Protocol writing

PROTOCOL WRITING
Dr. AMREEN SABA ATTARIYA
POST GRADUATE STUDENT, DEPT OF PHARMACOLOGY
M.R. MEDICAL COLLEGE, GULBARGA
INDIA
PROTOCOL

Outline of Talk
Criteria for a good research topic
Definition of protocol
Need for it
Format of protocol
Summary
References
Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

Criteria for a good research
topic
Feasible
Interesting
Novel
Ethical
Relevant.
These criteria have been collectively called the
FINER formula*
*Hulley et al., 2001 Mar 20, 2016
Dr.A.S.Attariya:ProtocolWriting

DEFINITION OF
PROTOCOL
(Greek word, protokollon - first page) means a
format procedure for carrying out a scientific
research.
A document that describes the objective(s),
design, methodology, statistical considerations
and organization of a trial.*
*Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice.1.44
protocol. Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

NEED FOR A RESEARCH
PROTOCOL
 Detailed plan of the study.
 Forces the investigators to clarify their thoughts and
to think about all aspects of the study
 Necessary guide if a team is working on the research
 Essential component of a research proposal submitted
for funding.
 Ensures study is conducted, data are collected,
analyzed & integrated in scientifically rigorous,
ethical, consistent & timely manner.

PROCESS OF WRITING A
PROTOCOL
Literature Review
Determine END POINTS
Formulate HYPOTHESIS/ RESEARCH QUESTION
Draft a protocol
PEER REVIEW
Final Version
Amendments Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

PROTOCOL
DEVELOPMENT TEAM
1.Pharmaceutical Physician.
2.Clinical Research Manager.
3Quality Assurance Manager.
4.Statistician.
5.Drug Supplier Representative.
6.Data Management Personnel.
7.Regulatory Authority Representative.
8.Safety Group Representative.
9.Investigators.
10.Expert in Therapeutic Area.
11.Legal Representative.

FORMAT FOR THE PROTOCOL*
1. Project title
2. Background information
3. Trial objective and purpose
4. Trial design
5. Selection and withdrawal of subjects
6. Medicine and dosage
7. Assessment of safety and efficacy
8. Statistics
9. Quality control and quality assurance
10. Ethics
11. Data handling and record keeping
12. Publication policy
13. References
14. Appendices
Mar 20, 2016
*Maiti R: Post Graduate topics in pharmacology, 1st
ed. Page 62-68

PROJECT TITLE
Descriptive and concise.
Scientifically sound, clear, detailed*
*Requirements for clinical trial protocol and protocol amendments
ICH GCP guidelines.

SHOULD INCLUDE
 Protocol/ study no. and protocol
version no. with date
 Study design, disease of interest.
 IND(investigational new drug) name / no. of
investigational drugs
 Comparative Medicinal Product
 Sponsors, Investigators
 Clinical Laboratories, other Institutions

BACKGROUND
RATIONALE
 Equivalent to the introduction in a research paper.
 Should answer WHY and WHAT
 Brief description of the most relevant studies
published on the subject should be provided to
support the rationale for the study.
 The available nonclinical and clinical information on
an investigational product should be adequate to
support the proposed clinical trial*.
Mar 20, 2016
*principles of ICH-GCP

RESEARCH
QUESTION(PICOT)
P- POPULATION
I- INTERVENTION
C- COMPARISON
O- OUTCOME
T- TIME

OBJECTIVES
 Simple, Specific, and Stated In Advance

Objectives ---SMART
Specific
Measurable
Attainable
Realistic
Time-bound.

