Clinical Trial Protocol

Why do a clinical trial?

To answer a clinical problem To gain new knowledge about a new or established treatment To support a claim -for gaining government regulatory approval -for marketing a drug, device, or technique

What is a protocol?
A clinical trial protocol contains a study plan on which the clinical trial is based ICH guidelines state: A document that describes the objective(s), design, methodology, statistical considerations and organization of a trial The protocol usually also gives the background and reason the trial is being conducted, but these could be provided in other documents referenced in the protocol (such as an investigators brochure).

what is the purpose?

Instructs study team on exactly what to do

Explains the study to the outside world

Provides a reviewable document for

necessary approvals

Guiding principles
Ethics
Scientific validity and integrity Medical relevance

Regulatory and medico legal issues

Costs

Anatomy of a typical study protocol

oIntroduction and rationale oStudy objectives: primary and secondary oOverall study design oStudy flow sheet oEnrollment criteria oSpecific study procedures oRandomization oIntervention oOutcome measurements oProtocol deviations oData analysis and statistics oEthical considerations (Declaration of Helsinki)

Study protocol outline

Element
1. Research questions 2. Significance (background) 3. Design Time frame Epidemiologic approach

Purpose
What questions will the study address? Why are these questions important? How is the study structured?

4. Subjects Selection criteria Sampling design

5. Variables Predictor variables Confounding variables Outcome variables

Who are the subjects and how will they be selected?

What measurements will be made?

6. Statistical issues Hypotheses Sample size Analytic approach

How large is the study and how will it be analyzed?

Title

Major headings in a protocol

Investigators, institutional affiliations, & qualifications

Summary/Abstract 1. Introduction
Literature review; Motivation for the study (problem); Purpose; Specific objectives; Implementation objectives

2. Methods
Definition of terms; Study design; Study population and sampling; Measurements; Pilot studies

3. Logistics and time schedule

Responsibilities of investigators and of staff; Time schedule

4. Data management and analysis 5. Resources

Available resources; Budget and budget motivation

6. Ethical and legal considerations 7. Reporting of results 8. Appendices

Components of a research proposal

A. B. C. D. Title page Table of contents Abstract Project Description

E. F. G. H.

1. 2. 3. 4. 5. 6.

References Budget and Justification Human Subjects Appendices

Introduction Problem statement and significance Goals and objectives Methods and procedures Evaluation Dissemination

Main protocol elements

The above protocol outlines have these as main elements: Population Question Relevance Study design and variables Timeframe

To understand these, we need to revisit some epidemiology

General information
Title page:
Protocol title, protocol identifying number and date. Any amendment(s) should also bear the amendment number(s) and date(s).

Name and address of the sponsor and monitor(if other than the sponsor) Confidentiality statement Table of contents

Easy reference tool

Typical Inclusion criteria Subject must have disease of interest Subject must have a certain amount of disease Subject must understand study and agree to participate Other Typical exclusion criteria

Subject must not be on an active treatment

Subject must not be allergic to intervention Pregnancy, breastfeeding child Other

Subject inclusion criteria.

Subject exclusion criteria.

Subject withdrawal criteria (i.e., terminating investigational product treatment/trial treatment) and procedures specifying: (a) When and how to withdraw subjects from the trial/ investigational product treatment.

(b) The type and timing of the data to be collected for withdrawn subjects.
(c) Whether and how subjects are to be replaced. (d) The follow-up for subjects withdrawn from investigational product treatment/trial treatment.

6. Treatment of Subjects The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.

Medication(s)/treatment(s) permitted (including rescue medication) or not permitted

before and/or during the trial. Procedures for monitoring subject compliance.

7.Assessment of Efficacy Specification of the efficacy parameters. Methods and timing for assessing, recording, and analyzing efficacy parameters. 8. Assessment of Safety Specification of safety parameters. The methods and timing for assessing, recording, and analyzing safety parameters. Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses. The type and duration of the followup of subjects after adverse events.

9. Statistics Used to determine the significance of the study data based on laws of probability Also used to determine the power of a study (i.e. number of patients needed to recruit) A description of the statistical methods to be employed, Including timing of any planned interim analysis. The number of subjects planned to be enrolled. In multicenter trials, the number of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on the power of the trial and clinical justification. Criteria for the termination of the trial. Procedure for accounting for missing, unused, and spurious data.

Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in the protocol and/or in the final report, as appropriate). The selection of subjects to be included in the analyses (e.g.. all randomized subjects, all dosed subjects, all eligible subjects, evaluateable subjects).

10. Direct Access to Source Data Documents The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial- related monitoring, audits, IRB/IEC review, and regulatory inspection(s) by providing direct access to source data/documents.

11. Quality Control and Quality Assurance

12. Ethics Description of ethical considerations relating to the trial.

13. Data Handling and Recordkeeping

14. Financing and Insurance Financing and insurance are addressed in a separate agreement

15. Publication Policy Publication policy, if not addressed in a separate agreement. 16. Supplements