OVERVIEW OF PROTOCOL

A protocol is the written mechanism

(document) that describes how the
clinical trial design will be
implemented.
 OVERVIEW OF PROTOCOL
Definition: (Indian GCP)
A document that states the
background, objectives, rationale,
design, methodology (including the
methods for dealing with
AEs,withdrawals etc) and statistical
considerations of the study. It also
states the conditions under which
the study shall be performed and
managed.
 OVERVIEW OF PROTOCOL

PROTOCOL (ICH-GCP)

A document that describes the

objective(s), design, methodology,
statistical consideration and
organization of a trial.
A protocol usually also gives
background and rationale for the
trial.
The term protocol refers to protocol
& protocol ammendment(s)
 OVERVIEW OF PROTOCOL

PROTOCOL AMMENDMENTS: (ICH-

GCP)

A written description of a change(s)

to or formal clarification of a
protocol.
 OVERVIEW OF PROTOCOL

“ A well designed study relies

predominantly on a thoroughly
considered, well-structured &
complete protocol.”
 OVERVIEW OF PROTOCOL
The contents should generally include
(ICH-GCP):
2. General Information
3. Background Information
4. Trial Objectives and Purpose
5. Trial Design
6. Selection and Withdrawal of Subjects
7. Treatment of Subjects
8. Assessment of efficacy

(contd)
 OVERVIEW OF PROTOCOL

The contents should generally include(ICH-

GCP)
2. Assessment of Safety
3. Statistics
4. Direct Access to Source
Data/Documents
5. Quality Control and Quality Assurance
Procedures
6. Ethics
7. Data Handling and Record Keeping
(contd)
 OVERVIEW OF PROTOCOL

The contents should generally include

(ICH-GCP)
2. Financing and Insurance
3. Publication Policy
4. Supplements. E.g. Enclosures like
DoH, PIS/ICF etc.
 OVERVIEW OF PROTOCOL
Components of a Protocol (Sch ‘Y’)
II. Title page
c. Full study title
d. Study/Protocol number & version
e. Name & address of sponsor
VI. List of Investigators, with
addresses where study will be
conducted
VII. Clinical Laboratory details, with
name and address.
VIII.Table of contents
(contd)
 OVERVIEW OF PROTOCOL
Components of a Protocol (Sch ‘Y’)
IV.Table of Contents:
3. Background & Introduction
4. Study Rationale
5. Study Objective(s)
6. Study Design
7. Study Population
8. Inclusion/Exclusion Criteria (Subject
Eligibility)
9. Study Assessments
10.Study Conduct
(contd)
 OVERVIEW OF PROTOCOL

Components of a Protocol (Sch ‘Y’)

IV.Table of Contents :
3. Study Treatment
4. AE/SAEs
5. Ethical Considerations
6. Study Monitoring & Supervision
7. IP Management
8. Data Analysis (including Statistics)
9. Undertaking by Investigator
10.Appendices
 OVERVIEW OF PROTOCOL
Relevant Components of a Protocol (Indian
GCP)
• General Information
• Objectives and Justification
• Ethical Considerations
• Study Design
• Inclusion, Exclusion and Withdrawal of
Subjects
• Handling of the Product(s)
• Assessment of Efficacy
• Assessment of Safety
• Statistics
• Data Handling and management
• Quality control and quality assurance
• Finance and insurance
 OVERVIEW OF PROTOCOL
Essential Components in a Protocol:
1. General Information
c. Title,number,version & date
d. Name,address & contact details of
sponsor,CRO, monitor
e. Responsible persons of the
Sponsor/CRO,including medical expert
f. List of Investigators,with details
g. Name(s) of other institutions e.g.
Central lab
 OVERVIEW OF PROTOCOL
Essential Components in a Protocol:
2. Objectives & Justification
c. Aims of study & phase of study
d. Information on investigational product
e. Summary of findings from pre-clinical
studies
f. Summary of potential risks & benefits
g. Route of administration, dosage
regimen & duration of therapy.
h. GCP compliance statement &
Regulatory requirement compliance
i. Inclusion/Exclusion criteria
 OVERVIEW OF PROTOCOL

Essential Components in a Protocol:

3. Ethical Considerations
c. General aspects
d. IC process, in detail
e. Other information to patients
OVERVIEW OF PROTOCOL
Essential Components in a Protocol:
4&5. Study Design & I/E & withdrawal of
subjects
c. Primary & Secondary efficacy parameters
(end points)
d. Study design
e. Concomitant medications
f. Study treatment details
g. Duration of participation of each subject
h. Discontinuation criteria
i. Investigational Product (IP)
j. Randomization & rules for breaking the
random code
k. Statistical justification for number of
OVERVIEW OF PROTOCOL
Essential Components in a Protocol:
6. IP Handling
c. Safety & storage conditions of study
material, including IP
d. Labeling details for IP
OVERVIEW OF PROTOCOL

Essential Components in a Protocol:

