Clinical Trial Protocol

Dr. M.P.Venkatesh
Associate Professor
Dept. of Pharmaceutics
Regulatory Affairs Group
JSSCP, Mysuru
Trial Documents
• Protocol
• Investigator Brochure
• Informed Consent Document
• Case report forms
• Clinical study reports and summaries
• Contracts and agreements
• Diary cards

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“The beginning is the most
important part of the work.”

Plato (427 BC–347 BC), Greek author and

philosopher
What is Protocol?
• The protocol is a document that provides the background and framework for
the planned study and describes how it will be implemented.

• Protocols are written by trial sponsor personnel, individual investigators,

clinicians, scientists, or any combination of these individuals.
• In the United States, the trial sponsor submits the final protocol to the U.S.
Food and Drug Administration (FDA) as part of an Investigational New Drug
(IND) application or Investigational Device Exemption (IDE) application.

• The FDA must approve the protocol before the sponsor can initiate the
clinical trial at the investigative sites. However, not all protocols, require FDA
review and approval.
• Protocols for clinical investigations of marketed drugs, protocols that are post-
marketing (phase 4), and observational protocols (that is, there is no
investigational product under study) do not need FDA approval before starting
the trial;
• They do however require Institutional Review Board (IRB) approval.

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Components of Protocol
Sample Table of Contents for a Protocol
• Introduction
• Background
• Rationale
• Previous Animal/Human Studies
• Objectives
• Endpoints
• Trial Design
• Subject Selection
• Randomization
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• Treatment Plan
• Schedule of Assessments
• Test Article
• Preparation, Packaging, and Labeling
• Dosing Schedule
• Storage, Dispensing, and Disposal/Return
• Accountability Records
• Data Collection
• Adverse Event Reporting
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• Statistical Analysis
• Ethical Considerations
• Informed Consent
• Confidentiality
• Benefits/Risk of Harm
• Inclusion of Women, Children, and Minorities
• Monitoring
• Subject Compensation
• Publication of Results
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Background and Rationale for the study
• The background section of the protocol includes results from pre-clinical
studies and previous clinical trials with a description of the disorder and
Safety & Efficacy information from previous studies.

• The rationale for the study should clearly state the reason the trial is being
conducted and should be consistent with the background information
provided.
Study Organisation
• The organizational structure of the study is based on protocol needs, financial
considerations, and logistical issues presented by the study design.
End Points
• The objectives of the study are often stated as primary and secondary
endpoints (variables).

• Endpoints are measures believed to quantify the potential effect of a

treatment or therapy under study. In addition to clinical endpoints, quality of
life and economic factors may also be identified as endpoints.

• A clinical endpoint should be

1. Relevant and easy to interpret;
2. Clinically apparent and easy to identify; and
3. Sensitive to treatment differences.
What is a protocol?
• Written document
• What is the question?
• What is the outcome?
• What are the interventions?
• Intervention
• For whom?
• When and for how long?
• How many participants are needed
• How can we optimise potential risk and benefit?

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Background Information
• Literature review
• What prompted you to think of the study?
• Safety assessment
• Therapeutic need
• New drug delivery system
• New dosage schedule
• Exploring new indications
• Therapeutic drug monitoring for safety/efficacy
• Regulatory filing

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What is the aim/question?
• Is it clearly defined?
• What can the results demonstrate compared to the present knowledge?
• Are there ongoing studies addressing the same aim?
• Can the trial provide information which can enhance/improve patient care?

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Aim of the study
• Avoid multiple aims in a single study
• Comparison of efficacy of 2 antihypertensive drugs
• Effect on diurnal blood variation
• Efficacy with respect to
• Age
• Sex
• Associated conditions
• Makes the study design complex and often difficult to execute
• Advisable to consider not more than 2 aims at a time

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End Points
• Primary end points
• Directly related to the clinical benefits
• Secondary end points
• May be related to safety and tolerability profile

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What is the hypothesis?
• Depends upon the aim
• Null hypothesis
• Both the treatments are equal : A=B
• Alternative
• A#B : 2 sided/tailed possibility of outcome
• A>B or B>A 1 sided/tailed possibility of outcome

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Patient Selection : Inclusion Criteria
• Precise diagnostic limits/criteria of the disease to be treated
• Systolic BP >140 mm Hg in sitting position
• Glycosylated Hb > 7.5%
• Acute myocardial infarction
• ECG changes of AMI : q waves, ST elevation
• Raised CPK, CPK-MB
• Age limits (lower and upper)
• Sex
• Associated disorders
• Concomitant treatments
• Run in period required to establish baseline?
• Effect of non drug therapy

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Patient Selection : Exclusion Criteria
• Pregnancy, lactation
• Associated conditions, treatments
• Contraindications to study treatment
• Consider relative contraindications as well
• Patients not likely to attend follow up or comply with treatment

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Criteria for Evaluation of Efficacy
• Necessary for efficacy comparison
• Definition of end point
• Mortality
• Completion of study treatment duration
• Achieving target values
• Blood pressure, glycemia parameters
• Define the techniques/methods/conditions
• Sitting and standing blood pressure
• Analytical method for lipid estimation : Central laboratory
• 24 hour urine output for protein estimation
• Calibration of equipments
• Weighing machine, BP instruments

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Criteria for Evaluation of Efficacy
• Schedule of tests
• Frequency : practical and ethical considerations
• Who will measure the parameters?
• Investigator
• Trained rater
• Always the same rater especially for qualitative assessment
• Skin lesions, localised signs of inflammation
• Two independent observers : evaluation of angiography
• Differences between them
• Statistical techniques for analysis

