International conference on

harmonization
CRAA
The long form of ICH is the “International Conference
on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use”.
 What is ICH?

• ICH is a joint initiative involving both regulators and

research-based industry representatives of the EU,
Japan and the US in scientific and technical
discussions of the testing procedures required to
assess and ensure the safety, quality and efficacy of
medicines.
Need to Harmonize
• Awareness on critical evaluation of medicinal products Medical
tragedies
• 1960-70: rapid increase in laws, regulations & guidelines on
medicinal products
• Widening market opportunities for Pharma industry
• Duplication of work
• Raising cost of health care
• Timely Access of Patients to Safe & Effective “New Drugs”
• Need to meet public expectation
 Aims of ICH
• Provide a unified standard EU, US, Japan

• Developed in accordance with existing standards in US, EU,

Australia, Canada, Nordic Countries, and WHO

• Unify registration requirements for new products

• Reduce medicinal product development costs: more economical

use of animal, human and material resources.

• Accelerate medicinal product licensing times: avoid repeat testing

in different regions.

• Increases patent protection times through reducing delay in

licensing times.
 The Ideal Objective
One Submission For All 3 Regions
– Administrative
– Labeling
– Technical Information
• Summaries
• Data
ICH – GCP : Evolution
1980s - EC
– Pioneered harmonization of regulatory requirements
– Develop single market for medicinal products
– Demonstrated feasibility of harmonization
• 1989, Paris - WHO Conference of Drug Regulatory Authorities

– IFPMA – discuss joint regulatory-industry initiative

– ICH conceived
• Apr, 1990, Brussels – EFPIA

– Birth of ICH
– ICH Steering Committee established
The Early Meetings
• At the first SC meeting of ICH the Terms of Reference were
agreed

• The Topics selected for harmonization would be divided into

Safety, Quality and Efficacy.

• Six-party Expert Working Groups (EWGs) were agreed to be

set up

• The "pattern" of ICH work was also established in those early

Steering Committee meetings

• The ICH "Process" was first drawn up at the Steering

Committee meeting in Washington, March 1992 and amended
in Tokyo, September 1992.
ICH constitution

• ICH parties- EU, FDA, EFPIA, MHW Japan, JPMA

• Observers
• IFPMA
ICH Process

• Consensus building
• Start of regulatory action
• Regulatory consultation
• Adoption of tripartite harmonized text
• Implementation
Structure of ICH - Administration
Organization

Steering committee (SC): Policy Issues

Expert working group (EWG): Technical Guidelines
The International Federation of Pharmaceutical
Manufacturers Association (IFPMA) : provides the
Secretariat who supports the SC.
 Expert Working Groups

SAFETY EFFICACY

REGULATORY
QUALITY
COMMUNICATIONS

• An EWG for each ICH Topic

• 6 Topic Leaders - one from each ICH party
• Develop consensus on technical issues
• Result in ICH Guidelines (S, E, Q, M)
SC & EWG
• Steering Committee (SC)
– 2 members from each of the 6 co-sponsors
– Meets twice a year
– Operates within the Terms of Reference
– Determines policies & procedures
– Selects topics for harmonization
– Monitors progress of harmonization initiatives

• Expert Working Group (EWG)

– Appointed by SC for each topic
– Review difference in requirement between 3 regions
– Develop scientific consensus to bridge the gap
– Report to SC
The ICH Secretariat

• The Secretariat operates from the IFPMA

• Preparations for, and documentation of, meetings of the

Steering Committee

• Technical documentation and for liaison with the

speakers for the Conference.

IFPMA

• The research-based pharmaceutical industry in 56

countries throughout the world.

• IFPMA runs the ICH Secretariat.

ICH Processes
• ICH members develop guidelines through step-wise process
• Applicable to:
– – Drugs
– – Biologics
– –Medical devices (test articles)

• Approved by ICH members, then adopted by National

Regulatory Authorities
 Who are the members?

ICH is comprised of representatives from the six cosponsoring parties as well

as three Observers and the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA):

Japan: the Ministry of Health & Welfare (MHW) and the Japan
Pharmaceutical Manufacturers Association (JPMA)

EU: the European Commission (EC) and the European Federation of

Pharmaceutical Industries’ Associations (EFPIA)

USA: the Food & Drug Administration (FDA) and the Pharmaceutical
Research and Manufacturers of America (PhRMA)

Observers:
•The World Health Organization (WHO)
•The European Free Trade Area (EFTA), represented at ICH by Switzerland
•Canada, represented at ICH by Health Canada
Over 45 Harmonized Guidelines

• Safety - 7 topic headings/14 guidelines

• Efficacy - 12 topic headings/14 guidelines

• Quality - 7 topic headings/19 guidelines

• Medical Dictionary - MedDRA

• Electronic Standards - ESTRI, E2B

• Common Technical Document - CTD

 ICH

Finalized Guidelines:

Efficacy (E1 to E12) wherein GCP is E6 (1996)

Quality (Q1 to Q6)
Safety (S1 to S7 & M3)
Multidisciplinary (M1, M2, M4)
 Quality Guidelines
Stability

Q1A: Stability Testing of New Drugs and Products (Second

Revision)

