Protocol writing

PROTOCOL WRITINGDr. AMREEN SABA ATTARIYAPOST GRADUATE STUDENT, DEPT OF PHARMACOLOGY

M.R. MEDICAL COLLEGE, GULBARGA INDIA

PROTOCOL

Outline of TalkCriteria for a good research topic

Definition of protocol

Need for it

Format of protocol

Summary

References

May 1, 2023Dr.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 May 1, 2023

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. May 1, 2023Dr.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. May 1, 2023Dr.A.S.Attariya:ProtocolWriting

PROCESS OF WRITING A PROTOCOLLiterature Review

Determine END POINTS

Formulate HYPOTHESIS/ RESEARCH QUESTION

Draft a protocol

PEER REVIEW

Final Version

Amendments


PROTOCOL DEVELOPMENT

TEAM1.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 title2. Background information3. Trial objective and purpose4. Trial design5. Selection and withdrawal of subjects6. Medicine and dosage7. Assessment of safety and efficacy8. Statistics9. Quality control and quality assurance10. Ethics11. Data handling and record keeping12. Publication policy13. References14. Appendices

May 1, 2023*Maiti R: Post Graduate topics in pharmacology, 1st ed. Page 62-68 Dr.A.S.Attariya:ProtocolWriting

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

InstitutionsMay 1, 2023Dr.A.S.Attariya:ProtocolWriting

BACKGROUNDRATIONALE 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*.

May 1, 2023*principles of ICH-GCPDr.A.S.Attariya:ProtocolWriting

RESEARCH QUESTION(PICOT)

P- POPULATION

I- INTERVENTION

C- COMPARISON

O- OUTCOME

T- TIME


OBJECTIVES Simple, Specific, and Stated

In Advance


Objectives ---SMART

SpecificMeasurableAttainableRealisticTime-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 typesNon-Comparative: usually used to assess a treatment’s safety and tolerability.

Comparative design used when comparing treatments:Cross-over Parallel




BIASSelection/ Allocation biasObserver bias

HOW TO AVOID???

RandomisationBlinding


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 CRITERIARECOMMENDATIONS*:

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, 1996Fuks A, J Clinal Epidemiology, 1998


SUBJECTS WITHDRAWAL CRITERIA

When and how to withdraw subjects from trialType and timing of the data to be collected from withdrawn subjectsWhether and how to replace subjectsFollow up for subjects withdrawn


STUDY ASSESSMENTPlans, 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 DURATIONInclude 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-UPThe 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 EVENTSProvide 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 sponsorLists of expected adverse events

Procedures used for evaluation & handling of AE


Types of relationship of AE with drug: -1. Definite2. Probable3. Possible4. Unknown5. Not likelyAction taken by Investigator: - 1. None2. Increase in the surveillance3. 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 agendaSource document verificationData clarification/ rectificationClose out meeting/ site closureTrial supplies accountingRecords preservation & archivingPatient screening logPatient identification logICFSource documentsCRFPublication 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?




The RIGHTS, SAFETY & WELL

BEING of SUBJECTS are the most

important than interests of science

& society.May 1, 2023Dr.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 investigatorIt 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 trial2. 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 researchPurpose of the research and the length of the studyDescription of risks and benefitsDiscussion of alternative therapiesConfidentiality policyCompensation for injuryContact for further questions/informationStatement of voluntary participation

*OHSR Information Sheet 6: Guidelines for Writing Informed Consents (ohsr.od.nih.gov/info/sheet6.html )


PurposePurpose

ProcedureProcedure

41May 1, 2023Dr.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 projectsIt 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

BudgetIn clinical trial, statement of insurance should be mentioned


BUDGETBudget 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.


REFERENCESThe 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)


APPENDICESInvestigator’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


TEMPLATESThe 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.html


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#informed


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 perDECLARATION OF HELSINKIGCP

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 62-687. Protocol template for clinical trials.8. WHO-Informed consent form template9. 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.


http://www.who.int/rpc/research_ethics/guide_rp/en/

THREE WORDS SUMMARISE THE

SUCCESS IN CLINICAL TRIAL

PLANNINGPLANNINGPLANNING


May 1, 2023

SUBJECT’S SAFETY

IS ABOVE

ALLDr.A.S.Attariya:ProtocolWriting

THANKYOU


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


May 1, 2023CFR- code of federal regulations Dr.A.S.Attariya:ProtocolWriting

When to stop a clinical trialDuring 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. May 1, 2023

CQ'S WEB BLOG ON THE ISSUES IN BIOSTATISTICS AND CLINICAL TRIALS.FRIDAY, MARCH 09, 2012Futility Analysis in Clinical Trials - Stop the trial for futilityDr.A.S.Attariya:ProtocolWriting

http://www.nejm.org/doi/pdf/10.1056/NEJMoa072113

http://www.nejm.org/doi/pdf/10.1056/NEJMoa072113

Protocol writing

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