercial exhibit areas, are staffed by scientific personnel only, and have no commercial materials for distribution. Concerning the dissemination of scientific reprints, DDMAC indicated that pharmaceutical companies may distribute an article about an approved product as long as its principal focus is on FDA-approved uses or indications and is published in a reputable peer-review journal. In all of those instances, the companies must use promotion information in the reference text that is consistent with the products approved labeling. 26.2. Public Relations Materials FDA considers product-specific public relations materials as labeling if it is included in press releases, kits, or backgrounders and used with the media. It thus requires that all such materials be fairly balanced, containing both the positive findings and uses of the product plus a fair representation of the warnings, side effects, and common adverse reactions associated with the products use. FDA has no formal requirement that public relations material for drugs be submitted to the agency for review. However, if a significant drug is about to be approved by FDA, the agency often requests the materials for review. If the pharmaceutical company concerned decides to ignore the agencys comments on the materials, it does so at its own risk. When a company plans to make a major public announcement about a drug, it is normally a good idea for the company to provide the press materials to the FDA Office of Public Affairs, plus the appropriate office within CDER (35).
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26.3.
Drug Sampling
The use of samples as an effective part of the marketing/promotion effort has become a point of contention in recent years and deserves each companys close attention relative to effective promotion versus violations of intended use in promotion. The use of drug samples to physicians by company sales representatives, or through the mail, is controlled by the Prescription Drug Marketing Act of 1987 (PDMA). Under PDMA, physicians must request samples in writing and include the name, address, professional designation, and signature of the practitioner who makes the request. The identity and quantity of the sample requested must also be provided, plus the name of the manufacturer and the date (36). This law was passed in order to correct alleged abuses such as diverting the samples into channels where the drug could be sold. FDA has indicated that decades of sampling abuses have resulted in the sale of misbranded, expired, and adulterated pharmaceuticals to consumers. The matter of sample abuse in promotion has become such an urgent issue to the FDA that in the October 3, 2002, issue of the Federal Register, the Office of the Inspector General (OIG), Department of Health and Human Services stated: The provision of drug samples is a widespread industry practice that can benefit patients, but can also be an area of potential risk to the pharmaceutical manufacturer . . . PDMA. . . . The Prescription Drug Marketing Act of 1987 governs the distribution of samples and forbids their sale. A drug sample . . . is intended to promote the sale of the drug (37). A case in point was the situation in which the FDAs Office of Criminal Investigation and other law enforcement agencies charged a former pharmaceutical sales representative with failing to comply with federal regulations governing distribution of free drug samples to physicians. The sales representative allegedly provided samples of a steroid product used in the treatment of prostate cancer to urologists who had not provided a written request for the samples as required by law. Apparently, the sales representative was
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instructed by the district manager and other company officials to use the samples as a tool to help obtain sales of the drug (38). This issue is so critical that all drug manufacturers have been urged by their trade associations to closely follow PDMA requirements including all documentation that is required. The Pharmaceutical Research and Manufacturers Association (PhRMA), in the July 1, 2002, New Marketing Code indicated that product samples should be provided for patient use in accordance with the Prescription Drug Marketing Act. It is quite clear to marketing executives that product samples are designed as an integral part of promotion to physicians, to be used as starters for patients being treated. The industry is in full agreement that abusive uses of product samples should never be tolerated. However, the current usage of samples, as mandated by FDA, has substantially increased sampling costs as part of the marketing budget for promoting each product. And yet there do not appear to be any controls on how the physicians (who request samples) actually use the product samples. It is likely that sample distribution by pharmaceutical companies and sampling dispensing to patients by doctors will be clearly maintained and new laws/guidelines to previous abuses will be passed. 26.4. Single-Sponsor Publications Because the FDA regulates only materials sponsored by FDA-regulated companies, there is a question about whether or not publications by independent publishers can be regulated, regardless of company influence (41). There has been much controversy and misunderstanding concerning single-sponsor publications financed by pharmaceutical firms because these publications often involve parties, such as organizations that sponsor continuing medical education programs, or medical journals that publish these documents as supplements. Single-sponsor publications, including product monographs, are closely monitored by the CDER because there
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is the potential that such publications can be clearly influenced by companies that want to promote unapproved product indications. In general, FDA regards the publication as labeling, and thus the publication must accurately portray the uses of the drug concerned and provide the traditional fair balance. In other words, FDA believes that simply because a medical journal or other commercial publication is involved in a singlesponsor publication, the sponsoring company is not relieved of regulatory responsibility. 26.5. Company Representatives Drug-Detailing Activities This is most companies strongest form of promotion and one that is always under the focus of FDA. FDA considers all of the materials utilized by drug sales representatives as subject to the advertising/promotion regulations. Therefore, during a products preapproval stage, sales representatives may not provide physicians with materials about product indications or information that is not yet approved. Often the question arises as to whether or not drug sales representatives are permitted to provide physicians with published clinical studies that appear in peer-approved medical journals. The FDAs position is that if it concerns an approved indication for the product, it can be provided to the medical profession. However, if an unapproved product indication is discussed in the article (i.e., for a marketed product or during the preapproved stage), the article may not be given to physicians at that time. An exception to this position would be the instance in which the physician requests the article from the representative. It may then be provided, but FDA prefers that such requests be handled by the medical department of the company concerned. Verbal statements made by sales representatives to physicians about their products are also subject to FDA regulation but are virtually impossible for the FDA to monitor. An enforcement action by the FDA against a drug company in this area has not occurred.
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26.6. Exhibits Exhibits for drugs at medical meetings and conventions have become an increasingly popular part of the products/companys overall promotion efforts. Thus, FDA considers all such materials used at these medical meetings to be subject to all of the marketing and advertising/promotion regulations for prescription drugs. Even the text of materials that are displayed at exhibits must meet FDA advertising/promotion regulations. Because of FDA oversight, pharmaceutical companies need to pay as close attention to exhibit materials as they do to other regulated materials, such as print advertisements. Exhibits that present drugs during the preapproval stage will be considered violative by FDA if the materials mention a specific product indication. The same would apply to an exhibit that mentioned an unapproved indication for an approved drug. The pharmaceutical industry also has been reminded by FDA that all text for program books used at professional meetings must meet pharmaceutical advertising regulations for full disclosure if the company descriptions contain information about the drug indications or usage. 26.7. Responding to Requests for Information Generally, DDMAC has assured the industry that their individual, nonpromotional responses to unsolicited requests for information will not be considered promotional labeling if each firm maintains documentation concerning the nature of the requests and shows no pattern that suggests that these requests were solicited by the sponsor (i.e., the firm). DDMAC further notes that the use of toll-free telephone numbers disclosed in promotional labeling or advertising, which invite or somehow prompt requests for information, are considered to be forms of solicitation and thus are subject to all advertising and labeling requirements. 26.8. FDA Policies for Broadcast Media The informal FDA policy regarding the use of broadcast media in promotion is one guidance provided to the industry.
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If changes in broadcast advertising are required, FDA notifies the companies directly by letter and, subsequently, releases the changes required to the trade press. When it was decided that all video new releases should be routinely submitted to FDA at the time of first use, this change in policy was communicated directly in a letter to all holders of approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs). This information was also provided to the trade press for dissemination. 26.9. FDA Criteria for Advertising Electronically
Policies were developed by FDA, over a number of years, concerning physician-oriented television advertising that is product specific. Such advertising, now, must refer, in the advertisement, to the page in the Physicians Desk Reference (PDR) or PDR Supplement that contains full product prescribing information. The network concerned must also provide a toll-free telephone number that the viewers can call to hear a reading of the brief summary package insert for the product. In addition, FDA requires that the product generic name must be used in the ad and that fair balance must be included in the body of the advertisement, including major product warnings, side effects, adverse reactions, etc. Further, for products required to carry special warnings (i.e., PI Back Box Warnings), information must be provided in the audio portion of the ad. The FDA was concerned that physicians not receive confusing or contradictory messages in any video broadcast advertisements that might obscure or undermine important product warning information (40). 26.10. FDA Policy on Video News Releases Health-related stories on television are among the most compelling subjects for the TV viewers and, as such, are attractive to pharmaceutical companies via video news releases (VNRs). VNRs can be used by TV stations in a manner that makes them seem to be original segments produced by the TV stations. A variant, called a B-roll, is a video that contains raw footage of the manufacturing process, interviews, animations, or other
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information but not put together in a finished news segment form. Though specific rules for VNRs have not been set forth, FDA did issue a letter to all holders of NDAs and ANDAs that they submit the following when the VNR is product oriented: 1. 2. 3. The VNR source or sponsor should be made clear to the TV station. All product information or references should be within the approved labeling for the product. When a specific product is mentioned, there should be a fair balance. In other words, the major warnings, adverse reactions, and side effects related to the product should be mentioned. Normally, a product package insert should accompany the VNR. If the VNR is sent by satellite, a scroll of the package insert should be included. For a product that is the subject of an NDA or ANDA, the VNR should be submitted to CDER when it is initially issued or disseminated. This includes accompanying information issued at the same time, i.e., letters, scripts, press releases, and package inserts (41).
