clinical trial protocol and regulatory guidelines

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Developing clinical
trail protocols
Name – Shweta Dhongade
M.Pharm pharmaceutics

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DEFINITION:
 A Protocol is a live master document and the guidelines ICH E6 defines a
protocol as the document that describes, the objectives, designs, methodology,
statistical considerations, and organization of a clinical trial; and ensures the
safety of the trial subjects and integrity of the data collected. In case of any
amendments to the protocol, the same should be put up before the IRB for
approval before it is implemented.
 The Central Drugs Standard Control Organization (CDSCO) has guidelines for
clinical trial protocols, including application process, inspection, and adverse
events.
 Applications for clinical trials are submitted in Form CT-04 through the
SUGAM/NSWS portal.
 SUGAM- System for Unmanned Gateways Approval of Manufacturers
 NSWS- National Single Window System

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GUIDELINES
 Developing a clinical trial protocol requires adherence to several international and national
guidelines to ensure ethical integrity, scientific validity, and regulatory compliance.
 Here are the key guidelines:
 International Guidelines-
(A) ICH-GCP (International Council for Harmonisation - Good Clinical Practice)
 ICH E6 (R2) - Good Clinical Practice (GCP)
The gold standard for clinical trials worldwide.
Covers trial design, conduct, data recording, and reporting.
Ensures participant rights, safety, and confidentiality.
 ICH E8 - General Considerations for Clinical Trials
Provides principles for trial design and development.
 ICH E9 - Statistical Principles for Clinical Trials
Defines statistical methodologies for trial data analysis.

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 (B) WHO Guidelines (World Health Organization)
 WHO Handbook for Good Clinical Research Practice (GCP)
Provides global standards, particularly useful for low-resource settings.
 WHO ICTRP (International Clinical Trials Registry Platform)
Requires trials to be registered for transparency.

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 Indian Guidelines
(A) ICMR (Indian Council of Medical Research)
 ICMR National Ethical Guidelines for Biomedical & Health Research (2017).
(B) CDSCO (Central Drugs Standard Control Organization)
 New Drugs and Clinical Trials Rules, 2019
 Regulates clinical trials, ethics committees, and drug approvals.
(C) ICH-GCP India Adaptation (Schedule Y)
 Part of the Drugs and Cosmetics Act (1945).
 Covers regulatory requirements specific to India.

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Aims of protocol:
 To raise the question to be researched and clarify its importance.
 To gather existing knowledge and discuss the efforts of other
researches who have worked on the related questions (Literature
review).
 To formulate a hypothesis and objectives.
 To suggest the methodology required for solving the question and
achieving the objectives.
 To discuss the need and limitations in achieving the objectives

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Tools of the protocol-
• It ensures the safety and health of all the study participants
• It provides a particular study plan
• It defines and manages the trial, and thus it should be strictly
followed by all the study investigators
• It guarantees the integrity of knowledge, allowing the mixture and
comparison of knowledge across all investigators and/or study sites
• It informs the study administrators, which regularly are a contract
research organization(CRO)
• It is required to get ethical approval from the Research Ethics
Committee or Institutional Review Board (IRB)

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The components of the protocol-
1) Title of the study
2) Administrative details
3) Project summary
4) Introduction and background (Literature review)
5) Study objectives
6) Methodology
7) Data managements and Analysis Plan
8) Project management: Work plan (Timeline - proposed schedule)
9) Strengths and limitations of the study
10) Issues for ethical review and approvals
11) Operational Planning and Budgeting (Budget Summary)
12) Reference System
13) Annexure

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1) Title of the Study:
 Title of proposal should be accurate, short and concise.
 It should make the main objective clear, convey the main purpose of the
research and mention the target population.
 Carry maximum information about the topic in a few words

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2) Administrative Details:
 The following administrative details and a protocol content
summary should follow the title page:
1. Contents page list of relevant sections and sub-sections with
corresponding page number.
2. Signature page is signed by senior members of the research team
and dated to confirm that the version concerned has been approved
by them.
3. Contact details for the research team members listing postal and e-
mail addresses and telephone numbers for members of the research
team.

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3) Project Summary:
 The summary should be distinctive, concise and should sum up all the essentials
of the protocol.
4) Introduction:
 The introduction should concisely present the project background and directly
state the research topic.
 The literature review must highlight the positives, negatives, and limitations of
cited studies, incorporating the latest publications.
 It should logically lead to the research aims by identifying gaps in existing studies.
 The introduction should also emphasize the study's importance, its contribution to
society, and how it addresses these gaps.
 The research question must be clear and precise, forming the foundation for
project design and ensuring readers easily grasp its significance.