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Data Collection
• Crucial information with impact on outcome measurement
• Information to check comparability of groups
• Demographic characteristics
• Physiological characteristics
• Onset of signs and symptoms
• Prognostic factors
• Concomitant illness
• Concomitant therapy

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Data Collection
• Is there enough room for noting each result?
• Logical order for data collection
• Advantages and disadvantages of order of data collection

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Clinical Tolerability : Adverse Events
• Open ended questions
• Description of the event occurred in detail
• Treatment administered for the AE
• Outcome
• Close ended questions
• Demographic details
• Date, time, manufacturing details of medication
• Severity, duration
• Laboratory investigations performed

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Clinical Tolerability : Safety Monitoring
• Justification for lab evaluation
• Routine tests for a new drug
• Directed by pharmacological effects
• Laboratory evaluation
• Which tests?
• Before and the end of study
• Central lab/site
• Which method?
• Symptom check list

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Compliance
• Treatment
• Procedure
• Medication
• Non drug treatment
• Dietary restrictions
• Exercise regimen

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Measuring Compliance
• Questionnaire
• Diet recall
• Tablet count
• During follow up visit
• Collect used strips/blister/containers, unused medication
• Presence of markers
• Colour markers for urine, stools, saliva
• Measurement of drug/metabolite in biological fluids
• Recording device incorporated in packaging
• Memory aids in packaging
• Printing day/dates, illustrations

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Experimental Design
• Prospective, randomised
• Matched subjects
• Demography
• Severity of disease
• Factorial design
• Interaction of 2 or more factors : dietary restriction and drug
• Cross over
• Partial/incomplete blocks
• Complete cross over
• Wash out period
• Latin square design

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Factorial Design
Exercise No exercise

Drug

Placebo

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Multiple Stratification
Blood pressure

Blood Low Intermediate High

lipids
Low A A C

Intermediate A B C

High B D E

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Stratification
Age
<45 years >45 years

Males

Females

4 groups per treatment

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Latin Square Design

P1 P2 P3 P1 P2 P3

S1 A B C S1 C B A

S2 B C A S2 A C B

S3 C A B S3 B A C

Mirror Image of Latin Square

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Random Allocation of Treatment
• By packaging number
• Opening sealed envelopes containing randomisation codes
• By telephone
• Remote data entry

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Blinding of Study Treatment
• Ask a jury to discover dissimilarity between the active and placebo
• Can the code be easily broken by the clinical effects?
• If yes, change the design

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Use of Placebo
• Ethical justification
• Must ensure that no patient is denied of treatment

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 Placebo Active comparator

Objective Real pharmacological Equivalence testing

effect
Difference sought Large Small

Analysis 1 tailed 2 tailed

Sample Small large

Problem Ethical considerations Choice of standard

treatment

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Blinding Procedures
• Single blind
• Double blind
• Who holds the code?
• Double dummy
• Test active+Reference placebo
• Test placebo+Reference active
• Emergency : Who and how the code is broken?
• Individual envelopes
• Check the envelopes at the end of trial

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Comparing Combination Components
• Comparison of combination of with each of its components
• A (Active) + B (Placebo)
• A (Placebo) + B (Active)
• A (Active) + B (Active)
• A (Placebo) + B (placebo)

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Treatments to be Compared
• Which treatments?
• New with established therapy
• New with placebo
• Formulations and indications registered

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Treatments to be Compared : Dosage and Administration
• BA BE data for new formulation
• Fixed dosage for all
• Corrected for
• Body weight, surface area, severity of disease
• Titration for
• Maximum tolerated dose
• Target/optimal clinical benefit
• Time of administration
• Relation to food

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Treatments to be Compared : Dosage and Administration
• Wash out
• Concomitant medication : Drug interactions
• Safety
• Efficacy
• Will the results be based on the consumption of concomitant medication?
• Rescue analgesic
• Antacids

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Data Analysis
• Hypotheses to be tested
• One tailed or two tailed comparison
• Criteria for comparability of groups
• Intention to treat analysis
• Statistical methods to be used
• Level of significance for rejecting hypotheses

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Data Analysis : Interim Analysis
• Must be decided a priority
• Who will conduct?
• Which method?
• Will the blinding code be broken?
• If so, what about the blinding of remaining patients?
• Who will know the test results?
• Monitoring committee or investigators or patients
• Information to the ethics committee and or regulatory authorities
• Decisions to continue or stop the trial
• Who will take the decision?

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Basis for Estimation of Sample Size
• Published data of similar studies
• Consider impact of geographical variation, ethnic/racial variation
• Retrospective analysis of data
• Estimates of
• Variability
• Expected clinically relevant efficacy measure
• Pilot study

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Imperfect Data
• Causes for missing data
• Information not available/recorded
• Lost to follow up
• Intolerance to study treatment
• Lost data
• Consent withdrawal
• Protocol violation
• Withdrawal for safety issues by
• Investigator
• Ethics committee

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Multicentric Trials
• Estimate No of patients from each centre
• Consider substitution of centre
• Slow enrolment
• Plan investigators’ meetings
• Protocol discussion
• Trial initiation
• Appoint study coordinators
• Translation of documents
• Consent form
• Patient information

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Publication Policy
• Report writing committee
• Authorship
• Investigators, co-investigators, interdisciplinary collaborators
• Interim report
• Final report
• Conference presentation
• Dissertation or thesis

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The Protocol
• Title derived from aim
• Acronym (Optional)
• Identification No
• Version No
• Revision dates
• Summary table
• Flow-charts

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Golden Rules of GCP

⚫ Write what you want to do

⚫ Do as you write
⚫ Write what was actually done

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Golden Rules of GCP

If something is not
written down, probably
it was not done!

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Thank You

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