4.
5.
Though there has been some controversy over the use of VNRs, Pharmaceutical companies . . . have become enamored with the VNR because it allows them to circumvent the usual restrictions concerning the use of television advertising to promote their prescription products directly to the consumer (42). However, FDA has treated VNRs the same as it treats written press releases. The VNR is treated as labeling when specific products are mentioned and requires fair balance, discussing not just the product benefits, but also the major risks of the drug. 26.11. Infomercials Infomercials are extended advertisements used on commercial and cable television. They may appear in the format of an
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entertainment or television show and have not been commonly used to promote prescription medicines to consumers. Though the FDA does not have a specific written policy on infomercials, they are regarded as advertisements that are subject to established advertising and labeling regulations. To the extent that an infomercial mentions a drug or treatment, it must meet all disclosure and fair balance requirements. 26.12. Radio-Television Media Tours and the Use of Celebrities When a pharmaceutical firm sponsors a radio-television interview tour, FDA considers any product-specific content of the interview to be subject to regulations. This applies even if the spokesman concerned is not employed by the pharmaceutical firm. It has been especially concerned when celebrities appear on such tours. Though there are no FDA regulations prohibiting either the use of celebrities to endorse prescription drugs or the use of radio-TV tours with paid spokespeople, its expressed concern has served to discourage the use of celebrities and product-specific radio-TV tours in general. FDA believes that firms that hire spokespersons, or use their employees in this role, should train them to keep their promotional statements in line with the products approved labeling or to provide the perspective necessary to assure fair balance for the product. 26.13. Guidelines for Advertising to Physicians on Radio Concerning the advertising of prescription drugs on radio, FDA does not object as long as the product advertisements contain clear information about the products side effects and contraindications and provide a balanced presentation of the benefits as well as the risks of the drugs promoted. 26.14. Telephone Advertising Communications by telephone that discuss prescription medicines are considered by FDA to be subject to the same requirements as for broadcast advertising. Those pharmaceutical
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firms that decide to disseminate product information to healthcare professionals or consumers via a toll-free telephone number must include a major statement that provides information about product side effects, warnings, precautions and contraindications before the listener can branch off to other segments of the telephone presentation. Just as with all prescription medicine advertisements, copies of the telephone recordings and scripts must be submitted to DDMAC at the time of initial use.
27. CHANGING IMPACT OF FDA CONTROLS Though the FDA was charged with the responsibility to regulate drug promotion throughout the years of its existence, it began to exert strong enforcement of the requlations in the late 1980s. It had an especially strong concern about the level of misleading promotion. This level of concern has focused on what the FDA considers exaggerations of claims, especially newly approved claims. For example, a pharmaceutical corporation was strongly warned by DDMAC concerning its cholesterol-lowering product DTC ad that appeared in major magazines and mistakenly suggested that this product lacked the side effects of other members of the same class. DDMAC stated a concern about a continuing pattern and practice of violative behavior. The company pulled the misleading ad. Several other pharmaceutical companies have been forced to correct promotions considered to be misleading by DDMAC (43). Increased pressure continues on FDA from external groups, while the U.S. Congress has and continues to exert significant pressure on the FDA to strictly enforce marketing and advertising/promotion regulations. Of added significance, the Office of Inspector General, in a new HHS draft guidance published in the October 3, 2002, Federal Register (44), indicated that drug companies should expect prosecution or other action if they do not change some of the ways that they market prescription drugs, including the
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giving of gifts, grants, and scholarships to physicians and health-care providers in exchange for help in promoting their products. The OIG went to the extent of strongly recommending that pharmaceutical manufacturers should designate a compliance officer to serve as the point person to oversee these compliance activities. Throughout all of its regulating activities over the years, FDA has expressed concern that there should always be a fair balance in a companys claims for the efficacy of its products and its indication of the potential adverse reactions associated with each products usage. This applies to product labels, brochures, booklets, ads, mailing pieces, etc. It has appeared that the FDA would like to increase its regulatory authority, but potential future trends may put some limits on its ambitions in this regard.
28. POSSIBLE FUTURE FDA REGULATORY ACTIVITIES It is doubtful that many would challenge the benefits associated with FDAs efforts, over the years, to determine that drug manufacturers, in their efforts to market and promote their products, present to the health profession and the consumer a fair balance as to the efficacy and relative safety of their respective products. FDA controls and surveillances in this area have increased year by year, and the overall impact of FDA on drug companies marketing and advertising/promotion activities will continue in the future. However, recent happenings have begun to slow the overall regulatory efforts of the FDA relative to drug marketing and advertising/ promotion activities. In November 2001, the Bush administrations new leadership in the Department of Health and Human Services released an unprecedented directive that the FDAs warning and untitled letters to the pharmaceutical industry must first be cleared with the new FDA chief counsel, Daniel E. Troy. This was implemented because there were so many people
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and offices that could issue Warning Letters that they had lost their overall desired impact on the industry (45). Much concern has been brought forth that the directive would have a chilling effect on the FDAs watchdog activities. The HHS, however, indicated that it is expecting the FDA, as a result of the directive, to set forth priorities and enforce those priorities with a much improved effectiveness for their Warning Letters. Another development that has truly shaken the FDA is the Supreme Court Ruling in Western States v. Shalala, which endorsed the lower courts criticisms of the FDA culture. Basically, it said that the FDAs DDMAC . . . had no business, even with encouragement from the FDA Modernization Act of 1997, trying to curb the free speech of compounding pharmacists advertising their services (46). Several legal decisions have indicated that the FDA has been too accustomed to getting its own way in challenging hundreds of industry ads and other promotional pieces and has not paid enough deference to the First Amendment. Shaken by these decisions, FDA has begun to seek input from the public as to how it should balance statutory responsibilities with First Amendment obligations. Some of the input sought is whether certain promotional speeches about medicines is inherently misleading unless it complies with FDA requirements; whether its current DTC advertising policy is consistent with the effects of such ads or leads to overprescribing; whether product disclaimers should have the same type size as its claims; and whether off-label promotions undermine the approval authority of the FDA. Meanwhile, FDAs old guard has started to argue, internally, that the Supreme Court decision threatens its control over what is said about product effectiveness, thus allowing broadened product claims. However, a positive move by FDA has already taken place. The CDER released an article entitled Think It Through: A Guide to Managing the Benefits and Risks of Medicines, which reminds consumers of the benefits and risks associated with different drugs and provides helpful tips designed to minimize the potential risk of drug use (47).
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FDA is quite concerned that its authority will be undermined . . . if unapproved products can be promoted, or new uses of approved products can be promoted without FDA approval because it believes that neither consumers or physicians can properly evaluate information about what are extremely complex products that it regulates (48). However, the courts believe that, if a drug is lawfully marketed following its initial approval, physicians can legally prescribe products for off-label uses as they have access to the information on those uses. How this matter will ultimately be resolved is not at all clear. FDA must follow the mood of the courts, but the pharmaceutical industry has lost some of its luster due to pricing disclosures, some related scandals, and the general public disenchantment with overall corporate ethics. FDA will likely relax its regulatory activities, but should some health accidents occur due to the decision of the courts, then the regulatory pendulum will, undoubtedly, swing back in the agencys direction. Only time will tell if and what regulatory changes will occur and the degree to which FDAs regulatory controls of drug marketing and advertising/promotion will increase.
REFERENCES
1. Chronology of Drug Regulation in the United States: US FDA, Center for Drug Evaluation and Researchs, www.fda.gov/ CDER/about/history.htm. 2002, p. 1. Ibid, p. 4. Patrick, W., Know Your GovernmentThe Food and Drug Administration, Chelsea House Publishers, 1988, p. 16. Chronology of drug regulation in the United States: U.S. FDA, Center for Drug Evaluation and Research, www.fda.gov/CDER/ about/history.htm, 2000, p. 7. Ibid, p. 10. Ibid, p. 12.
2. 3. 4.
5. 6.
