Clinical Trial Protocol

Anand Kumar Gond

President ISPOR INDIA Student Chapter 2016
M.Pharm Pharmacology DIPSAR
University of Delhi (2016)
 Description

 Trial protocols are all the documents that describe the below aims:
 design,
 methodology,
 statistical considerations
 aspects related to the organization of clinical trials.

 Trial protocols provide the background and rationale for conducting a study, highlighting
specific research questions that are addressed, and taking into consideration ethical
issues.
 Trial protocols must meet a standard that adheres to the principles of Good Clinical
Practice, and are used to obtain ethics approval by local Ethics Committees or
Institutional Review Boards

Cipriani A, Barbui C. What is a clinical trial protocol?. Epidemiol Psichiatr Soc. 2010;19(2):116-117.
 Description

 A well-defined protocol for a clinical trial guarantees a successful outcome report.

 When designing the protocol, most researchers refer to electronic databases and
extract protocol elements using a keyword search.
 However, state-of-the-art database systems only offer text-based searches for user-
entered keywords.

Park J, Park S, Kim K, et al (2020) An interactive retrieval system for clinical trial studies with context-dependent protocol elements. PloS
one, 15(9), e0238290.
 Definition

 A protocol is a document that explicitly states the reasoning behind and

structure of a research project.
 The study protocol can be viewed as a written agreement between the
investigator, the participant and the scientific community.
 The protocol should include the right amount of details necessary for the
reader to understand the exactly what is needed to conduct the study.
 For example while studying blood pressure measurement should be
described more details in a protocol when a study on hypertension
conducted.
 Protocol Outline

 A protocol have following elements:

 Title page
 Signature page
 Background information and scientific rationale
 Objectives
 Study design
 Study population
 Study procedure
 Statistical considerations
 Subject confidentiality
 Informed consent process
 Literature References
 Supplements
 Title page

 The title page contains its title , the document, precise number,
sponsor and authors to the readers.
 Protocol title , Protocol identifying number and date.
 The protocol number clearly indicate version number.
 If there available any amendment it should be there.
 Name and address of Sponsor and monitors.
 Name and details of chief investigators for Multicenter trial and
principal investigator for single center trial.
 Names and title of qualified physicians, pharmacists and other
medical teams conducting trial.
 Name and address of clinical laboratory
 Signature page

 Signature details of all the healthcare professionals

involved in the trial including the contact details of
participating sites, sponsor, sponsor’s medical
advisor.
 Contents page

 This helps navigation throughout the larger number

of the documents of different people that are needed
for the trial.
 List of Abbreviations

 All abbreviations used should be listed and defined .

 Accepted international medical abbreviations should be used.
 Example foe ICH - The International Council for Harmonization of Technical
Requirements for Pharmaceuticals for Human Use
 Examples, AMA style, Harvard style etc.
 Compliance statement

 The protocol should include a statement that the trial will be conducted in compliance
with the protocol, GCP, applicable regulatory requirements.
 Background information

 A description of the background and general aim of the trial is a useful preliminary,
which helps to explain why the trial is considered scientifically worthwhile and how it
builds on experience gained from previous research.
 A detailed literature search provide clinical epidemiological data on disease under study.
Study Objectives/Aims, Endpoints and
Rationale

 Clinical study objectives are concise statements of major and minor questionnaires, The
author should reflect on the objectives and confirm that they represent valid and proper
questions.
 Study end points included in choosing the efficacy parameter to evaluate in a clinical
study it is especially beneficial if the parameter chosen can demonstrate end points
related to reduce progression or even reversal of the disease process.
 The Study rationale defined the need of the conduct of the study, how the results
obtained from the study will help to advance the needs of the scientific community and
add to the current understanding of the problem.
 Study Design

 The scientific integrity of the trial and the credibility of the data from the trial depends on
substantially on the trial design.
 It includes double blind, case control, cohort, cross sectional, others.
 Randomization