7. Efficacy assessment
c. Specification of efficacy parameters
d. Method(s) of measurement & recording
e. Time & periodicity measurement
f. Description of all tests to be carried out
OVERVIEW OF PROTOCOL
Essential Components in a Protocol:
8. Safety Assessment
c. Specify safety parameters
d. Recording & reporting of AEs/SAEs
e. Type & duration of follow-up in case of
AE/SAE
f. Methods & frequency of assessing &
recording safety parameters
OVERVIEW OF PROTOCOL
Essential Components in a Protocol:
9. Statistics
c. Description of statistical tests
d. Interim analysis
e. No. of subjects
f. Level of statistical significance
g. Procedures for Data handling
h. Procedures for deviations
i. Selection of subjects for final
analysis
 OVERVIEW OF PROTOCOL

10. DM & Data handling

11. QC & QA
12. Finance & Insurance
13. Publication Policy
14. Appendices
 OVERVIEW OF PROTOCOL
Protocol
Contents
Topic ICH-GCP Indian Sch’Y’
GCP
General √ √
Information
Background √ √
Information
Objectives √ √ √

Design √ √ √

(contd)
OVERVIEW OF PROTOCOL
Topic ICH- Indian GCP Sch’Y’
GCP
I/E Criteria √ √ √

Treatment of √ √ √
Subjects (product (& IP
handling) managem
ent)
Efficacy √ √ √
Assessment
Safety √ √ √
Assessment

(contd)
OVERVIEW OF PROTOCOL
Topic ICH- Indian GCP Sch’Y’
GCP
Statistics √ √ √

SDV √ √

QC/QA √ √

Ethics √ √ √

(contd)
 OVERVIEW OF PROTOCOL
Topic ICH-GCP Indian Sch’Y’
GCP
Data Handling √ √
& Archiving (including
SDV)
Finance/Insuran √ √
ce
Publication √ √
Policy

Supplements/ √ √
Appendices
 OVERVIEW OF PROTOCOL
Additional Activities
Time & event schedules for
additional activities to be
planned:
c. Preparing, packing & dispensing
CT material
d. IC/PI forms & translations
e. EC submission
f. Regulatory application
g. Data entry processes
h. Preparations of CRFs Contd
OVERVIEW OF PROTOCOL

Additional Activities

c. Study Monitoring manual

d. QA/QC of final Protocol
e. Signatures on protocol
CASE REPORT FORM
DESIGN AND FORMAT
 DEFINITION

A printed, optical, or electronic

document
designed to record all of the protocol
required information to be reported
to the
sponsor on each trial subject
GCP (consolidated Guideline) Section 1.11
 CRF
• The forms used to record the
patient’s data obtained during the
clinical study are collectively
called as CRF
• CRFs are
– Designed by the sponsor
– Completed by the Investigators
– Reviewed By the Monitor
– Entered by the Data Management
team
– Analyzed by the Biostatistician
INSTRUCTIONS FOR CRF DESIGNING

• Use inputs from the study team

• Request minimal free text
responses
• Record dates to help trace source
data
• There should be one CRF per
subject
• Any parameter that will not be
analyzed should not be included
 CRF RESPONSIBILITIES
Project Leads, manages, works with
Manager statistician, proves input on
design, reviews
Investigator Assures correct entering of CRFs

Monitor Checks for accuracy and

consistency
Data Manager Reviews and edits

Statistician Gives inputs, ensure CRF and

database tally
ROLE OF INVESTIGATORS

• Assure all patients data is collected as

per the protocol
• Record data in CRF as per the sponsor’s
requirements
• Assure consistency within the CRF
• Assure consistency between the CRF
and SD
• Assure corrections are made (if
required) as per monitor’s remarks
 ROLE OF INVESTIGATORS
• Sign the CRFs

• Retain Patient’s SD and CRFs and

assure that the monitor can access
them during all the site visits
 ROLE OF
MONITORS
• Review CRFs to check for
– Legibility and accuracy of the data
– Consistency with the SD
– Timely and accurate Adverse Event
reporting
– Study Drug Accountability
– Protocol Deviations
 ACCURATE
DOCUMENTATION
• Provides basis for safety and
efficacy evaluation of the drug
• Documents protocol adherence
and protection of human subjects
• Validates data integrity and
analysis
• The design of the CRF is a critical
factor in the capture of high quality
data
• CRF should be
– Well structured
– Easy to complete
– Specific enough to avoid collection of
unnecessary information
The size, Design, Content
and Complexity of the CRF
depends upon the stage and
design of the study
How to design a CRF?
• Two questions that need to be
addressed during the design
process are
– Why does this information need to be
collected?
– How is it going to be analyzed?
CONTENTS OF THE CRF
 Must be protocol driven
 Must contain sections on
 Study Number, Center Code, Patient
Number
 Name, signature of Investigator
 Version, Date, Page numbers
 Emergency Numbers
 Instructions for filling the CRF
 Study Flow Chart
 Inclusion /Non-inclusion criteria
 CONTENTS OF THE CRF
 Demography of Patients
 Medical History of Patients
 Concomitant Medications/ Previous
therapy
 Current Illness (Signs and Symptoms/
Diagnosis)
 Study Medication dosing details
 General Examination
 Laboratory Examination
 Special Examination
 CONTENTS OF THE CRF
 Adverse Event Reporting
 Serious Adverse Event Reporting
 Compliance Check
 Efficacy Parameters
 Safety Parameters
 Global Evaluation of Efficacy and
Tolerability
 End of Study Information
INSTRUCTIONS FOR FILLING THE CRF
• Enter Patient Number in CRF
• Ensure Patient Number in the CRF
corresponds to the study medication
packing
• Use only standard abbreviations
• For correction of any entries, strike out
the incorrect entry with one line and
enter correct entry alongside, initial and
date it
• Enter data in black ball-point pen only
 STUDY FLOW CHART