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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
FDA advertising and marketing promotion manual, June 1998, p. 5. Ibid, pp. 1314. FDA advertising and marketing promotion manual, October 1999, p. 21. FDA advertising and marketing promotion manual, October 1993, p. 15. FDA advertising and marketing promotion manual, March 1997, p. 23. Ibid, p. 25. Ibid, p. 29. FDA advertising and marketing promotion manual, May 1993, p. 39. Ibid, p. 7. Ibid, p. 7. Ibid, pp. 78. FDA advertising and marketing promotion manual, May 1997, p. 17. FDA advertising and marketing promotion manual, September 1997, p. 19. Ibid, pp. 1920. FDA advertising and marketing promotion manual, August 1994, p. 33. FDA advertising and marketing promotion manual, August 1997, p. 35. FDA advertising and marketing promotion manual, March 1998, p. 39. Liebman, M., Drug industry is a winner, Medical Marketing & Media, January 2002, p. 50. FDA advertising and marketing promotion manual, November 1997, p. 46. Dickinson, J., DTC ReportFDA Survey Data Supports DTC, June 2002, p. 32.
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27. 28. 29. 30. 31.
Ibid, p. 32. Dickinson, J., DTC Reportphysicians turned off by DTC ad, Medical Marketing & Media, September 2002, p. 40. FDA advertising and marketing promotion manual, November 1997, p. 48. Mack, J., You have a brochure on the web. Now what? Pharmaceutical Executive Supplement, March 2000, pp. 1618. Dickinson, J., DTC reportE-detailing gaining acceptance among physicians, Medical Marketing & Media, September 2002, p. 10. FDA advertising and marketing promotion manual, March 1998, p. 40. Ibid, p. 55. Ibid, pp. 5556. FDA advertising and marketing promotion manual, December 1996, p. 59. Ibid, pp. 6263. Federal Register, Vol. 67, No. 192, October 3, 2002, Notices, 62063. FDA charges TAP sales rep., Medical Marketing & Media, September 2002, p. 31. FDA advertising and marketing promotion manual, December 1996, p. 61. FDA advertising and marketing promotion manual, November 1996, p. 72. Ibid, p. 73. Ibid, p. 74. Liebman, M., Industry updateFDA keeps up the pressure, issues repeat ad warnings, Medical Marketing & Media, October 2002, p. 18. Federal Register, Vol. 67, No. 192, October 3, 2002, Notices, 62063.
32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.
44.
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45. 46. 47. 48.
Dickinson, J., As I see itBush reviews FDA letters to industry, Medical Marketing & Media, January 2002, p. 14. Dickinson, J., As I see itSupreme Court trims DDMACs, Medical Marketing & Media, July 2002, p. 14. FDA advises on drug benefits, risks, Medical Marketing & Media, October 2002, p. 32. Castagnoli, W., Rx marketing regulations hang on first amendment debate, Medical Marketing & Media, September 2002, p. 88.
21
Approval and Marketing of Nonprescription or OTC Human Drugs
WILLIAM J. MEAD Consultant Rowayton, Connecticut, U.S.A.
1. DEFINITION OF OVER-THE-COUNTER DRUG PRODUCTS Prior to the advent of the 1938 Food, Drug and Cosmetic Act (FD&C Act), technically all drugs could be marketed without a prescription. After passage of the Act, the U.S. Food and Drug Administration (FDA) decided on a case-by-case basis which drugs were to be considered prescription only and which could be sold over the counter (OTC), since the FD&C Act was silent on this matter. The usual key criterion used in
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this decision-making process was whether or not adequate directions for safe use existed for the products in question. The 1951 the Durham-Humphrey amendments to the FD&C Act addressed this issue head-on for the first time in what is now Section 503(b)(1) of the Act, saying that a drug requires a prescription if (a) it is one of certain habitforming drugs, (b) it is not safe for use except under competent professional supervision due to its toxicity, potential harmful effects, or method of use, or (c) it is specifically limited to prescription status by an approved New Drug Application (NDA). Thus, drug products (except as specified above) are nonprescription unless they require the supervision of a licensed practitioner for safe use. In other words, prescription status is by exception: if a drug product can be OTC, it must be OTC. It is obviously the second of the above categories that usually determines whether a drug should be considered for OTC status. FDA has a mandate from Congress to protect the public health (1). FDA also has the responsibility for publishing regulations or policy guidances to implement what the FD&C Act requires, including standards for safety, effectiveness, benefit/risk considerations, and labeling for OTC products. These standards now appear in x330.10(a)(4) of Title 21 of the Code of Federal Regulations. It is largely up to the judgment of FDA whether a drug product meets these standards. Safety for OTC use means a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use, as well as low potential for harm, which may result from abuse under conditions of widespread availability. Effectiveness means a reasonable expectation that when the drug is used by consumers with adequate directions and warnings, the product will provide clinically significant relief of the type claimed in the labeling for a significant proportion of the consumers who use it. The benefit-to-risk ratio takes into account the benefits provided by the product versus the risks or safety problems that may be involved with its use. FDA recognizes that while no drug can be considered totally safe, an OTC product must have sufficient benefits to justify whatever risks are likely to be connected with its proper use.
Nonprescription or OTC Human Drugs
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The labeling of OTC drug products must be clear and understandable and must be truthful in all respects without being false or misleading in any particular. The labeling must contain adequate directions for proper use as well as warnings against unsafe use, side effects, and adverse reactions. These must be in terms that make them likely to be read and understood by ordinary individuals (including individuals with low comprehension), under customary conditions of purchase and use. Label comprehension studies typically constitute an important facet of the decisions involved in allowing drug products to be sold without a prescription. The essential goal is to provide information to enable consumers to safely selfmedicate without the intervention of a health professional. It is assumed that the consuming public can recognize and self-diagnose the conditions being treated and can also satisfactorily manage self-treatment without medical supervision. This is usually relatively simple in that most OTCs are aimed simply at treating readily recognizable symptoms of minor discomfort, illness, or injury, such as itching, upset stomach, headache or muscle pain, or cold symptoms. Moreover, the use of an OTC drug does not necessarily mean that medical professionals are totally out of the picture, as it is not unusual for the initial diagnosis of the condition to be made by a physician. An example is vaginal yeast infections, not infrequently first diagnosed by a health-care professional and then self-medicated with an OTC product.
2. REASONS FOR INTEREST IN NONPRESCRIPTION DRUGS From the consumers point of view, there are definite motivations to use OTCs when such exist as an alternative to prescription drugs. Importantly, there is usually a significant monetary advantage to the consumer since OTCs are considerably less expensive than prescription drugs. Studies conducted for the trade association for health-care product manufacturers have confirmed the substantial savings for
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consumers through the use of nonprescription medicines (2). Moreover, the convenience factor, less lost work time, and the costs saved by not needing to visit a doctor are important considerations. The expanding availability of OTC drugs is also a particular boon to low-income and uninsured people (3). There is a growing sophistication and self-reliance among consumers, with increasing interest in and knowledge about appropriate self-medication. Health-related issues get considerable media attention these days, so that consumers today tend to be considerably more aware of the appropriate avenues of self-treatment than in previous times. Moreover, many other countries also allow certain drug products to be sold OTC that are presently marketed on a prescription-only basis in the United States, which necessarily puts some pressure on considerations of domestic prescription-to-OTC switch initiatives (4). Older adults in particular tend to experience increased minor medical problems, such as arthritis, sleeping difficulties, muscle aches and pains, headaches and colds, so that as the population ages, the demand for nonprescription drugs is escalating (5). From the manufacturers point of view, the increased sales of nonprescription medicines have tended to enhance corporate revenue and profitability. Moreover, as older prescription drugs are losing patent protection, at least some of the lost revenue can be recouped by offering OTC versions of the products through life-cycle product management. In other words, nonprescription drug products can be good business for the manufacturer. From the health professionals point of view, particularly in this age of managed care where medical practitioners often have an increased patient load, individuals with minor ailments and certain chronic conditions (e.g., migraines, vaginal yeast infections, allergies, etc.) can often handle their own care through responsible self-medication with OTCs, giving the health professionals additional time and availability for attending to more serious medical cases. Companies offering healthcare insurance encourage OTC self-medication by patients as a cost-containment strategy to reduce the more costly compensation of higher priced prescription products (6).
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Actual use studies of switched products indicate that consumers do use OTCs carefully and responsibly. Most do read and understand the information on OTC labels and are alert to the possible signs of tampering (7). Research has also indicated that OTC advertising does not exacerbate the problem of drug abuse as was once feared might be the case (8). Therefore, there are essentially no negative aspects to the current emphasis on the increased use of nonprescription drugs, provided the products meet the safety and effectiveness criteria for OTCness (9). Thus, from all points of viewconsumers, drug manufacturers, health-care professionals, and medical insurance carriersthere is indeed a growing interest in OTC drugs.