Primary Objective:
Main purpose of performing this
study and should be focused on one
question

Secondary Objectives:
Can be two or three can be dependent
or independent of the primary objective

CHOICE OF STUDY
DESIGN
Two main types
Non-Comparative: usually used to assess a
treatment’s safety and tolerability.
Comparative design used when comparing
treatments:
Cross-over Parallel

BIAS
Selection/ Allocation bias
Observer bias
HOW TO AVOID???
Randomisation Blinding

The protocol should provide information and
justification about sample size
Statistician can be consulted
STUDY POPULATION/
SAMPLE SIZE

ELIGIBILITY
CRITERIA
Eligibility criteria stated as either exclusion or
inclusion criteria
Define the population to be studied.
Inclusion criteria/Exclusion criteria should
reflect the wider population of patients.

ELIGIBILITY CRITERIA
RECOMMENDATIONS*:
The number of eligibility criteria should be kept
to a minimum.
Criteria should include only those absolutely
necessary to ensure scientific validity and patient
safety.
Eligibility criteria should be clearly defined and
verifiable by an external auditor.
* George SL, J Clinal Oncology, 1996
Fuks A, J Clinal Epidemiology, 1998 Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

SUBJECTS WITHDRAWAL CRITERIA
When and how to withdraw subjects from
trial
Type and timing of the data to be collected
from withdrawn subjects
Whether and how to replace subjects
Follow up for subjects withdrawn

STUDY ASSESSMENT
Plans, procedures and methods are described
in detail.
Details of this section ensure that:
 all observations are performed in a standard
manner.
 Sample collection procedure and laboratory
tests are performed in a standard manner

STUDY DURATION
Include a projected start date.
Provide the total length of time participants
will remain in the study or will be taking drug
including the follow up period.
Include an approximate end date of the study.

TIME WORK PLAN Example

SAFETY CONSIDERATIONS
THE SAFETY OF RESEARCH PARTICIPANTS IS
FOREMOST.
Specification of safety parameters.
The methods and timing for assessing, recording, and
analyzing safety parameters.

FOLLOW-UP
The research protocol must give a clear
indication of what follow up will be provided
to the research participants and for how long.
This may include a follow up, especially for
adverse events, even after data collection for
the research study is completed.

ADVERSE EVENTS
Provide a definition of an Adverse Event
(AEs) and Serious Adverse Event (SAEs) based
on the study.
This section should include:
Detailed information for reporting adverse events,
including reporting to the Drug control
authority, FDA and/or the sponsor
Lists of expected adverse events
Procedures used for evaluation & handling of
AE Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

Types of relationship of AE with drug: -
1. Definite
2. Probable
3. Possible
4. Unknown
5. Not likely
Action taken by Investigator: -
1. None
2. Increase in the surveillance
3. Dose modification, termination etc.
4. Treatment of AE

SAE will be immediately notified to
a. EC within 7 days
b. Sponsor (by investigator) within 24hrs or as
soon as possible

STUDY MONITORING &
SUPERVISION
Monitoring frequency and agenda
Source document verification
Data clarification/ rectification
Close out meeting/ site closure
Trial supplies accounting
Records preservation & archiving
Patient screening log
Patient identification log
ICF
Source documents
CRF
Publication policy

ETHICAL CONSIDERATIONS
General issues
Has every possible precaution been taken to
ensure the safety of the subject?
Are the assessments really necessary, especially
those that involve some risk to the subject
(e.g. invasive measurements)?
Is the comparator (especially if it is placebo)
ETHICAL to use or is the subject being
deprived of current proven effective
treatment?

Mar 20, 2016

The RIGHTS,
SAFETY & WELL
BEING of
SUBJECTS are the
most important
than interests ofMar 20, 2016Dr.A.S.Attariya:ProtocolWriting

ETHICAL CONSIDERATIONS:
THE DECLARATION OF HELSINKI
It is a statement of clinical principles to
provide guidance to physicians and other
participants in medical research involving
human subjects.
It confirms the role of the physician above
that of the investigator
It is a set of principles defining the standards
that should apply to biomedical research
worldwide

ETHICAL CONSIDERATIONS:
Informed consent.
Often comes in two parts:
1. Written information describing the
clinical trial
2. A form which the subject signs to document
that he/she has given consent to take part in the
study
Closely reviewed by ethics committees.
Consent is valid when freely given.