Wash-out
period 1 7 14 21

Treatment A /Dose

Day –3
Treatment B /Dose

Drug Visit 2 Visit 3 Visit 4

Dispensing
SCHEDULE OF OBSERVATIONS
Paramete Day Day 1 Day Day Day
r –3 7 14 21
Informed - - - -
Consent

Inclusion/  Revie - - -
Exclusion w
Lab - - -
Investigation
 
s
Compliance - -
Check
  
General     
Examinatio
n
 INCLUSION CRITERIA
Please Check all statements and tick ( ) the appropriate
box

• Morning stiffeness in and around joints Y

N
lasting 1 hour

If the answer is “No” to any of the above, please do not enroll the
patient
EXCLUSION CRITERIA

• Pregnant/ Lactating woman and woman Y

N
of child bearing potential not following
adequate contraceptive measures
DEMOGRAPHY OF PATIENTS
Patient’s Initials
Age (in years)

Sex M F
Weight (in Kg)
Height (in cm)
 CONCOMITANT
ILLNESS AND MEDICATIONS
Condition Name of Dosage Start Remark
The Drug Strength ed on s
(Generic) /
Hypertensio Atenolol Frequenc
50mg OD Date
n y

STUDY MEDICATION DOSING DETAILS

• Treatment A/B
• Dose: ____mg
• Frequency: OD/BID
GENERAL EXAMINATION
• VITAL SIGNS
• Body Temperature

• Pulse Rate

• Blood Pressure
LABORATORY EXAMINATION
 Complete Blood Count: Hb, WBC, RBC, ESR,
Platelets etc.

 Enzymes: Alkaline phosphatase, SGPT,

SGOT etc.
 Blood Sugar: Fasting, PP, HbA1C
 Urine Analysis
 ECG findings
 Other Investigations

Normal Lab values must be given

either in the CRF or separately
 SPECIAL EXAMINATION
• Depends on the type of the study
– For Pain, pain VAS score is analysed
– For Inflammation, swelling, redness,
local temperature, pain are analysed
– For RA, HAQ score is determined
– For hypertension, DBP, SBP average
of 3-6 readings are taken into
consideration
ADVERSE EVENT REPORTING
Did the patient experience any of the
following?
Event Y Severity Treatment Outcome
es/ Mild/Moderat If given Continued/
No e/Severe Drug, Dose resolved
Nausea

Abdomin
al
Discomfo
rt
SERIOUS ADVERSE EVENT REPORTING
 EFFICACY PARAMETERS
 By Investigator
 By Patients
Efficacy Evaluation

9%
10%

46%

35%

Excellent Good Average Poor

 TOLERABILITY PARAMETERS
Done either at the interim phase (in-
between visit) or at the end of the
study

 By Patients
 By Investigator
 CRF FOR BE STUDY
• Informed Consent with witness
• Volunteer Data, Emergency Contact
• Screening Form , Selection compliance
• Clinical Reports
• Check In - Check Out form
• Habit Form
• Activity Form
 CRF FOR BE STUDY
• Dosage Compliance
• Blood Collection Routine
• Centrifugation Record
• Vital Signs
• Food / water Controls
• Symptom Check List
• Adverse Event form
• Post Study Status Report
APPROACHES TO CRF
DESIGNS
 VISIT BY VISIT
CRF booklet is divided visit wise
into different parts by separators
• Easier for study coordinator
• Difficult to monitor and compare data
 LOG FORMAT
CRF booklet is divided assessment
wise
into different parts by separators.
OPEN Vs CLOSED DESIGN
 OPEN ENDED QUESTIONS

Give Details of Patient’s Medical History

 CLOSE ENDED QUESTIONS
Does patient have any clinically significant medical
history? YES NO If yes, fill the following details

Body System Norma Abnorma Comments

l l What? Since when?
CVS
Respiratory
System
CNS
Eyes/ Ear
LOOSE VS BOUND
 IDEAL CRF
• Present a high quality image
• Be easy to use and complete
• Provide Clear instructions
• Ask specific questions and offer
unambiguous criteria for answers
• Provide for accurate recording of
results
• Be as concise as possible
The success of the clinical trial
depends
not only upon the design of the
study
protocol but also upon the methods
employed to ensure that clinical
data are
of high quality and in suitable format
for
statistical analysis
 FUTURE?
• WEB- BASED TRIALS / E- Trials/
EDC
Investigators Site 1

Investigators Site 2 Web server

Investigators Site 3 Data Base

Internet
EXERCISE