3. ROUTES TO FDA APPROVAL OF OTCs 3.1. The OTC Review The 1938 FD&C Act for the first time required premarketing approval of any drug product meeting the Acts definition of a new drug. But, prior to the 1962 Kefauver-Harris amendments, it was only necessary to establish the safety of drug products (prescription or OTC), not the efficacy. When the efficacy requirement was added, all drug products (existing items as well as new products) were required to be proved effective. This was, of course, a tremendous task facing FDA. At that point in time there were literally hundreds of thousands of drug products on the market that had to be retroactively evaluated. Obviously FDA had to prioritize determining which products were indeed effective. In 1968 they established what was called the Drug Efficacy Study Implementation (DESI) to establish the effectiveness of those products originally marketed under approved New Drug Applications (NDAs) between the time of passage of the 1938 Act and the 1962 amendments. Lacking the staff and facilities to undertake this, FDA contracted the task to the National Academy of Sciences/National Research Council (NAS-NRC) to study data submitted by manufacturers as well as published literature, and then to make recommendations to FDA. This was accomplished by class or
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therapeutic category, using panels of experts. FDA then made the final decisions as to which products were and which were not considered to be sufficiently effective. Those failing to pass muster were ordered removed from the market. In many instances, manufacturers of products deemed not efficacious strongly disagreed, resulting in considerable litigation. While most of the products in the DESI review were prescription drugs, more than 400 OTC products for which there were approved NDAs were considered. The final DESI conclusions on those OTCs appeared in the Federal Register of April 20, 1972. Following the DESI review, FDA was faced with a similar retrospective review of literally hundreds of thousands of existing OTC drugs for which NDAs had never been submitted. While the 1962 amendments required such a review, they did not specify any procedures nor timetables for doing so. There was consideration of reviewing each product individually, but due to the immensity of the task it was decided to work instead by category. The outline of the procedures was published in the Federal Register of January 5, 1972, with the final details spelled out in the Federal Register of May 11, 1972. The process set forth the conditions under which OTC drugs would be considered to be generally recognized as safe and effective (GRAS/E) as defined in Section 505 of the Act, and not misbranded. This included labeling that would be neither false nor misleading and bearing adequate directions for use together with necessary caution and warning statements. Again, panels of experts with broad experience in various specialties were employed to make recommendations to the FDA. These experts included academicians, clinicians, toxicologists, pharmacists, etc., depending on the kinds of products being reviewed. The panels also included persons representing the interests of consumers. Their task was to consider and provide recommendations on acceptable active ingredients in each condition category, together with allowable quantities, claims, and labeling. Each panel was to prepare and submit a report, as to what should be permitted for each classification of OTC human drugs. The FDA then digested these, considering the medical, scientific, and legal issues, and at intervals
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published them in the Federal Registerfirst in the panel report as an Advanced Notice of a Proposed Rulemaking (ANPR) to give the public ample opportunity to comment as required by the Administrative Procedure Act. Eventually, each ANPR would progress to republication, first as a Tentative Final Rule (TFR) and then to a Final Rule (FR) or regulation that would be codified in the Code of Federal Regulations (CFR) and enforceable as law (10). This has been a very long, drawn-out process, and indeed still today has not been fully completed (11). It has been said that no other program in FDAs history has been more demanding in its scientific, organizational, and legal requirements. It has embraced about 800 active ingredients used for 2300 indications in about 300,000 marketed products (counting package sizes, dose forms, dose strengths, etc.) (12). The active ingredients considered for each class of products were listed as (a) Class I, GRAS/E and suitable for use, (b) Class II, unsafe and/or ineffective and should no longer be allowed in marketed products, and (c) Class III, probably safe and effective, but there are insufficient data available to permit classification and therefore further testing is needed to establish significant proof (13). FDA eventually decided that several hundred ingredients in Classes II and III (for specific uses) would be required to be taken off the market until and unless sufficient proof dictated otherwise (14). 3.2. OTC Monographs The end result of the OTC Review has been the establishment of a series of ingredient-by-category monographs that spell out in each Final Rule or regulation precisely what must be done to legally make and sell an OTC human drug product without obtaining an approved NDA. The OTC drug review system was initially established to evaluate the safety and effectiveness of all OTC drug products marketed in the United States before May 11, 1972, (the start of the OTC review) that were not covered by NDAs, as well as those OTCs that were covered only by safety NDAs that were marketed before the enactment of the 1962 amendments.
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It provided the ongoing framework to establish monographs to enable firms to make and market OTCs without the need and expense of going through the NDA route. This system for nonprescription drug regulation is based on regulatory standards for each category of such drugs. As implied above, not only are the active ingredients and their quantities subject to scrutiny and approval/disapproval by FDA in establishing the OTC monographs for each product category, but product labeling is also considered. This is because the safety and effectiveness of OTC drug products depends not only on the ingredients but also on clear and truthful labeling that can be readily understood by consumers. However, the publication of an OTC final monograph ` establishes standards vis-a-vis ingredients, dosage, indications for use, and certain details of labeling. If a manufacturer faithfully follows what is spelled out in a given OTC monograph and the product is made in full compliance with the cGMP regulations, neither further approvals nor clearances are required to make and market an OTC product. Obviously, the establishment where the product is made must be registered with FDA, and the product or products must be properly listed with the FDA. The approved OTC active ingredients are each specified in the United States Pharmacopeia (USP) describing the quality, purity, identity, and strength of the article. These monographs, coupled with the OTC monographs and FDAs inspection program, allow for adequate postmarketing control of OTC drug product quality. There are provisions for amending existing monographs (once a Final Regulation has been published for a given category of OTC drugs) and for the creation of new monographs. In addition, a final rule published in the Federal Register on January 23, 2002, provides procedures where OTCs covered by NDAs approved after 1972 and OTCs marketed solely in a foreign country can become eligible for inclusion in an OTC monograph. This is accomplished by submitting a time and extent application (TEA) to show that the product has been marketed to a material extent for a material period of time, and then once such an application has been approved,
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safety and effectiveness data can be submitted. Details regarding TEAs are covered in x330.14. The OTC monographs are codified in Part 330 of Title 21 of the Code of Federal Regulations. Under 21 CFR x330.5, the following OTC monographs have been or will be promulgated for these categories or classes of products: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (k) (l) (m) (o) (p) (q) (r) (s) (t) (u) (v) (w) (x) (y) (z) Antacids Laxatives Antidiarrheal products Emetics Antiemetics Antiperspirants Sunburn prevention and treatment products Vitamin-mineral products Antimicrobial products Dandruff products Oral hygiene aids Hemorrhoidal products Hemantics Analgesics Sedatives and sleep aids Stimulants Antitussives Allergy treatment products Cold remedies Antirheumatic products Ophthalmic products Contraceptive products Miscellaneous dermatological products Dentifrices and dental products Miscellaneous (all other OTC drugs not falling within the above categories)
The OTC monograph system provides a relatively straightforward way to legally bring OTC products to market, and this system has worked very well for sorting out which existing products are considered safe and effective. However, from a marketing perspective, the OTC Review is essentially a
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generic-based system, so that little can be created in the way of exclusive new products using this route. It is difficult to develop unique claims for what are essentially me too products, although some companies have been quite successful in using the OTC Review strategy, coupled with a positioning as the scientific leaders in the care of a particular condition. Technically, a company can petition the FDA to switch specific ingredients from prescription to OTC status via the monograph system, but in practice this is seldom done, the last being the switch of 1% hydrocortisone. This is in part because of the long time delays in FDAs process of acting upon such petitions. The Office of Compliance in FDAs Center for Drug Evaluation and Research (CDER) has published a document entitled the OTC Drug Monograph Implementation Compliance Program to assure systematic enforcement of final OTC drug monographs and other regulations under the OTC Drug Review. 3.3. The NDA Approach to OTC Product Approval By far the most common way now of obtaining approval to market a new entity as an OTC is by the New Drug Application process. In theory, companies could write an NDA in such a way as to go immediately over-the-counter on approval. However, in practice, it is almost universal to first market truly new drugs initially on a prescription-only basis and then later file a supplement to the NDA for permission for OTC sale. This is commonly referred to as the Rx-to-OTC switch, which is enormously popular and widely used, particularly around the time of the expiration of applicable patents. FDA evaluates NDA requests to switch drugs from prescription-only to OTC on a case-by-case basis. Abbreviated NDAs (ANDAs), covered in Section 505(j) of the FD&C Act, are used for obtaining FDA approval to market generic versions of prescription drugs after expiration of the patents. However, such generics must be essentially identical to the reference listed drug (RLD) regarding active ingredient, dosage form, strength, route of administration, and labeling.