QIB: Photostability Testing

Q1C: Stability Testing for New Dosage Forms

Q1D: Designs for Stability Testing of Drug Substances and

Drug Products

Q1E: Evaluation of Stability Data

Q1F: Stability Data Package for Registration

Applications in Climatic Zones
 Quality Guidelines

Validation

Q2A: Text on Validation of Analytical Procedures

Q2B: Methodology

Impurities

Q3AR: Impurities in New Drug Substances

Q3BR: Impurities in New Drug Products

Q3C: Guideline for Residual Solvents

 Quality Guidelines

Quality of Biotechnological Products

Q5A: Viral Safety Evaluation of Biotech Products

Q5B: Analysis of the Expression Construct in Cells

Used for the Production of r-DNA Derived Protein Products

Q5C: Quality of Biotechnological Products: Stability

Testing of Biotechnological/Biological Products

Q5D: Derivation and Characterization of Cell

Substrates Used for Production of
Biotechnological/Biological Products

Q5E: Comparability of Biotechnological/Biological

Products Subject to Changes in their
Manufacturing Process
 Quality Guidelines

Specifications
Q6A: Specifications for New Drug Substances and Products:
Chemical Substances

Q6B: Test Procedures and Acceptance Criteria for

Biotechnological/Biological Products

Good Manufacturing Practice

Q7A: GMP for Active Pharmaceutical Ingredients
 Safety Guidelines

Carcinogenicity Studies
S1A: Guideline on the Need for Carcinogenicity Studies of
Pharmaceuticals

S1B: Testing for Carcinogenicity of Pharmaceuticals

S1C: Dose Selection for Carcinogenicity Studies of

Pharmaceuticals

S1CR: Addendum: Addition of a Limit Dose and Related

Notes
 Safety Guidelines

Genotoxicity Studies

S2A: Guidance on Specific Aspects of Regulatory Tests

for Pharmaceuticals

S2B: A Standard Battery for Genotoxicity Testing of

Pharmaceuticals

Toxicokinetics and Pharmacokinetics

S3A: Note for Guidance on Toxicokinetics: the Assessment

of Systemic Exposure in Toxicity Studies

S3B: Pharmacokinetics: Guidance for Repeated Dose

Tissue Distribution Studies
 Safety Guidelines
Toxicity Testing

S4: Single Dose Toxicity Tests

S4A: Duration of Chronic Toxicity Testing in

Animals (Rodent and Non Rodent)

Reproductive Toxicology

S5A: Detection of Toxicity to Reproduction for Medicinal

Products

S5B(M): An Addendum to Toxicity to Male Fertility

 Safety Guidelines
Biotechnological Products
S6: Preclinical Safety Evaluation of
Biotechnology-Derived Pharmaceuticals

Pharmacology Studies
S7: A Safety Pharmacology Studies for Human Pharmaceuticals

S7B: Safety Pharmacology Studies for

Assessing the Potential for Delayed
Ventricular Repolarization (QT Interval
Prolongation) by Human Pharmaceuticals

Joint Safety/Efficacy (Multidisciplinary) Topic

M3(M): Maintenance of the ICH Guideline on Non-Clinical Safety
Studies for the Conduct of Human Clinical Trials for
Pharmaceuticals
 Efficacy Guidelines
Clinical Safety

E1: The Extent of Population Exposure to Assess Clinical Safety

E2A: Clinical Safety Data Management: Definitions and Standards for

Expedited Reporting

E2B: Maintenance of the Clinical Safety Data Management including the

Maintenance of the Electronic Transmission of Individual Case Safety
Reports Message Specification

E2C: Clinical Safety Data Management :Periodic Safety Update Reports for
Marketed Drugs

E2CA: Addendum to E2C

E2D: Post-Approval Safety Data Management: Definitions and Standards

for Expedited Reporting

E2E: Pharmacovigilance Planning

 Efficacy Guidelines
Clinical Study Reports
E3: Structure and Content of Clinical Study Reports

Dose Response
E4: Dose-Response Information to support Drug
Registration

Ethnic Factors
E5: Ethnic Factors in the Acceptability of Foreign
Clinical Data

Good Clinical Practice

E6: Good Clinical Practice: Consolidated Guideline
 Efficacy Guidelines
Clinical Trials
E7: Studies in Support of Special Populations:Geriatrics

E8: General Considerations for Clinical Trials

E9: Statistical Principles for Clinical Trials

E10: Choice of Control Group and Related Issues in Clinical Trials

E11: Clinical Investigation of Medicinal Products in the Pediatric

Population

Guidelines For Clinical Evaluation By Therapeutic Category

E12A: Principles for Clinical Evaluation of New Antihypertensive
 Multidisciplinary Guidelines

M1: Medical Terminology

M2: Electronic Standards for transmission of Regulatory

Information ESTRI

M3: Timing of Pre-clinical Studies in relation to Clinical Trials

M4: The Common Technical Document

ICH Guideline for GCP

•Glossary of Imp Terms

•Functions & Responsibilities of:

IRBs/IEC, sponsor, investigator

•Describes Format & Content of:

Clinical Trial Protocol
Investigator‘s Brochure

•Provides a List of Essential

Documents
 Revised ICH Terms of Reference

•To maintain a forum for a constructive dialogue between regulatory

authorities and the pharmaceutical industry

•To contribute to the protection of public health from an

international perspective

•To monitor and update harmonized technical requirements leading

to a greater mutual acceptance of research and development data
Revised ICH Terms of Reference

• To avoid divergent future requirements as a result of

therapeutic advances

• To facilitate the adoption of new or improved technical

research and development

• To facilitate the dissemination and communication of

information on harmonized guidelines
GCP: Evolution

WHO
ICH

USFDA
EU

ICMR
• Where can I get the guidelines?
• Go to the website: www.ICH.org