protocol aug10 2010 dr.aamirshaikh
TRANSCRIPT
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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 !