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ANDAs are abbreviated in that FDA relies on the finding of safety and efficacy of the pioneer RLD and therefore new clinical studies are not needed, although bioequivalence to the RLD is required to be established. But while ANDAs are a useful way to market for generics, the requirements do not match what is needed today for approval to switch a prescription drug to OTC status. However, there is another possible route to obtain NDA approval to market an OTC, other than the usual filing of a supplemental NDA by the originator of the product as mentioned above. This alternate way is covered in Section 505(b)(2) of the FD&C Act, established in 1984 by the Waxman-Hatch Amendments to encourage innovation without requiring costly and time-consuming duplication of previously conducted clinical studies. These 505(b)(2) applications are sometimes referred to as paper NDAs, although this is not strictly accurate in that that term was previously applied to approvals of drugs, based on scientific literature, that were duplicates of products approved after 1962. Under FDAs interpretation of Section 505(b)(2), the firm filing an application in this way can rely on published literature and/or on FDAs previous findings of safety and efficacy without obtaining a right to such reference from the original applicant. In certain circumstances, specific studies may be required to establish the applicability of the original clinical data to the modified formulation covered in the 505(b)(2) application. The innovation mentioned is a limited change from the pioneer drug, such as a different dosage form, strength, new combinations of active ingredients, route of administration, a different salt or polymorph of the active ingredient, or new indications for a previously approved ingredient. In October 1999, CDER published a draft guidance, entitled Guidance for Industry: Applications Covered by Section 505(b)(2). The firm filing an NDA application using the 505(b)(2) route is required to make certain certifications regarding the patent status. Final approval is contingent on satisfying the patent issues. Section 505(b)(2) can be used opportunistically to switch products from prescription to OTC status of products covered
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by a competitors NDA. An example is the competitive activity using this route in switching second-generation nonsedating antihistamine products. Some firms in the prescription drug industry strongly disagree with FDAs interpretation of certain aspects of Section 505(b)(2) and have questioned the legality of FDAs positions. An example of this is the contention over FDAs policy of relying on nonpublic proprietary data on safety and effectiveness contained in approved NDA files to support approval of 505(b)(2) applications. These issues may eventually be settled through litigation in the federal courts. In addition to Rx-to-OTC switches, Section 505(b)(2) can also be used for an NDA for a drug product that differs from a product described in an OTC monograph, such as a nonmonograph indication or a new dosage form. The Waxman-Hatch Amendments to the FD&C Act provide for marketing exclusivity for certain products with Section 505(b)(2) NDA approvals. Exclusivity provides the NDA holder limited protection from new competition in the marketplace for the innovation represented by its approved product. The limitation precludes approvals of other 505(b)(2) NDAs for certain periods of time. Exclusivity is available for new chemical entities (NCEs) and for significant changes in already approved drug products (such as a new use), which are considered to be innovative. The time periods for exclusivity differ. It is important to keep in mind that whether an OTC comes to market through the monograph system or through an NDA process, the standards of safety, effectiveness, and the need for clear, complete, and understandable labeling are the same.
4. THE PROPOSED THIRD CLASS OF DRUGS The current regulatory scheme for distributing medicines in the United States, as outlined above, is a two-tiered system with any given product being classified as either prescription-only or over-the-counter. In some other countries, however, there is a third class, sometimes called a pharmacy-only medicine (POM), where certain products are restricted and required to be kept behind the counter or in a locked glass case not accessible
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to consumers. POM places the pharmacist in a controlling position in terms of product recommendations, often favoring the generic (not branded) versions of OTC drug products. In the United States, the third class or POM class does not exist in that FDA has concluded that, as yet, no public health need has been shown for this form of distribution. The term transition class has been used in discussing POMs by some pharmacy interests as a way to make the concept seem more attractive to industry opponents. Transition class implies an interim period of time (e.g., 25 years) during which the product will be so classified. At the end of that period, the status would be reassessed and then classified either prescription-only or OTC. The concept is that until proved by substantial actual experience that a given product is sufficiently safe to be sold OTC, such items should only be dispensed by a pharmacist (but without requiring a prescription). Presumably the pharmacist would discuss the use of the product with the consumer, guiding him or her in its proper use, and over time pharmacists would become sufficiently knowledgeable about the safety and efficacy of the product that they could help the government decide whether it should be classified as a prescription-only or as an OTC drug. The concept of a third class of drugs has been brought up many times, including recently, by certain trade associations representing pharmacists and retail druggists. However, it has been rejected as being impractical and unnecessary by most pharmaceutical manufacturers, by FDA, and by the General Accounting Office (GAO) (15). In addition, Consumer Healthcare Products Association (CHPA), the trade association representing manufacturers of OTC drugs, strongly opposes the third class category (16).
5. HOMEOPATHIC DRUGS The Food, Drug and Cosmetic Act in Section 201(g)(1) recognizes as official the Homeopathic Pharmacopeia of the United States (HPUS) and its supplements, mentioned again in Section 501(b). The HPUS is published by the Homeopathic
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Convention of the United States, Washington, DC, and is available from Homeopathic Headquarters of America (Falls Church, VA). Some homeopathic drug products must be sold only by prescription, while others may be sold OTC. The criteria for determining which are which are the same for all drug products, including homeopathic drugs, as specified in Section 503(b) of the Act. In some instances HPUS specifies a distinction between prescription and nonprescription homeopathics based on strength. In general, however, homeopathic products intended for use in treating self-limiting conditions amenable to self-diagnosis of symptoms may be sold OTC, but otherwise they must be marketed as prescription products. Drug products containing homeopathic ingredients in combination with nonhomeopathic active ingredients are not considered to be homeopathic products. Moreover, homeopathic products must be clearly labeled as such. Homeopathic drugs must meet the standards for strength, quality, and purity contained in the HPUS. In general, the good manufacturing practice regulations in Part 211 of Title 21 of the CFR apply to all homeopathic drug products, prescription and OTC, with certain exceptions. More details about homeopathic products are contained in FDAs Compliance Policy Guide (CPG) 7132.15 entitled Conditions Under Which Homeopathic Drugs May be Marketed.
6. COSMETIC DRUGS It is not always obvious which products are legally drugs, cosmetics, or both. The difference is established by the intended use and the claims for the product in labeling, advertising, other promotional materials, or on the Internet. The decision can also be influenced by consumer perception as to what the product is expected to do, as well as by the inclusion of certain ingredients well known for their therapeutic uses. Even some aromatherapy products may be classified as drugs because of their intended use (17).
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Section 201(i) of the FD&C Act defines cosmetics as articles intended to be rubbed, poured, sprinkled, or sprayed on, or introduced into, or otherwise applied to the human body . . . for cleansing, beautifying, promoting attractiveness, or altering the appearance. On the other hand, Section 201(g)(1) defines drugs as (A) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease . . . and (B) articles (other than food) intended to affect the structure or any function of the body. . . . A few products actually fall under both definitions. For example, toothpastes that merely cleanse are cosmetics, but those that contain fluoride are also drugs. Shampoos that simply clean the hair are cosmetics, but those containing antidandruff ingredients are also drugs. Underarm products that just deodorize are cosmetics, but those that are antiperspirants are also drugs. Cosmetic products that make sun-protection claims (sunscreens) are also drugs. The combination products must comply with the requirements for both cosmetics and drugs. As mentioned above, drugs are subject to FDA approval, with OTCs in general requiring either an approved NDA or compliance with the appropriate OTC monograph. Cosmetics (with the exception of color additives) do not require premarket approval. Firms making drug products (including OTCs) must register their establishments and list their drug products, whereas these steps are voluntary and not mandatory for cosmetics. There are also differences in labeling between OTCs and true cosmetics. For example, OTCs and cosmetic drugs must include the drug facts required in x201.63 of Title 21 of the CFR, while true cosmetics do not. There are also differences in the way the ingredients must be listed on the label in that combination drug cosmetics must list the active ingredients alphabetically, followed by the inactives in order of predominance. Importantly, too, there are no good manufacturing practice (GMP) regulations for true cosmetics, but cosmetic drug products require strict adherence to the drug GMPs contained in parts 210 and 211 of Title 21 of the Code of Federal Regulations. The FDA Modernization Act of 1997 amended Section 704 of the FD&C Act to allow FDA to inspect plants that
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manufacture products regulated as both drugs and cosmetics to be inspected in the same ways as are prescription drug manufacturing facilities, including FDAs right to ask to see most documentation. However, this records inspection does not apply to facilities making only true cosmetics, albeit all cosmetic manufacturing establishments are subject to FDA inspection.