Informed consent content.
OHSR(Office of Human Subject Research)
recommends the following be included*:
Statement that the study involves research
Purpose of the research and the length of the study
Description of risks and benefits
Discussion of alternative therapies
Confidentiality policy
Compensation for injury
Contact for further questions/information
Statement of voluntary participation
*OHSR Information Sheet 6: Guidelines for Writing Informed
Consents (ohsr.od.nih.gov/info/sheet6.html ) Mar 20, 2016

PurposePurpose
ProcedureProcedure
41Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

riskrisk
BenefitsBenefits
Alt. RxAlt. Rx
confidentialityconfidentiality

financefinance
Add. Info.Add. Info.
signsign

DATA MANAGEMENT AND
ANALYSIS
Data Collection
Data Management
Data Retention

PROBLEMS
ANTICIPATED
This section should discuss the difficulties
that the investigators anticipate in successfully
completing their projects
It should also offer possible solutions to deal
with these difficulties.
“An investigator who does not anticipate any
problem probably has not thought out the
details of the project carefully”.

FINANCING AND
INSURANCE
Budget
In clinical trial, statement of insurance should
be mentioned

BUDGET
Budget itemization:
• recurring and non recurring costs
• Patient care costs
• Travel
• Data processing
• Communications
• Secretarial expenses
• Publication/dissemination of
information about the outcome of the
project. Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

REFERENCES
The protocol should end with relevant references on the
subject.
Attached with the Protocol
1. CRFs(Case Record Forms)
2. Daily Record-keeping forms
3. SOPs(Standard Operating Procedures)

APPENDICES
Investigator’s Statement.
Patient Information Sheet.
Patient Screening Form.
Drug Movement Form.
Drug Destructive Form.
SAE Form

GOOD WRITING
MATTERS
“…Many existing clinical trials contain
problems such as incompleteness, ambiguity,
and inconsistency. Most of the errors are
introduced during the protocol writing
process*…”
Poorly written inclusion criteria have resulted
in a number of ineligible and inevaluable
patients being enrolled to a study.
*Weng C, Medinfo, 2004

PROTOCOL AMENDMENT
“Any change to the protocol document or
Informed Consent that affects the scientific
intent, study design, patient safety, or
human subject protection is considered an
amendment, and therefore must be
approved by your IRB*…”
*NCI CTEP Amendment Request Submission Policy,
Version Date May 14, 2004
(http://ctep.cancer.gov/guidelines/templates.html

NIH Guidance on Protocol
Writing
Protomechanics:
http://www.cc.nih.gov/ccc/protomechanics/
The Office of Human Subjects Research:
http://ohsr.od.nih.gov/info/info.html
The NCI Investigators’ Handbook:
http://ctep.cancer.gov/handbook/index.html

TEMPLATES
The NIH phase III template:
http://www.ninds.nih.gov/funding/research/
clinical_research/ProtocolTemplate.htm
The Cancer Therapy Evaluation Program (CTEP)
Templates (phases I–III; based on NIH model):
http://ctep.cancer.gov/guidelines/templates.h
tml

INFORMED CONSENTS
Office of Human Subjects Research
http://ohsr.od.nih.gov/info/info.html
The Office for Human Research Protections
(OHRP):
http://www.hhs.gov/ohrp/policy/index.html#inform
ed

SUMMARY OF THE
TALK
Protocol is a BRIEF OUTLINE of what the study is
and how it is going to be carried out.
The contents must be presented in a CLEAR AND
LOGICAL sequence.
Success of a protocol lies in its CLARITY AND
COMPLETENESS.
Good writing of protocol matters.
Study to be conducted in compliance to the protocol
which has received EC APPROVAL.

