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 third-party vendor 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.

Procedures

The coordinating investigator will ensure that the protocol describes the objective(s), design, methodology, statistical considerations, organisation and estimated time frames for the trial. The protocol should also 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 human subject protection and the reliability of trial results. The coordinating investigator should identify and evaluate risks to the critical trial processes and data. Pre-defined quality tolerance limits should also 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 - Template.

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 chapter 6 of the ICH Guideline for Good Clinical Practice (GCP) E6 (R2).

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 (mostly cardiology trials).

An example of the different kinds of committees can be found here.

When a DMC is involved in a 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 - Template must be written. The charter should be submitted together with the clinical trial application.

The protocol should preferably be written in English to avoid translation issues when publishing. TransCelerate BioPharma Inc. has developed an protocol template together with a.o. a library of therapeutic guidelines. A slightly adapted Protocol - Template based on the TransCelerate’s template is available at norcrin.no.

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 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.

Access to TransCelerate’s library is as follow:

Go to: transceleratebiopharmainc.com
Scroll down to “Tools and resources”.
In “Clinical Template Suite (CTS); Template, Resources and Use Guidance”, choose “CPT” if you want to access the protocol template, or “SAP” for the statistical analysis plan.
Click on “CPT Templates” or “SAP Templates” in the column on the left.
Under “Basic Word Version”, click on “Common Protocol Template (CPT)” or “SAP Template”.

You might need to fill in a download request.

The protocol template includes a Protocol Synopsis - Template. Most countries, including Norway, require in addition a synopsis in local language, 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.

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. An SAP template is available on Transcelerate’s website.

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

Review and approval

The protocol should be reviewed prior to finalisation to ensure it contains all the required information listed in the Protocol Content Checklist - Template The checklist should be used to ensure that the requirements are met prior to submitting the protocol to the Competent Authority and Ethics Committee(s). If the TransCelerate protocol template was used it is not necessary to use the checklist.

It is recommended that the coordinating investigator asks other persons 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). For example, other investigators, trial personnel, 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 and statisticians who can advise in respect to choice of design, statistical methods and provide statistical input (power calculation, sample size, etc.).

The protocol shall be signed by the sponsor representative.

More details on the preparation of applications to the Competent Authority(ies) and Ethics Committee(s) can be found in the Application Process, Approvals - SOP 1.9.a.

Procedures for changes to an approved protocol and possible need for re-approval is described in SOP Modifications after Trial Start – SOP 1.9.c.

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 Study Files – SOP 1.6.a. It is recommended that the Protocol Version Tracking Log - Template is used to keep a record of protocol versions.