7. DIETARY SUPPLEMENTS Although many dietary supplement products look very much like OTCs and are marketed over the counter, the regulatory schemes for these two classes of self-care products are quite different. Dietary supplements are considered to be a special class of foods, not drugs, under the Dietary Supplement Health and Education Act (DSHEA) of 1994. A dietary supplement is a product intended to supplement the diet and that contains one or more dietary ingredients such as vitamins, minerals, herbs or other botanicals, amino acids or other specific ingredients. These products are in the form of tablets, hard-shell or soft-gel capsules, powders, or as liquids intended for consumption in small quantities. Only products that are intended for ingestion can be considered to be dietary supplements, i.e., topicals, transdermals, and sublingual products are not dietary supplements. Under DSHEA, dietary supplements may be legally marketed with truthful and nonmisleading claims to affect the structure or function of the body, but not with claims that state or imply that they are intended to prevent, diagnose, mitigate, treat, or cure disease (except for health claims specifically authorized by the FDA for use). Disease claims may cause the products to be legally classified as drugs and therefore subject to provisions of the FD&C Act and/or regulations pertaining to drugs. The intended use of a product may be established through product labels and labeling, catalogs, brochures, audio and videotapes, Internet sites, or other circumstances surrounding the distribution of the product. Unlike OTC drugs that are regulated by CDER, dietary supplements are regulated by the Center for Food Safety and
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Applied Nutrition (CFSAN). The regulations covering labeling, allowable claims, appropriate ingredients, and good manufacturing practices are significantly different between OTCs and dietary supplements.
8. OTCs AND GOOD MANUFACTURING PRACTICE Section 501(a)(2)(B) of the FD&C Act says that a drug shall be deemed to be adulterated if the methods used in, or the facilities used for, its manufacture, processing, packing or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. This applies to all drug products sold in the United States, whether prescription, OTC, or homeopathic (although there are certain exceptions applicable to homeopathic drugs). The GMP regulations are in Parts 210 and 211 of Title 21 of the Code of Federal Regulations. In addition, FDA has published many guidance documents on various GMP topics. FDAs Compliance Policy Guide (CPG) 7132.10, entitled CGMP Enforcement PolicyOTC vs. Rx Drugs, makes it clear that the GMP regulations are the same for OTC drug products as for prescription drugs. Section 704 of the FD&C Act authorizes investigators from the FDA to
enter any factory, warehouse, or establishment in which food, drugs, devices, or cosmetics are manufactured, processed, packed, or held for introduction into interstate commerce . . . and to inspect . . . all pertinent equipment, finished and unfinished materials, containers therein. In the case of any factory, warehouse, establishment, or consulting laboratory in which prescription drugs, non-prescription drugs intended for human use . . . are manufactured, processed, packed, or held, the inspection shall extend to all things therein (including records, files, papers, processes, controls, and facilities) bearing on
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whether prescription or non-prescription drugs intended for human use . . . are adulterated or misbranded within the meaning of this Act. . . .
Thus, establishments involved with manufacturing and/or warehousing OTC drug products are subject to inspection by FDA and can be cited for any GMP violations found and may then be subject to certain regulatory actions resulting from such findings. This applies not only to establishments within the United States but also to those in other countries if the products are exported for sale in the United States. Prior to the passage of the FDA Modernization Act of 1997 (FDAMA), prescription and OTC drug manufacturers were subject to the same GMP regulations, but FDAMA clarified the fact that investigators are entitled to review all OTC manufacturing records that could show whether a product has been adulterated or misbranded. This amended Section 704(a)(1) of the FD&C Act to extend the authority of FDA to inspect company records for OTCs to the same extent as for prescription drugs. This provision of course also applies to cosmetic drug products. Similarly, Sections 510(b) and (c) of the FD&C Act require the registration of the establishments of all producers of drugs, including OTCs. Further, the Drug Listing Act of 1972 requires each registered drug manufacturer to inform FDA of all of the drugs it manufacturers or processes. The mechanism for complying with these requirements are also contained in x207.25(a) and (b) of Title 21 of the Code of Federal Regulations (18).
9. LABELING OF OTC DRUGS For many years FDA has had regulations on the required labeling of OTC drug products, both to be in conformity to the FD&C Act and the Fair Packaging and Labeling Act (FPLA). These regulations are intended to enable consumers to obtain accurate information regarding the products, their indications, ingredients, and safe usage, as well as the quantity of contents
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to facilitate value comparisons. The labels are required to show the dosage strength, as well as the name and address of the manufacturer, packer, or distributor. In short, OTC drug labels must contain all of the information the consumer needs for safe and effective use without the supervision of a health professional. In addition, the manufacturers, through their trade associations, have voluntarily diligently studied and worked over the years to improve the legibility of OTC drug labels, considering such factors as type faces and font sizes, layout, and contrast. The FDA Modernization Act amended Section 502(e)(1) of the FD&C Act to require OTC labels to list the quantity or proportion of each active ingredient present, not merely the names of the actives as previously. An alphabetical list of inactive ingredients must appear on the outside container of the retail package and also on the immediate container, if determined to be appropriate by the FDA (19). In 1997 FDA proposed to establish a standardized format for the labeling of OTCs, to make the key information clear, simple, and user-friendly. After thorough study, including input from many companies, academia, trade associations, and consumer organizations, the new format appeared as a final regulation in the Federal Register for March 17, 1999. Among other details, this requires what is known as a drug facts box listing the active ingredient, purpose of the product, uses, directions, inactive ingredients, warnings, and other information (20). Regulations for the standardized format appear in x201.66 of Title 21 of the Code of Federal Regulations, while the definition of the principal display panel is in x201.60, the definition of the statement of identity is in x201.61, and the declaration of net quantity of contents is in x201.62. FDA has published guidance documents on labeling OTCs using the standardized format (21). A drug product that is not in compliance with these requirements is subject to regulatory action as a misbranded drug. Most OTCs require an expiration date as specified in x211.137. There are specific exceptions for certain products if their labeling does not bear dosage limitations and they are established as being stable for at least 3 years. This type of
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exception applies, for example, to creams or ointments intended to relieve itching. Moreover, under x211.137(e), homeopathic drug products are exempt from the requirement for expiration dating. Under x201.17, when an expiration date is required, it must be on the immediate container and also on the outer package (if there is one) unless it is easily legible through the outer package. It is not acceptable to place the expiration date on a cap, since there would be a chance of a mix-up in that caps might inadvertently by switched from one product to another by the consumer. It is satisfactory to apply the expiration date on the crimp-end of a tubed product, however. The expiration date is established by appropriate stability studies described in x211.166, on an adequate number of batches, in the container/closure system in which the product is marketed. A written stability program is required and must be followed, using meaningful, specific, reliable, stabilityindicating test methods and storage conditions. The absence of an expiration date, except for products specifically exempt, is cause for FDA to initiate regulatory action against the product and/or the responsible firm. Out-of-date drug products are considered by FDA to be adulterated, and any sale of adulterated products may result in regulatory action such as seizure or injunction.
10. CHILD-RESISTANT PACKAGING Under the Poison Prevention Packaging Act (PPPA) enacted in 1970, hazardous substances require child-resistant (CR) packaging, simply called special packaging in the PPPA and the implementing regulations. A hazardous substance is defined in the Federal Hazardous Substances Act, and this does include certain specific foods, drugs, cosmetics, and dietary supplements. Thus, some (but not all) OTC drug products require CR packaging. The purpose is to protect children from serious personal injury or serious illness from handling, using, or ingesting hazardous substances.
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The Consumer Product Safety Commission (CPSC) enforces the PPPA. The implementing regulations are in Title 16 of the Code of Federal Regulations, Parts 17001750. Since the list of products requiring child-resistant packaging changes from time to time, it is prudent for manufacturers to keep abreast of the regulations, particularly the list entitled Substances Requiring Special Packaging, in x1700.14 or to contact CPSC in case of doubt. The PPPA does not specify what kinds of packaging are considered to be child resistant, leaving this up to the CPSC to establish. A testing protocol is specified in Section 1700.20 of the CPSCs regulations. This involves testing with both small children to assure they cannot easily get at the product within a reasonable time, and also testing with adults to be sure that the features are not so restrictive as to make it overly difficult for them to open and reclose the package. A concern is that if packages are too difficult for adults to use, they will simply be left open in some instances, which could put children in the household at risk. Over the years, various makers of packaging components have devised a number of package types that comply. CPSC is convinced that their data conclusively indicate that CR packaging has saved over 800 childrens lives from accidental poisoning from aspirin and other drugs (22). Section 1700.5 of CPSC regulations and Section 4(a) of the PPPA authorize manufacturers and packagers of products required to be in CR packages to offer one single size or SKU of the products in a non-CR version for the convenience of elderly or handicapped persons who might otherwise be inconvenienced by having to deal with CR packaging. Such packages must be conspicuously labeled This Package for Households Without Young Children within a square or rectangular borderline, in conspicuous and easily legible capital letters, on the principal display panel of the immediate container and also on any outer container or wrapping used in the retail display of the product. ASTM International (Conshohocken, PA) has a committee D10 on packaging, including a subcommittee D10.31 on Child Resistant Packaging and Closure Systems. This group has
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issued a number of standards and test methods, including one entitled D3475-03 Standard Classification of Child-Resistant Packages. There is no regulatory requirement for OTC manufacturers to test their packages for CR compliance, but if the CPSC learns of a product requiring CR packaging where the CR feature is not functioning well, a recall may be needed and/or the firm involved may be penalized. Consequently, to avoid regulatory problems with the CPSC as well as to avoid possible product liability issues, many manufacturers do test their packages. Since the testing protocol is difficult to conduct, many firms use specialized outside contract organizations to conduct the tests.
