“Foundation workshop on Clinical and

Laboratory Medicine Research”

Clinical Trial Protocol

Moving Academy of Medicine and Biomedicine

and National Institute of Research on
Reproductive Health (NIRRH)

NIRRH, Parel, Aug 10, 2010

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 Session Outline
• Protocol - To begin with…
• Structure - Protocol Contents
• Resources and Tools
• Case Study/Group Exercise
• Conclusion

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 What is a “protocol”?
A protocol is the written mechanism that describes how the
clinical trial design will be implemented.
Spilker, B. 1991
A document that describes the objective(s), design,
methodology, statistical considerations and organization of a
trial. It usually also gives the background and the rationale
for the trial. ICH-GCP 1.44

“Macro-Elements of a Protocol”
Clinical (Trial) Development - Knowledge and Science
Clinical Trial Conduct- Execution and Project Management
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 Establishing the need for a CT
• What is the scientific/research question which
needs to be answered ?
• Can it be done without a CT?
• If not, what is the least complex approach?
• Will the answers develop new/advance/
contribute to “generalizable knowledge”?
• Is it ethically justified?

Think of a protocol…
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 The thinking behind the
research question……
Do participants, in Clinical Research Training Course in
NIRRH, who drink coffee with their lunch, perform better
during the group interactions of the post lunch lecture?

Phase I: Is coffee safe for human consumption?

Phase II: Does coffee work? At what dose?
Phase III: Is coffee more efficacious than tea?
Phase IV: Can coffee be used more effectively?
Is it useful for other conditions or purposes?
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CT objectives vs design: which comes first?

• CT design is the framework by which trial

objectives will be met
• Design choice – Multiple perspectives
– Medical / Scientific
– Ethical
– Commercial / Marketing
– Regulatory
– Others

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Protocol helps align…

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 Protocol: title page
• Title (short, succinct, specific)
– drug/procedure, indication, design, study population
– not more than 20-25 words

• Protocol identifier
• Details of participants in protocol
– investigator(s)/sponsor(s)/laboratory(ies)
– other contributing personnel/authority(ies)

• Date of final protocol and its amendment(s)

• Approval signature of principal participants
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 Protocol contents (1)
1.0 INTRODUCTION
2.0 OBJECTIVES
2.1. Primary objective
2.2. Secondary objectives
3.0 STUDY DURATION
4.0 NUMBER OF SUBJECTS
5.0 COMPLIANCE WITH GOOD
CLINICAL PRACTICE & ETHICAL
CONSIDERATIONS
5.1. Regulatory and Institutional
Review
5.2. Informed Consent
6.0 CRITERIA FOR SUBJECT SELECTION
6.1. Inclusion Criteria
6.2. Exclusion Criteria
7.0 METHODOLOGY
7.1 Study Design
7.2 Study Schedule
7.3 Study Visits
7.4 Study Evaluations/Procedures
7.5 Definition of Efficacy Endpoints
7.6 Efficacy Analyses
7.7 Study Treatments
7.8 Termination of the Study
8.0 SAFETY REPORTING
8.1. Serious Adverse Events / Others
8.2. Abnormal Laboratory Test Results
& Physical Examination Findings
8.3. Laboratory Tests
8.4. Patient Discontinuations ℠
 Protocol contents (2)
9.0 STUDY MANAGEMENT AND MATERIALS LIST OF APPENDICES
9.1 Study Materials • Investigators and investigating
9.2 Study Documentation sites
9.3 Monitoring and Quality • Declaration of Helsinki
• Informed consent form (ICF),
Assurance
Case report form (CRF) &
10.0 CONCOMITANT THERAPY
Prescribing Information
11.0 CONFIDENTIALITY • Advertisement and subject
12.0 DATA ANALYSIS recruitment procedure
13.0 COMMUNICATION AND PUBLICATION • Study flow chart & Subject
OF RESULTS screen / recruitment log
14.0 REFERENCES
• Others
15.0 STUDY PROTOCOL AGREEMENT
SIGNATURE PAGE
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 1.0 Introduction
• Generally includes
– background (disease / treatment)
– purpose or intent (hypothesis)
– rationale
• No more than 2 pages
• Reference available data appropriately

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 2.0 Objective(s)
A concise statement of major (primary) and minor
(secondary) questions that the project is designed to answer

• No more than 2 primary and 3 secondary

• Should be clear, complete and concise
• Should be feasible in terms of...
– time/money/manpower/practicality
• Should not be amended after initiation of study
– superiority vs equivalence