SUMMARY OF THE
TALK
Scientific consideration,Practical Considerations
Ethical conduct as per
DECLARATION OF HELSINKI
GCP
Primary concern- SUBJECT’s SAFETY

REFERENCES
1. Mahmoud F. Fathalla. WHO Regional Publications Eastern Mediterranean
Series 30, A Practical Guide for Health Researchers, 2004
2. Chowta NM, Shenoy A, Kamath A :Manual of practical pharmacology for
MBBS, 1st
ed, page 55-58.
3. Integrated addendum to ICH E6(R1): Guideline for good clinical practice
E6(R2) dated 11 June 2015.
4. OHSR Information Sheet 6: Guidelines for Writing Informed
Consents(ohsr.od.nih.gov/info/sheet6.html )
5. NCI CTEP guidelines (http://ctep.cancer.gov/guidelines/templates.html)
6. Maiti R: Post Graduate topics in pharmacology, 1st
ed. Page 62-68
7. Protocol template for clinical trials.
8. WHO-Informed consent form template
9. WHO Guide for writing a Research Protocol for research involving human
participation: http://www.who.int/rpc/research_ethics/guide_rp/en/,
accessed on 02.01.2015.

THREE WORDS SUMMARISE
THE SUCCESS IN CLINICAL
TRIAL
PLANNING
PLANNING
PLANNING Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

Mar 20, 2016
SUBJECT’S
SAFETY
IS
ABOVE
ALLDr.A.S.Attariya:ProtocolWriting

THANK
YOU

ASSESSMENT OF PT COMPLIANCE

How do I know whether study is completed
Human subject research activities are considered
completed once all research-related interventions and
interactions with human subjects have been completed,
all data collection and analysis of identifiable private
information described in the IRB-approved research
plan have been finished , and primary analysis of either
identifiable private or deidentifed information is
completed.
http://www.hhs.gov/ohrp/investigatefaq.html#q10 Mar 20, 2016Dr.A.S.Attariya:ProtocolWriting

Mar 20, 2016
CFR- code of federal regulations Dr.A.S.Attariya:ProtocolWriting

When to stop a clinical trial
During a clinical trial, we can perform interim analysis (or DMC, DSMB review) for
three different reasons:
Interim analysis for safety
1) with pre-specified stopping rule (for example stop the trial if we see # of cases of
Serious Adverse Events)
2) without pre-specified stopping rule (rely on DMC members to review the overall
safety)
Interim analysis for efficacy: To see if the new treatment is overwhelmingly better than
control - then stop the trial for efficacy
Interim analysis for futility: To see if the new treatment is unlikely to beat the control –
then stop the trial for futility - this is called ‘futility analysis’.
In situations 2 and 3, the criteria for stopping rule for efficacy could be different from
the stopping rule for futility, but need to be pre-specified.

Contd.
An example for futility analysis: in the beginning of the trial, we assumed 65%
successful rate for new treatment group and 50% successful rate for control
group. We would like to establish the superiority. In the middle of the study, we
did an interim analysis. The interim analysis showed 55% successful rate for new
treatment group and 50% successful rate for control group. Based on the results
from interim analysis, we can calculate the probability and conditional power: if
we continue to finish the study, what is the probability of new treatment group
better than control? If this probability is too small and meet the pre-specified
criteria, we would stop the trial for futility. If this probability is reasonable, we
can continue the trial as pre-planned or we can continue the trial with the
sample size adjustment (typically increase due to the smaller effect size).
In a paper by Miller et al “
Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer
”, one pre-planned interim analysis and two additional interim analyses were
performed and three stopping rules (for safety, for efficacy, and for futility) were
pre-specified and evaluated. It is reasonable to assume that none of these
stopping rules was triggered since the study was not stopped.
Mar 20, 2016
CQ'S WEB BLOG ON THE ISSUES IN BIOSTATISTICS AND CLINICAL TRIALS.
FRIDAY, MARCH 09, 2012
Futility Analysis in Clinical Trials - Stop the trial for futility

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