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5) Study Objectives (Aims):
 The aims should be clearly stated, arising logically from the literature review and
research question or hypothesis. They must be concise, feasible, and realistic,
considering local conditions. The aims should directly align with the study's
purpose, outlining what it seeks to accomplish.
 The objectives should be (SMART objective): Specific, Measurable, Achievable,
Relevant and Time based.
 Assessment of Efficacy - This section describes the methods which will be used to
determine the success of the Treatment including Criteria for determining the
treatment’s effectiveness and Methods and timing for recording, assessing and
analyzing the effectiveness criteria.
 Assessment of Safety - This section outlines the study's monitoring process and
how adverse events will be managed. It covers methods and timing for
recording, assessing, and analyzing safety criteria, procedures for reporting
adverse events and illnesses, and expedited reporting protocols.

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6) Methods and Materials:
 It is crucial part of the protocol and should describe the ‘Where’, ‘Who’, ‘How’
the research is going to be conducted.
 It explains the study design, procedures and the techniques which are used to
achieve the proposed objectives.
 It gives the proposed methodology for data collection and processing.
 It assures that the hypothesis are going to be confirmed or rejected.
 The materials and methods are grouped into various subheadings:
a) Study design
b) Study population
c) Sample size
d) Proposed intervention
e) Data collection methods, instruments used

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a) Study design-
 A study design is a plan that helps researchers find answers to their questions.
 The choice of design depends on the study’s goals and available resources.
 It explains how data will be collected and analyzed to ensure fair and accurate
results.
 Suitable research design depends on the purpose of study-
purpose Study design
To determine frequency and
burden of a disease
• Cross-sectional survey
(Prevalence) Cohort study
(Incidence)
To identify the risk factors • Cohort study
• Case-Control study
To determine prognosis of a
disease
• Cohort study
To determine
efficacy/effectiveness of a new
treatment
• Clinical trials
• Community intervention
To evaluate community programs • Evaluation

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b) Study population-
• This section details the study subjects, selection procedures, and sample size
calculation.
• It defines inclusion, exclusion, and eligibility criteria, along with conditions for
discontinuation.
c) Sample size-
• Sample size calculation is suggested for economical and ethical reasons.
• The calculation of the sample size must be explained including the power of the
sample.
• The sampling technique should be mentioned.
• Each step involved in the recruitment of the study subjects should be described
according to the selection criteria (inclusion and exclusion criteria).
• “Informed consent” should be mentioned (Permission granted in full knowledge of
the possible consequences).

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d) Proposed intervention:
A detailed description of the intervention should be provided, outlining all activities in
sequence.
 For drugs: Mention brand and scientific names, manufacturer details (company, city,
country), route, dosage frequency, and treatment duration.
 For apparatus: State the name and manufacturer details.
 Personnel: Clearly define who is responsible for the interventions.
e) Data collection methods, instruments used Data collection tools are:
• Retrospective data (medical records)
• Questionnaires
• Interviews (Structured, Semi-Structured)
• Laboratory test
• Clinical examinations.
• Description of instruments, tools used for data collection, as well as the methods used
to test the validity and reliability of the instrument should be provided.

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7) Data Management and Analysis:
 This section explains how data will be analyzed with the help of a statistician.
 It includes the statistical tests used to check results, the variables studied, and the
software (with version) if used.
8) Project Management & Work Plan:
 A work plan outlines research activities with a timeline for each phase.
 A clear schedule helps organizing the structure of the trial.
 All personnel, including investigators and assistants, should be properly trained for
their roles.
9) Strengths and Limitations:
 It is important to mention the strengths or limitations of the study, i.e., what study
can achieve or
cannot achieve is important, so as to prevent wasteful allocation of
resources.

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10) Ethical Considerations:
 The study must follow the Declaration of Helsinki and receive ethics committee
approval before starting.
 Explain benefits, risks, and any physical, social, or psychological effects.
 Provide study participants with full information, including alternative treatments.
 Ensure informed consent, detailing study purpose, risks, confidentiality, and
voluntary participation, including the right to withdraw at any time.
11) Operational Planning & Budgeting:
 The budget should outline expenses for manpower, transport, instruments, lab tests, and
drugs. It must include costs for personnel, equipment, supplies, communication, patient
care, and data processing, with justifications.
 A detailed budget estimate should be attached in the annexure
12) Reference System:
 Referencing acknowledges sources and prevents plagiarism.
 It helps readers trace information. Failing to cite sources or credit team members
is considered plagiarism, making proper referencing essential in research.

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13) Annexure:
 The following annexes are to be attached at the end of the protocol:
1. Informed consent form.
2. Letters from ethics committees.
3. Study questionnaire (copies of any questionnaires or draft questionnaires).
4. Case Record Forms (CRFs).
5. Budget details.
6. Curriculum Vitae (CV) of the chief investigator and co-
 investigator and their role in the study. It will ensure that the role of each
investigator is well defined.

