CT SOP version no 2.0.

Main changes from CT SOP no. 1.0. Adapted to the wording of ICH GCP E6 (R3).

The sponsor has overall responsibility for ensuring that clinical drug trial protocols are managed in compliance with this SOP.

The sponsor’s responsibilities shall be described in the quality system of the sponsor institution. Tasks are delegated according to SOP Roles and Responsibilities in clinical trials implemented in the institution.  

The sponsor may transfer any or all of the sponsor's trial-related duties and functions to a service provider such as a Contract Research Organisation (CRO), but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf. Transfer of duties shall be specified in a written agreement.

The coordinating investigator has the responsibility for ensuring that the writing, reviewing and approving of protocols is in compliance with this SOP.

All staff who are involved in writing, reviewing and approving clinical drug trial protocols, must possess the necessary qualifications for the task.

The coordinating investigator will ensure that the protocol is fit for purpose, meaning it should be clear, concise, consistent and operationally feasible. Unnecessary complexity, procedures and data collection should be avoided, and sponsor should not place unnecessary burden on
participants and investigators. 

The protocol describes the objective(s), design, methodology, statistical considerations, organisation and estimated time frames for the trial. The protocol should give the background and rationale for the trial and should be designed to provide answers to a specific research question.

The protocol provides the basis for an application for approval of the clinical drug trial by the Competent Authority and Ethics Committee(s). A summary of the protocol may also be the basis for an application for funding of the project.

Risk assessment

During protocol development and in order to comply with GCP requirements, the coordinating investigator should identify those processes and data that are critical to ensure protection of the participants and the reliability of trial results. The coordinating investigator should identify, evaluate and manage risks critical to the trial processes and data.

Examples of factors to consider are engagement of stakeholders (including patients), benefit/risk of the investigational product and trial interventions, study objectives & meaningful clinical study design, e.g. relevant eligibility criteria, feasibility , protection of participants' rights and safety, qualification/training needs, data collection needed to meet the study objectives and minimization of bias (randomization, blinding).

Pre-defined quality tolerance limits should be established e.g. a drop-out rate of 5% is acceptable, but if it becomes higher the coordinating investigator will implement measures in order to reduce drop-out such as informing the patient better. Appropriate risk reduction activities related to the investigational medicinal products or procedures are usually described in the protocol, whereas risks in a broader sense can be done using Risk Assessment.

It is recommended to build adaptability into the protocol for example, by including acceptable ranges for specific protocol provisions, and thereby 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. 

Preparation of the draft protocol

The requirements for the content of a protocol are specified in Regulation (EU) no 536/2014 Annex 1, section D and appendix B of the ICH Guideline for Good Clinical Practice (GCP) E6 (R3).

The protocol must be written in English. TransCelerate BioPharma Inc. has developed an protocol template. A slightly adapted Protocol based on the TransCelerate’s template is available at norcrin.no.

Protocols must have a version number and date. When revising a protocol, the version number and date must be updated. The revised protocol should have a document history listing previous versions with number and dates.

The protocol should be carefully considered so as not to unnecessarily exclude particular participant populations (e.g sex, understanding of languages). Certain trials (e.g., early phase, proof of concept trials, bioequivalence studies) may not require such a heterogeneous population.

If the trial involves decentralised elements (study procedures performed outside the investigator's institution, e.g. closer to the participant's residence) details should be described in the study protocol. The procedure Transfer of Clinical Trial Tasks to other Hospitals (decentralised trials) - SOP 1.13.b should be consulted. 

The protocol must be uploaded in the Clinical Trial Information System (CTIS) in two versions, where one eventually will be public and is recommended to be without any personal data (names).  An appendix has therefore been added at the end of the template to gather all the names. This appendix should be deleted from the version uploaded for publication.

For the application in CTIS a Protocol Synopsis is required in local language for all participating countries. This is a separate document and not to be confused with the protocol synopsis section in the trial protocol. See Q&A Annex II.

The coordinating investigator should also consult EMA Scientific Guidelines for various types of trials, various therapeutic areas and biostatistics issues.

Committees

The coordinating investigator should consider establishing committees to oversee specific aspects of the trial, e.g.

• An executive committee or trial management committee.
• A steering committee.
• A data monitoring committee (DMC).
• An endpoints adjudication committee (e.g. in cardiology trials).

Examples of  different kinds of committees can be found here.

When a DMC is established for a clinical trial the role of the DMC must be described in the protocol. The published guideline from the European Medicines Agency (EMA) on DMC should be followed and a Data Monitoring Committee Charter must be written. The charter should be submitted together with the clinical trial application.

Committees established for purposes that could impact participant safety or the reliability of trial results should include members with relevant expertise and with managed conflicts of interest, have written operating procedures (e.g., charters) and document their decisions.

Safety

Description of safety recording should be adapted to the acquired knowledge about the investigational medicinal product(s) (IMP(s)) and the use IMP(s) in the trial, see ICH guideline E19 on a selective approach to safety data collection in specific late-stage pre-approval or postapproval clinical trials.

Statistics

Statistical methods and how the data will be analysed must be outlined in the protocol. To maintain transparency, the description should be sufficiently detailed to allow a complete reproduction of the following results.

Due to the complexity of modern statistical analyses, a separate Statistical Analysis Plan (SAP) is highly recommended. The SAP should pre-specify all statistical analyses and must be finalised prior to enrolment in open trials and prior to database lock for blinded trials. Any analyses not specified in the protocol or SAP should be regarded as post-hoc analyses. 

Review and approval

It is recommended that the coordinating investigator ask others who will be involved in the trial to review the protocol prior to submission for internal approval or to Competent Authority(ies) and Ethics Committee(s).  Preferably reviewers should be other investigators, study nurses, laboratory personnel, pharmacist etc. who will perform trial tasks, have experience and can provide useful input on how the trial procedures should be implemented. In addition, the coordinating investigator should, as early as possible, contact research support units including statisticians who can advise in respect to choice of design, statistical methods and provide statistical input (power calculation, sample size, etc.) and provide cost estimates for services such as monitoring, data management and statistics. Quality control of the statistics should be documented. 

The protocol shall be signed by the sponsor representative. The investigator/institution should sign the protocol or an alternative contract to confirm agreement with the sponsor.  

More details on the preparation of applications to the Competent Authority(ies) and Ethics Committee(s) can be found in the SOP Application Process and Approvals.

Procedures for changes to an approved protocol and possible need for re-approval is described in SOP Modifications after Trial Start.

Documentation

All approved versions of the protocol and correspondence with the Competent Authority and Ethics Committee(s), will be filed in trial master file; see SOP Study Files. It is recommended that the Protocol Version Tracking Log is used to keep a record of protocol versions and dates for implementation.

• Protocol - Template
• Protocol Synopsis - Template
• Protocol Version Tracking Log - Template
• Clinical Trial Protocol Site Signature Form - Template
• Risk Assessment - Template
• Data Monitoring Committee Charter - Template
• Protocol Deviation Handling Plan - Template