11. NATIONAL UNIFORMITY The FDA Modernization Act added a new Section 751 to the FD&C Act and for the first time mandated that in general, no state or political subdivision may establish requirements for nonprescription drug products regulated by FDA that differ from or are in addition to the requirements of the Food, Drug and Cosmetic Act, the Poison Prevention Packaging Act, or the Fair Packaging and Labeling Act. Among other things, this established that states cannot require labeling of OTCs differing from what FDA requires. This applies to any nonprescription drug, whether under an NDA, ANDA, or a monograph. This was a significant step, as prior to this change individual states on occasion required special labeling, which obviously greatly complicated OTC manufacturing, warehousing, and physical distribution.
12. TRADE ASSOCIATION FOR OTCs The leading trade association in the United States involved primarily with nonprescription drugs is the Consumer Healthcare Products Association (CHPA), previously known first as the
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Proprietary Association (PA) and then later as the Nonprescription Drug Manufacturers Association (NDMA). The CHPA was founded in 1881 and represents over 200 companies involved in the research, manufacturing, and distribution of OTC medicines. CHPA members represent over 90% of retail sales in the OTC marketplace. CHPA organizes and sponsors meetings and seminars on a range of topics applicable to the manufacturing and marketing of OTC drugs. It also has established voluntary codes and guidelines for the self-care industry on a variety of matters. CHPA is located in Washington, DC, and has a web site at http://www.chpa-info.org.
13. IMPRINTING SOLID ORAL DOSAGE FORM OTC DRUGS As is the situation with prescription drugs, OTC tablets, capsules, or similar drug products intended for oral use (with certain exceptions listed in x206.7) must be clearly marked, debossed, or imprinted with a code that, in conjunction with the products size, shape, and color, permits the unique identification of the product and the manufacturer or distributor of the product. This became a final rule in the Federal Register of September 13, 1993, as amended on April 21, 1995, now codified in x206.3 and 206.10 of Title 21 of the Code of Federal Regulations.
14. THE NATIONAL DRUG CODE The National Drug Code (NDC) was originally established in connection with the reimbursement program under Medicare, but has become a universal product identifier for human drugs. The NDC directory consists of all prescription drugs and some (but not all) OTCs. It is strictly a voluntary matter, in that OTCs may have NDC numbers, but are in no way required to do so. Inclusion of a firm of its products in the National
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Drug Code Directory does not denote approval by FDA, nor does absence of an NDC number have any negative implications. Under x201.2 of Title 21 of the Code of Federal Regulations, if a firm has an NDC number, they are requested but not required to have it appear on the product labeling, but if used, it should be displayed as indicated in x207.35(b)(3).
15. TAMPER-EVIDENT PACKAGING Prior to 1982 there were no regulations regarding packaging designed specifically to make evidence of tampering obvious to the consumer. This changed suddenly on September 30, 1982, due to a health emergency in Chicago where seven people died after taking cyanide-laced Tylenol capsules. A number of manufacturing executives from the OTC drug industry quickly assembled in Washington, DC, to assess the situation and to formulate steps to minimize the likelihood of future similar occurrences. This group was called the Expert Committee on Tamper-Resistant Packaging. Their goal was to consider what should be done to change OTC packages to improve consumer safety and product integrity. They defined tamper-resistant packaging (as it was then called) and evaluated features and equipment to provide tamper evidence for OTC packages. The Expert Technical Committee met with top FDA officials to help draft what soon became x211.132 of the GMP regulations. The final regulation on tamper-resistant packaging (TRP) was published in the Federal Register on November 5, 1982, less than 5 weeks from the advent of the first poisonings. On February 25, 1983, certain exemptions to the requirements were published, followed by a clarification published April 19, 1983. The regulation required that any OTC drug product (except a dermatologic, dentifrice, insulin, or lozenge product) for retail sale be in a tamper-evident package so that a breach of the package would be reasonably expected to produce visible evidence to consumers that tampering had occurred. It was established that it is essentially impossible to develop a practical package that is tamper-proof, thus the
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term tamper-resistant was adopted, which in 1998 was changed to tamper-evident. FDA wisely elected to avoid setting specific standards of performance. However, Compliance Policy Guide (CPG) 7132a.17, entitled Tamper-Resistant Packaging Requirements for Over-the-Counter Human Drug Products, was published. This provides background and a list of technologies that are considered acceptable. In 1986 people died after ingesting Extra-Strength Excedrin capsules tainted with cyanide. Also in 1986, there were other tragic incidents of tampering with Tylenol capsules, this time in New York. FDA responded by amending the TRP regulation in the Federal Register, on February 2, 1989, to require OTC drug products in two-piece hard gelatin capsules to use at least two separate tamper-resistant features, or at least one such feature if the capsules themselves were sealed. Then, in February 1991 two people in Washington state died from taking bogus Sudafed cold capsules containing cyanide, despite adequate TRP and despite the fact that the tampering should have been obvious to the victims. There was talk at that time of banning capsules altogether as a dosage form, but strong objections were raised by many so this concept was eventually dropped. It was concluded that over and above the TRP, what was urgently needed was consumer awareness of the potential problems so that each individual would be alert to signs of tampering. The TRP regulations were revised in a final rule, published in the Federal Register for November 4, 1998, changing the term to tamper-evident packaging (TEP) instead of tamper-resistant pakaging (TRP). This version of the regulation requires the product labeling to refer to all packaging features used to comply with the tamper-evident regulation, including those on the secondary package, the immediate container or closure, and any capsule sealing technologies used. It also requires two-piece hard gelatin capsules to be sealed. FDAs Compliance Policy Guide (CPG) 7132.14, entitled Control and Accountability of Labeling Associated with Tamper-Resistant Packaging of Over-the-Counter Drug Products, establishes that portions of tamper-evident
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packaging that contain labeling (e.g., shrink seals imprinted with the product name) need to be carefully controlled and reconciled. Similarly, controls are required for parts of the packaging that may be part of the container-closure system. While the deaths resulting from tampering have received wide media attention, there have been many other lesser incidents of tampering with less drastic outcomes. Obviously, tampering remains a significant potential problem, particularly in these times of concern about the possibility of bioterrorism. In October 1983, the Federal Anti-Tampering Act was signed into law. This defines tampering and sets forth strict penalties for persons found guilty of tampering. A great many convictions have resulted from this law, further emphasizing that tampering remains a significant issue.