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 3.0 Study duration

• Specify a start and end date of project

• Do not be too ambitious / slow
• Organize (self and team)
– major and minor events
– discuss timelines with study personnel
– fix timelines for each event
– build in reasonable flexibility
– build in contingency plans too
– update study team regularly

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 4.0 Number of subjects (sample size)

• Should be based on the primary objective(s)

• Should describe possible subgroup/stratification
• Define what is a completed case/observation
• Define what will be done with incomplete
cases/observations (ITT/LOCF)
• As a clinician, one should endeavor to:
– understand the reason for choosing a method for sample
size calculations
– document the method used and its rationale

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 Statistical concepts / tests
• Statistics
– magnitude of expected
difference (effect)
– estimated variability of study
parameters (S.D.)
– error (p<0.05)
– error (0.10) {1- =
power (1- 0.1 = 0.9 or 90%)}

• And some more considerations……

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 What influences late phase clinical trial design and numbers?
Cardiovascular Studies - An example
Acute Coronary Event

“Primary Prevention” “ACS Patient” “Stable CHD” Patient

1-2% have CV event in 1 yr >15% have CV event in 1 yr 5-6% have CV event In 1 yr

Regulatory environment  Significance, Power, and Sample size

Standard of care  Superiority vs Non-Inferiority vs Equivalence

And also…some specifics

 P value vs Confidence Interval
 Statistical vs Clinical significance
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5.0 GCP/Regulatory/IRB compliance

• Incorporate a statement of

– ICH-GCP compliance

– adherence to Declaration of Helsinki (most recent version)

– compliance with local/central regulations and laws

• Describe IC process in detail

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 6.0 Selection criteria (1)
• Helps define study population characteristics
• Consider possible risks and benefits to subjects
• Since criteria determine recruitment they should
– should be non-contradictory, precise, clear
– not be too narrow or broad (homogenous vs heterogenous)
– should be fairly “tight” (to allow meaningful interpretation)
• Inclusion criteria and/or exclusion criteria
• Four general categories of criteria
– characteristics of study subjects
– characteristics of disease and its treatment
– environmental and other factors
– results of screening examinations

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 6.0 Selection criteria (2)
• Characteristics of study subjects
– gender, age, weight, pregnancy / lactation
– race, socio-economic status, diet/nutritional status
– use of caffeine / tobacco / alcohol / drugs
– physiological, anatomical/ psychological considerations

• Characteristics of disease and its treatment

– present clinical status (disease / no disease / stage of disease)
– medical history (allergies, diseases, medications)
• Environmental and other factors
– subject recruitment and cooperation
– participation in another trial
• Results of screening examinations
– physical, laboratory and other investigation parameters
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 7.1 Study design
• Should include the following:
– type of clinical study

– trial design with treatment sequences

– controls

– level of blinding & randomization method

– treatment structure (length of treatment, dose and regimen)

– other bias-reducing factors

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 7.2, 3 & 4 Study schedule & visits
• Timing and description of all procedure(s), observation(s) and
assessment(s) for efficacy and safety at the following:
– screening visit(s)
– baseline visit /Follow up visit(s)
– final visit (Women in the cohort were followed to death – ed)
• Cover essential aspects clearly in protocol
• Ensures uniformity in methodology and collection of data for all
procedure(s), observation(s) and assessment(s)

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7.5 Efficacy variables - “endpoints”
• The variable capable of providing the most clinically
relevant and convincing evidence related to the
primary objective of the trial is the endpoint

• Factors influencing selection

– primary vs secondary
– direct vs surrogate
– objective vs subjective
– specificity vs sensitivity
– validity, accuracy, precision
– Time, effort, cost, complexity
– Clinical relevance
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An endpoint is not an endpoint is not an endpoint ……..
C-XRAY vs QCA vs IVUS ……
A
Atheroma
Lumen

B
A
Rupture Site
B

Lipid Core

Waters et al. Circulation. 1993;87(suppl II):II-38–II-47. ℠

 7.6 Efficacy analysis
• Define subjects to be included / not included in
analysis
– Efficacy evaluable subjects
e.g., randomized, received at least <period> of Rx, <##>
follow ups
– Intent-to-Treat (ITT) evaluable subjects
e.g., randomized, received at least one dose and at least
one follow up

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 7.7 Study treatment
• Description of treatments
– identity, formulation details and prescribing info.
– packaging, labeling, storage and expiry
– method of randomization, blinding, and breaking of blind
– dosage, timing of dose, frequency, duration
– guidelines for titration (if applicable)
– dispensation, returns and accountability
– treatment compliance
– method of documentation in CRF
– proof of receipt and dispatch

