Appendix B. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)

ICH HARMONISED GUIDELINE
GOOD CLINICAL PRACTICE (GCP) E6(R3)

23 January 2025. Date for coming into effect 23 July 2025

Clinical trials should be described in a clear, concise and operationally feasible protocol. The protocol should be designed in such a way as to minimise unnecessary complexity and to mitigate or eliminate important risks to the rights, safety, and well-being of trial participants and the reliability of data. Protocol development processes should incorporate input from relevant interested parties, where appropriate. Building adaptability into the protocol, for example, by including acceptable ranges for specific protocol provisions, can reduce the number of deviations or in some instances the requirement for a protocol amendment. Such adaptability should not adversely affect participant safety or the scientific validity of the trial. For additional information, refer to ICH E8(R1) General Considerations for Clinical Studies, ICH E9 Statistical Principles for Clinical Trials and ICH E9(R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials.

The contents of a trial protocol should generally include the following topics, which may vary depending on the trial design. Investigator site-specific information may be provided on separate protocol page(s) or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.

B.1 General information

B.1.1 Protocol title, unique protocol identifying number and date. Any amendment(s) should also bear the amendment number(s) and date(s).

B.1.2 Name and address of the sponsor.

B.1.3 Name and title of the person(s) authorised to sign the protocol and the protocol amendment(s) for the sponsor.

B.2 Background information

B.2.1 Name and description of the investigational product(s).

B.2.2 A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.

B.2.3 Summary of the known and potential risks and benefits, if any, to human participants.

B.2.4 Description of and justification for the route of administration, dosage, dosage regimen and treatment period(s).

B.2.5 A statement that the trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory requirement(s).

B.2.6 Description of the population to be studied.

B.2.7 References to literature and data that are relevant to the trial and that provide background for the trial.

B.3 Trial objectives and purpose

A clear description of the scientific objectives and the purpose of the trial. Information on estimands, when defined (see ICH E9(R1)).

B.4 Trial design

The scientific integrity of the trial and the reliability of the results from the trial substantially depend on the trial design. A description of the trial design should include:

B.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.

B.4.2 A description of the type and design of trial to be conducted (e.g., double-blind, placebo- controlled, parallel design, adaptive design, platform/umbrella/basket, trials with decentralised elements) and a schematic diagram of trial design, procedures and stages.

B.4.3 A description of the measures taken to minimise/avoid bias, including:

        (a) Randomisation

        (b) Blinding

B.4.4 A description of the investigational product(s) and the dosage and dosage regimen of the investigational product(s), including a description of the dosage form, packaging and labelling.

B.4.5 Preparation (e.g., reconstitution) and administration instructions where applicable, unless described elsewhere.

B.4.6 A description of the schedule of events (e.g., trial visits, interventions and assessments).

B.4.7 The expected duration of the participant’s involvement in the trial and a description of the sequence and duration of all trial periods, including follow-up, if any.

B.4.8 A description of the “stopping rules” or “discontinuation criteria” and “dose adjustment” or “dose interruption” for individual participants, for parts of the trial or for the entire trial.

B.4.9 Accountability procedures for the investigational product(s), including the placebo(s) and other comparator(s), if any.

B.4.10 Maintenance of treatment randomisation codes and procedures for breaking codes.


B.5 Selection of participants

B.5.1 Participant inclusion criteria.

B.5.2 Participant exclusion criteria.

B.5.3 Mechanism for pre-screening, where appropriate, and screening of participants.

B.6 Discontinuation of trial intervention and participant withdrawal from trial

The investigator may choose to discontinue the participant from the trial. Conversely, the participant may decide to withdraw from the trial or stop treatment with the investigational product (see sections 2.8.10(l), 2.8.10(m) and 2.9.1). The protocol should specify:

(a) When and how to discontinue participants from the trial/investigational product treatment;

(b) The type and timing of the data to be collected for withdrawn/discontinued participants, including the process by which the data are handled, in accordance with applicable regulatory requirements;

(c) Whether and how participants are to be replaced;

(d) The follow-up for participants who have discontinued the use of the investigational product.

B.7 Treatment and interventions for participants

B.7.1 The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the criteria for dose adjustment(s), the route/mode(s) of administration and the treatment period(s), including the follow-up period(s) for participants for each investigational product treatment/trial treatment group/arm of the trial.

B.7.2 Medication(s)/treatment(s) permitted (including concomitant and rescue medication) and not permitted before and/or during the trial.

B.7.3 Strategies to monitor the participant’s adherence to treatment.


B.8 Assessment of efficacy

B.8.1 Specification of the efficacy parameters, where applicable.

B.8.2 Methods and timing for assessing, recording and analysing efficacy parameters. Where any trial-related committees (e.g., independent data monitoring committee (IDMC)/adjudication committees) are utilised for the purpose of assessing efficacy data, the committees’ procedures, timing and activities should be described in the protocol or a separate document.

B.9 Assessment of safety

B.9.1 Specification of safety parameters.

B.9.2 The methods, extent and timing for recording and assessing safety parameters. Where any trial-related committees (e.g., IDMC) are utilised for the purpose of assessing safety data, procedures, timing and activities should be described in the protocol or a separate document.

B.9.3 Procedures for obtaining reports of and for recording and reporting adverse events.

B.9.4 The type and duration of the follow-up of participants after adverse events and other events such as pregnancies.

B.10 Statistical considerations

B.10.1 A description of the statistical methods to be employed, including timing and purpose of any planned interim analysis(ses) and the statistical criteria for the stopping of the trial.

B.10.2 The number of participants planned to be enrolled and the reason for the choice of sample size, including reflections on or calculations of the power of the trial and clinical justification.

B.10.3 The level of significance to be used or the threshold for success on the posterior probability in a Bayesian design.

B.10.4 The selection of participants to be included in the planned analyses, a description of the statistical methods to be employed and procedures for handling intercurrent events and accounting for missing, unused and spurious data. These should be aligned with the target estimands, when defined (see ICH E9(R1)).

B.10.5 Statement that any deviation(s) from the statistical analysis plan will be described and justified in the clinical trial report.

B.11 Direct access to source records

The sponsor should ensure that it is specified in the protocol or other documented agreement that the investigator(s)/institution(s)/service provider(s) will permit trial-related monitoring, audits, regulatory inspection(s) and, in accordance with applicable regulatory requirements, review by the institutional review board/independent ethics committee (IRB/IEC), providing direct access to source records.

B.12 Quality control and quality assurance

B.12.1 Description of identified critical to quality factors, associated risks and risk mitigation strategies in the trial unless documented elsewhere.

B.12.2 Summary of the monitoring approaches that are part of the quality control process for the clinical trial.

B.12.3 Description of the process for the handling of noncompliance with the protocol or GCP.

B.13 Ethics

Description of ethical considerations relating to the trial.

B.14 Data handling and record keeping

B.14.1 Specification of data to be collected and the method of its collection. Where necessary, additional details should be contained in a clinical trial-related document.

B.14.2 The identification of data to be recorded directly into the data acquisition tools (i.e., no prior written or electronic record of data) and considered to be the source record.

B.14.3 A statement that records should be retained in accordance with applicable regulatory requirements.

B.15 Financing and insurance

Financing and insurance, if not addressed in a separate agreement.

B.16 Publication policy

Publication policy, if not addressed in a separate agreement.

Author: 

Author: © European Medicines Agency, 2025. Reproduction is authorised provided the source is acknowledged.

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