16. ADVERTISING OF OTCs The FDA and the Federal Trade Commission (FTC) by statute have overlapping jurisdiction of advertising, labeling, and promotion of foods, drugs, cosmetics, medical devices, and dietary supplements. In general, FDA regulates advertising of prescription drugs, but FTC has the primary responsibility for enforcing the laws against false or misleading advertising of OTC drugs. FDA and FTC have a long-standing mutual understanding of their respective roles, which has worked well over the years. Both agencies are committed to prevent deception of the public and to coordinate to promote consistency and eliminate duplication of effort. The two agencies work in harmony and keep each other informed on a variety of issues. The FTC focuses its enforcement resources on those practices likely to cause the most harm to consumers, which usually involves health and safety claims. But in general, FTC strives to eliminate deceptive and unsubstantiated advertising claims that could lead to consumer misinformation by marketers attempting to obtain an unfair competitive advantage. Section 5 of the FTC Act gives the FTC broad authority to
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prohibit unfair or deceptive acts or practices, while Sections 12 through 15 prohibit the dissemination of misleading claims for food, drugs, devices, and cosmetics. FTC can and does issue cease-and-desist orders and can seek civil penalties in federal court for violations of such orders. The courts have ruled that an advertiser is responsible for all claims, express and implied, that are reasonably conveyed in advertising and that advertisers are strictly liable for violations of the FTC Act. The FTC obviously prefers voluntary self-regulation. One step in this is accomplished through the actions of the Council of Better Business Bureaus. Their National Advertising Division (NAD) investigates complaints about the truthfulness and accuracy of national advertisements and encourages corrective action be taken as appropriate. When an advertiser or challenger disagrees with the NADs findings, NADs decisions can be appealed to the National Advertising Review Board (NARB) for additional review. Many complaints brought by a challenger (usually a competitor, but sometimes a consumer, trade association, local Better Business Bureau, etc.) involving the accuracy and truthfulness of advertising claims are settled through the NAD/NARB process without involving the FTC. In most instances, advertisers voluntarily agree to modify or discontinue potentially misleading advertisements. The NAD publishes a periodical 10 times a year entitled NAD Case Reports: Voluntary Self-Regulation of National Advertising, and more than 3000 decisions are now available for review. The Council of Better Business Bureaus also publishes Dos and Dont in Advertising in loose-leaf form and on CD-ROM, with periodic updates, including laws, guides, industry self-regulatory guidelines, and NAD case summaries. Consumers get much of their information about OTC drug products through advertising, and they tend to accept the claims on faith. This puts a burden on the advertisers to follow high standards in the wording of and the substantiation of claims. Misplaced reliance on claims can result in consumers delaying seeking professional help, which can result in postponing needed medical treatment. The leading trade association of OTC drug manufacturers, the CHPA, strongly urges its
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member companies to follow its voluntary code of advertising practices. Moreover, the media (especially television networks) typically insist on seeing claims substantiation prior to running OTC advertising. But because there are occasionally unscrupulous advertisers despite the guides and voluntary programs, the FTC is vigilant in its enforcement efforts to assure that claims are substantiated and consumers are not deceived in their efforts to handle their own health needs. An increasing problem is the advertising and promotion of medical products (including OTC drugs) on the Internet. While the Internet offers tremendous benefits to consumers in both convenience and choice of information, it also makes fraud and deception easier. Consequently, FDA, the FTC, state governmental agencies, and the National Consumers League have teamed up and are closely monitoring the Internet in an attempt to minimize health fraud as well as false and unsubstantiated claims. Strong enforcement actions are taken when necessary against fraudulent marketing practices of OTCs on the Internet. CDERs Office of Compliance has an Internet Health Fraud Team within its Division of New Drugs and Labeling Compliance (formerly called the Division of Labeling and Nonprescription Drug Compliance).
17. FDAs OVERSIGHT OF OTC DRUGS As described above, establishments manufacturing, packaging, or warehousing OTC drug products must be registered with FDA, and the products handled duly listed. Such establishments are subject to inspection by FDA for full compliance with the current GMP regulations. Also, as described above, OTCs must either be in compliance with the appropriate OTC monograph requirements or be subject to an approved NDA or ANDA. Labeling must conform with regulations, including lot numbers and expiration dates. Where tamper-evident and/or child-resistant packaging is required, OTCs must be in compliance.
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In addition, FDA has a Nonprescription Drugs Advisory Committee (NDAC) that coordinates the activities on establishing or modifying the OTC monographs and on considering switches from prescription to nonprescription status (or vice versa). In its original charter in 1991, it was named the OTC Drugs Advisory Committee (ODAC), but since this sounded confusingly similar to the Oncologic Drugs Advisory Committee, the name was changed. This committee may also advise the agency on other topics related to OTCs, such as scientific programs related to FDAs mission and regulatory responsibilities. The committee consists of a core of 14 voting members invited to serve overlapping 4-year terms. Temporary subcommittees are established as needed to address specific issues. The meetings of the NDAC are held in accordance with the provisions of x14.22 of Title 21 of the Code of Federal Regulations. Management and support services for the NDAC are provided by CDER. When the OTC subject matter overlaps with one or more expert advisory committees, as is often the case for an Rx-to-OTC switch application, NDAC will meet in joint session with the appropriate prescription drug advisory committee. There is within CDERs Office of Drug Evaluation V (ODEV) a division of over-the-counter drug products (DOTCDP), which is responsible for all OTC review matters and for those aspects of Rx-to-OTC switch applications relating to consumer labeling and use. By mutual agreement, the clinical aspects of a switch application are the purview of the relevant medical review staff of another division or office, and the OTC division consults with other staff groups within CDER (such as the Office of Drug Safety on certain adverse event reporting matters). CDER has a specific Manual of Policy and Procedures (MaPP) covering the interaction between the OTC division and other CDER medical review divisions. There is also in the Office of Compliance (OC) an OTC drugs team responsible for maintaining current knowledge of the regulatory status of OTC drugs, keeping the FDA district offices informed on OTC regulatory issues, working with the district office in obtaining appropriate evidence to
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support enforcement actions involving OTCs, monitoring product labeling to help assure compliance, working with agency personnel and the regulated industry to resolve issues of mutual concern and similar matters related to compliance issues in the OTC field. In the Division of New Drugs and Labeling Compliance (DNDLC) in CDERs Office of Compliance is an OTC Drugs and Health Fraud Branch, responsible for compliance and enforcement issues related to labeling for OTC drugs. With this organizational structure, combined with FDAs inspectional force in the field, there is a well-defined and time-tested system of oversight of OTCs. This serves well both current activities and future OTC issues.
REFERENCES
1. 2. FDA white paper, Protecting the public health: FDA pursues an aggressive enforcement strategy, June 23, 2003. Kline & Company, Inc., Economic benefits of self-medication, a final report to the Nonprescription Drug Manufacturers Association, May 15, 1997. Schondelmeyer, S.W., Economic aspects of switch, in Proceedings Drug Information Association Workshop Rx-to-OTC Switch, Rockville, MD, May 1989. Roper Starch Worldwide, Self-care in the new millennium: American attitudes toward maintaining personal health and treatment, a report prepared for the Consumer Healthcare Products Association, March 2001. United Seniors Health Cooperative Special Report, Aging and health: the role of self-medication, Washington, DC, 1998. Kunz, K., Economics of self treatment . . . in a managed care setting, J. Managed Care Pharmacy, Vol. 2, No. 3, May/June 1996, p. 253271. Press release, American consumers support self-medication and practice it responsibly, Nonprescription Drug Manufacturers Association, Washington, DC, January 1994.
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A. D. Little confirms OTC advertising doesnt cause drug abuse, NDMA Scientific News Bulletin, Washington, DC, March 18, 1991. Soller, R.W., OTCness, Drug Information Journal, Vol. 32, 1998, p. 555560. Mercill, A.W., The grand design, in Proceedings of the 1975 Manufacturing Controls Seminar, The Proprietary Association, Cherry Hill, NJ, October 1975. Oppenheimer, D.C., Its been a long four yearsFDAs OTC drug product review, Pharmaceutical Technology, June 1997, p. 6566. FDAs OTC Review, NDMA Executive Newsletter, Washington, DC, May 1, 1992. Progress Report: The OTC Drug Review, FDA Consumer, February 1979, p. 1822. Gilbertson on OTC review, NDMA Executive Newsletter, Washington, DC, November 16, 1990. General Accounting Office, Nonprescription Drugs: Value of a Pharmacist-Controlled Class Has Yet to Be Demonstrated, Report GAO/PEMD-95-12, August 1995. News release from the Consumer Healthcare Products Association, CHPA statement reaffirming commitment to the U.S. two-class system of drugs, Washington, DC, May 27, 2003. CHPA also has a fact sheet on this available at http:// www.chpa-info.org/pdfs/05_27_03_Third_Class_of_Drugs.pdf (accessed July 9, 2003). FDA, Is it a cosmetic, a drug, or both? (or, is it soap?), July 8, 2002, available at http://www.cfsan.fda.org.gov/$dms/cos-218.html (accessed January 18, 2003). FDA, Drug registration and listing, available at http:// www.fda.gov/cder/drls/registration_listibg.htm (accessed August 11, 2002). FDA, Guidance for industry: national uniformity for nonprescription drugsingredient listing for OTC drugs, Procedural Guidance No. 2, April 1999.
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FDA, OTC labeling: questions and answers, October 2002, available at http://www.fda.gov/cder/otc/label/quesanswers.htm (accessed May 25, 2003). FDA, Guidance for industry: labeling OTC human drug products using a column format, March 2001, available at http:// www.gov/cder/guidance/3594fnl.htm (accessed May 25, 2003). Remarks by Ann Brown, Chair of CPSC, before the Usability Professionals Association breakfast in Washington, DC, on June 23, 1998, available at http://www.upassoc.org/outreach/ govt.ind.brown.html (accessed June 29, 2003).
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The Pharmaceutical Regulatory Process

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The Pharmaceutical Regulatory Process

Copyright 2005 by Marcel Dekker

DRUGS AND THE PHARMACEUTICAL SCIENCES

Copyright 2005 by Marcel Dekker

DRUGS AND THE PHARMACEUTICAL SCIENCES

Copyright 2005 by Marcel Dekker

Copyright 2005 by Marcel Dekker

Copyright 2005 by Marcel Dekker

Copyright 2005 by Marcel Dekker

Copyright 2005 by Marcel Dekker

Copyright 2005 by Marcel Dekker

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Copyright 2005 by Marcel Dekker