 Randomization is a technique to ensure that statistical significance tests may be used in

a valid manner. It is a process by which patients in a clinical trial are randomly assigned
to receive one of the treatments being evaluated.
 Randomization is used to reduce the bias in assigned patients to treatment and is
usually implemented through a randomization code.
 Protocol Summary

 It is on to two page long provide the reader the sufficient information to understand the
rationale, objectives and methods to be used.
 It contains title, phase of study, sample size, gender, age , general health status,
geographical locations, inclusion and exclusion criterion, number of sites, study
duration, primary and secondary outcomes, methods for the outcomes of study design.
 Inclusion Exclusion Criterion

 Any Clinical trail requires a precise definition of which patients are eligible for
the inclusion and exclusion criterion.
 Inclusion criteria constitutes the definition of the patient characteristics
required for entry into the clinical trial.
 Screening

 It based on interview , review of medical records, physical

examinations and laboratory values. A screen is an
evaluation potential patients to determine their eligibility to
enter a clinical trial.
 Sample Size

 The number of patients required for the clinical trial refers to number of patients who
finished the trial rather then the number which included.
 Numerous biases and errors in a clinical trial may be minimized by increasing the
number of patients entered until adequate power is obtained.
 Statistics

 This includes the statistical methods involved .

 Timing of any planned interim analysis, methods of statistical analysis for primary endpoints
and secondary endpoints, intent to treat rule of any interim analysis of administration.
 Treatment Schedule

 Concomitant treatment and Rescue medication:

 Medications/treatments permitted and not permitted before or during drug trial needs to
be specified.

 Procedures of monitoring subject compliance.
 The protocol should elaborated how blinding subjects , researchers, associates as
appropriate will be achieved.
 Procedures such as watching subjects swallow investigational products .
 Assessment of Efficacy and
Assessment of Safety

 Specification of the efficacy parameters:

 What measurements to be made, when, why and how.
 Methods and timing for assessing recording and analyzing efficacy parameters
 The methods and timing for assessing , recording and analyzing the safety parameters
 Procedures for eliciting reports and for recording and reporting adverse event and
intercurrent illness.
 Post treatment period

 Post treatment refers to time after the trial medicine has been discontinued. The major
purposes of a post treatment period are to check for any withdrawal effects and to
ensure the patients safety.
 Clinic visits to conduct post treatment evaluations may be scheduled as part of a clinical
protocol.
Direct access to source data/Documents;
Quality control and Quality assurance

 The sponsor should ensure that it is specified in the protocol other written agreement
that the investigator will permit trial related monitoring, audits, regulatory review and
inspections, providing direct access to source documents.

 Provide control and assurance on GCP quality of data collection.

 Ethics; Informed Consent

 An early code for ethical behavior is the famous hippocratic oath. The helsinki doctrine,
performed by IRB or ethics committee.
 Informed consent is defined as patient being given adequate information about clinical
trial understanding voluntarily accepting terms and conditions of clinical trials ,
Data Handling and record keeping

 Data retrieval, database management data entry and validation, security ,

storage, rules of handling , audit verification, record retention, location.
Financing and Insurance; Publication
Policy

 Financing and insurance should be discussed if not addressed in a separate

agreement.
Tables figures, dates and references
and supplements

 Separate sections should be devoted for tables, figures, authors, and date
references and supplements.
 Protocol deviations/Study
termination

 The reasons for withdrawing the patients from the study should be specified
in protocol.
 Appendices

 Based on the protocol relevant appendices should be added:

 SmPCs, Data Sheets, Investigational products, batch numbers, Dosage forms tablets,
capsules etc,
 Method of collecting patient sample.
 Clinical Labs tests
 Scoring system ECOG
 Patients parent /guardian permission.
 Declaration of Helsinki
 Reference

Prepared by class lectures notes of

professor SK Gupta (HOD Clinical
Research session 2015-2017)