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Protocol Amendment –
 A protocol amendment is a written change to the study plan.
 Must be submitted to and approved by the Institutional Review Board (IRB)
before implementation.
 Exceptions: Immediate hazard elimination or minor administrative changes (e.g.,
contact details).
 If FDA-regulated, approval from both the FDA and IRB is required before
implementation.
Protocol Amendments & Informed Consent -
 Participants must be informed of protocol amendments.
 If significant, the Informed Consent form may need revision and re-signing.
 Amendments differ from protocol clarifications, which guide study conduct
without altering the protocol or risk-benefit ratio.
 Clarifications usually don’t require IRB approval but should be documented and
shared with investigators.

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References-
 Protocol Writing in Clinical Research Article in Journal of Clinical and Diagnostic
Research · November 2016
 Review Article- Development and Writing of Clinical Trial ProtocolSupriya Nikam*,
Akash Inde, Anjali Jambhulkar, Abhilasha Ghule
 https://hub.ucsf.edu/protocol-development
 https://www.slideshare.net/slideshow/developing-the-clinical-trial-protocol-ppt/
266590490

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Institutional Review Board (IRB)
 An Institutional Review Board (IRB), also known as an Independent
Ethics Committee (IEC), is a group that reviews and monitors
biomedical and behavioral research involving human participants.
The primary goal of the IRB is to ensure that research is conducted
ethically, protecting the rights, safety, and well-being of
participants.

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Background
 The IRB was established to protect the rights, safety, and well-being
of human research participants.It originated from ethical principles
like the Nuremberg Code, Declaration of Helsinki, and Belmont
Report.It ensures that research complies with national and
international guidelines, such as ICH-GCP (International Conference
on Harmonization - Good Clinical Practice), FDA regulations, and
European regulatory standards.

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Composition
 The IRB must be diverse and include members with different
expertise to ensure a comprehensive review of research proposals.
 Key Members:
 1. Medical/Scientific Expert – Evaluates scientific validity and risk-
benefit ratio.
 2. Ethicist/Legal Expert – Ensures ethical principles and regulatory
compliance.
 3. Non-Scientific Member – Provides a non-technical perspective,
representing community concerns.

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4. Layperson (Community Representative) –
Ensures research is understandable and ethical
from a participant's viewpoint.
5. Specialists (if needed) – May include
pharmacists, statisticians, or social scientists for
specific studies.
Note: The IRB must have at least five members,
including at least one non-affiliated member to
prevent institutional bias.

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Responsibilities of the IRB
1. Review & Approval of Research Proposals – Ensures ethical and
regulatory compliance before approval.
2. Informed Consent Process Oversight – Verifies that participants are
fully informed about risks, benefits, and rights.
3. Risk-Benefit Assessment – Ensures that potential benefits justify any
risks involved in the study.

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4. Safety Monitoring & Pharmacovigilance –
Ensures continued participant protection during
clinical trials.
5. Regulatory Compliance – Adheres to FDA (21
CFR 56), ICH-GCP, HIPAA, and local regulatory
guidelines.
6. Ongoing Review & Monitoring – Conducts
periodic reviews of ongoing research, including
auditing study sites.
7. Handling Participant Complaints & Ethical
Violations – Investigates and takes necessary
actions if ethical breaches occur.

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IRB Procedure
 Steps in the Review Process:
1. Submission of Research Proposal – Researchers submit protocols,
consent forms, and supporting documents.
2. Preliminary Review – IRB screens applications for completeness.
3. Full Board or Expedited Review:Full Board Review: High-risk studies
undergo comprehensive discussion.Expedited Review: Minimal-risk
studies may be approved by a subset of the IRB.

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4. Approval, Modifications, or Rejection – IRB can
approve, request modifications, or reject studies.
5. Ongoing Monitoring – Regular updates, safety
reports, and annual reviews are required.
6. Final Study Closure – Ensures proper completion
and reporting of research outcomes.

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Maintenance of Records &
Documentation
 The IRB is responsible for maintaining records for regulatory
compliance and audits.
 Key Documents Maintained:Approved Research Protocols – All
versions of study proposals.
 Meeting Minutes – Records of IRB discussions and decisions.Informed
 Consent Documents – Approved templates and participant
signatures.

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• Communication Logs – Correspondence with
investigators and regulatory bodies.
• Annual Reports & Safety Monitoring Records –
Includes adverse event reports and periodic
reviews.
• Record Retention:Typically, IRB records must be
retained for at least 3-5 years after study
completion, per FDA (21 CFR 56.115) and ICH-
GCP guidelines.

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References
 Clinical Trials and Human Research: A Practical Guide to Regulatory
Compliance – By Fay A. Rozovsky and Rodney K. AdamsFDA
 Regulatory Affairs: A Guide for Prescription Drugs, Medical Devices,
and Biologics – Edited by Douglas J. Pisano and David
 MantusGuidebook for Drug Regulatory Submissions – By Sandy
Weinberg, Published by John Wiley & Sons