Protocol Aug10 2010 Dr.aamirShaikh

8/8/2019 Protocol Aug10 2010 Dr.aamirShaikh

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Clinical Trial Protocol

Moving Academy of Medicine and Biomedicineand National Institute of Research onReproductive Health (NIRRH)

NIRRH, Parel, Aug 10, 2010

Foundation workshop on Clinical and

Laboratory Medicine Research


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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 atrial. It usually also gives the background and the rationalefor 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 questionDo participants, in Clinical Research Training Course inNIRRH, 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 Criteria6.2. Exclusion Criteria

7.0 METHODOLOGY

7.1 Study Design

7.2 Study Schedule

7.3 Study Visits

7.4 Study Evaluations/Procedures7.5 Definition of Efficacy Endpoints

7.6 Efficacy Analyses

7.7 Study Treatments

7.8 Termination of the Study

8.0 SAFETY REPORTING8.1. Serious Adverse Events / Others

8.2. Abnormal Laboratory Test Results

& Physical Examination Findings

8.3. Laboratory Tests

8.4. Patient Discontinuations


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Protocol contents (2)

9.0 STUDY MANAGEMENT AND MATERIALS

9.1 Study Materials

9.2 Study Documentation

9.3 Monitoring and Quality

Assurance

10.0 CONCOMITANT THERAPY

11.0 CONFIDENTIALITY

12.0 DATA ANALYSIS

13.0 COMMUNICATION AND PUBLICATION

OF RESULTS

14.0 REFERENCES

15.0 STUDY PROTOCOL AGREEMENT

SIGNATURE PAGE

LIST OF APPENDICES

Investigators and investigating

sites

Declaration of Helsinki

Informed consent form (ICF),Case report form (CRF) &

Prescribing Information

Advertisement and subject

recruitment procedure

Study flow chart & Subjectscreen / recruitment log

Others


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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 incompletecases/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 expecteddifference (effect)

estimated variability of studyparameters (S.D.)

error (p


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What influences late phase clinical trial design and numbers?

Cardiovascular Studies - An example

>15% have CV event in 1 yr 5-6% have CV event In 1 yr1-2% have CV event in 1 yr

Primary Prevention ACS Patient

Acute Coronary Event

Stable CHD Patient

Significance, Power, and Sample size

Superiority vs Non-Inferiority vs Equivalence

P value vs Confidence Interval

Statistical vs Clinical significance

Regulatory environment

Standard of care

And alsosome specifics


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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) andassessment(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 allprocedure(s), observation(s) and assessment(s)


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7.5 Efficacy variables - endpoints

The variable capable of providing the most clinicallyrelevant and convincing evidence related to theprimary 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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7.6 Efficacy analysis

Define subjects to be included / not included in

analysis

Efficacy evaluable subjects

e.g., randomized, received at least 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 andtolerability

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 andreasonable representation

Sponsors should be consulted before independent publications areplanned by investigator

No attempt to limit the investigators right to publish


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14, 15.0 References and Signatures

To complete the document..


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1971

ProtocolReview

Process

Principal Investigator

Writes Protocol

IRB

Review

Revisions to

Protocol Requested

Final IRB

Approval

Then..


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And Now

Beyond 2000 Protocol Review Process

R


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The IUATLD booklet - 2001

TABLE OF CONTENTS

3. GETTING STARTED IN RESEARCHResearch question and protocol

4. STRUCTURING RESEARCH: STUDY DESIGNDesigns of study and study types

5. THE SUBJECT OF RESEARCHPopulation, sampling methods, sample size

6. MEASUREMENT IN EPIDEMIOLOGYCollection and management of data

7. CONDUCTING RESEARCH PRACTICALSTEPS

Study conduct; checking, coding, entering data

8. INTERPRETING RESULTSData analysis, interpretation, and report writing

9. OTHER ISSUES IN RESEARCHIPR and ethics

Resources 1

R 2


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Resources 2

http://www.cc.nih.gov/ccc/protomechanics/

These are the NIHs 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

Resources 3


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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

Resources 3

Resources 4


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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.htmlGuidelines for writing research protocols

http://ohsr.od.nih.gov/info/sheet6.html

Guidelines for writing informed consent documents

Resources 4

Resources 5


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www.clinicalresearchresources.com

Resources 5

Clinical Research Resources

Clinical Research Resources,LLC, is the leading publisherof regulatory compliancepublications for the regulatedpharmaceutical, biotech, and

health care industries,serving nearly all of the top50 pharmaceuticalcompanies 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 Trialsin the US, the EU, Japan,

India and Canada, to
http://www.clinicalresearchresources.com/books/bookstore.htmlhttp://www.clinicalresearchresources.com/books/bookstore.html


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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 !

Protocol Aug10 2010 Dr.aamirShaikh

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