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 7.8 Termination of study
• Rules for discontinuation of study subjects
• Rules for termination of study
– safety/efficacy
• Mention of the bodies who are authorized to terminate /
suspend study ...
– IRB/EC/regulators/investigators/sponsor

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 8.0 Safety reporting
• Definitions
– Adverse events (AEs)
– Serious adverse events (SAEs)
• Reporting obligations & timelines
• Methods and measurements to assess safety and
tolerability
– clinical examination
– laboratory investigation
• Clear definition of “abnormality”
• Discontinuation of subjects

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 9.0 Concomitant therapy

• Any treatment other than the study treatment(s)

• To be recorded in the CRF with as much details possible
• Specify all prescription and non-prescription therapies
permitted/disallowed (before, during & after)
• Supplemental / rescue / escape medications
• Ensure that these match with other criteria

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 10, 11.0 Study materials & management
• Materials: describe
– all that is to be supplied by sponsor
e.g., CRFs, questionnaires, patient diaries, other forms
– what is accountable and returnable
– what, who and where used/unused supplies can be destroyed

• Documentation: describe
– how supplied materials should be used
– what forms to be used, how and when to be filled
– verification of source documents and archival method
– what documents will be given to sponsor
– how confidentiality will be maintained
– who, how and when monitoring/audits will be conducted

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 12.0 Data analysis
• Outline the analysis plan
– who does data entry and analysis
– method of analysis for safety and efficacy
– how to account for missing/unused/spurious data
– interim analysis (if planned)
– termination rules of study
– data processing and statistical methods

• Any deviation from this plan should be justified and documented

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 13.0 Publication & Communication

• Specify who has the ownership of ...

– documents (specify which)
– data
– results
– publication (authorship)
• Ensure appropriate study participants receive a fair, accurate and
reasonable representation
• Sponsors should be consulted before independent publications are
planned by investigator
• No attempt to limit the investigator’s right to publish

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14, 15.0 References and Signatures

To complete the document…..

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 Then….. Principal Investigator
Writes Protocol

IRB
1971 Review
Protocol
Review Revisions to
Protocol Requested
Process
Final IRB
Approval
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 And Now…
Beyond 2000 Protocol Review Process

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 Resources 1
The IUATLD booklet - 2001
TABLE OF CONTENTS
3. GETTING STARTED IN RESEARCH
Research question and protocol
4. STRUCTURING RESEARCH: STUDY DESIGN
Designs of study and study types
5. THE SUBJECT OF RESEARCH
Population, sampling methods, sample size
6. MEASUREMENT IN EPIDEMIOLOGY
Collection and management of data
7. CONDUCTING RESEARCH PRACTICAL
STEPS
Study conduct; checking, coding, entering data
8. INTERPRETING RESULTS
Data analysis, interpretation, and report writing
9. OTHER ISSUES IN RESEARCH
IPR and ethics ℠
 Resources 2

http://www.cc.nih.gov/ccc/protomechanics/
These are the NIH’s guidance documents for
protocols proposed for the Warren Grant
Magnuson Clinical Center. Subjects include:
– Protocol content
– Roles and responsibilities
– Regulatory compliance
– Scientific and statistical design
– Compensation and reimbursement issues
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 Resources 3

Cancer Therapy Evaluation Program (CTEP)

http://ctep.cancer.gov/guidelines/
Contains guidelines and resources for clinical
cancer trials conducted under NCI auspices,
including:
– Investigators’ Handbook
– Protocol templates (phase I, II, & III)
– Regulatory and process guidance

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 Resources 4

Office of Human Subjects Research (OHSR)

http://ohsr.od.nih.gov/info/info.html
List of OHSR guidance documents, including:
http://ohsr.od.nih.gov/info/sheet5.html
Guidelines for writing research protocols

http://ohsr.od.nih.gov/info/sheet6.html
Guidelines for writing informed consent documents

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Clinical Research Resources
www.clinicalresearchresources.com
Resources 5
Clinical Research Resources,
LLC, is the leading publisher
of regulatory compliance
publications for the regulated
pharmaceutical, biotech, and
health care industries,
serving nearly all of the top
50 pharmaceutical
companies in the world.
Currently publish 25 titles,
most at only $14.95/copy,
covering GCP, GMP, GLP,
Drug Labeling and Marketing,
Clinical Writing and Statistics,
HIPAA, and Conducting Trials
in the US, the EU, Japan,
India and Canada, to
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Group Exercise/Home Assignment

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 In Conclusion
• Designing and Developing a “good” protocol is
an intellectual and creative group task

• Thinking ahead about challenges - scientific,

ethical, regulatory, commercial, logistical and
cultural, will influence success

• Seek the joy, and enjoy…..

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Thank - You !