As a full-service CRO who helps many sponsors develop their clinical strategy and the associated study protocols, the release of an International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) protocol template is of great interest to PROMETRIKA. Step 2 of the ICH harmonized guideline on the clinical electronic structured harmonized protocol (CeSHarP) occurred in September 2022. This draft guidance was released for public consultation in December 2022, together with technical specifications and an electronic template. The guidance provides detailed information to be included in each section of a clinical protocol, expanding on the information currently included in the ICH GCP guidance. For those of us working in this regulated industry, it is a welcome addition.

When my colleagues and I first saw this guidance, we were pleased that ICH had finally provided an updated, considered protocol format for the industry. It has been nearly 30 years since ICH E3 – Structure and Content of Clinical Study Reports (July 1996) was issued, giving guidance on CSR development. But no harmonized approach to protocol development has been provided by ICH until now. Over the years, industry practices and collaborations have honed protocol elements and templates, sometimes in response to advancing technologies. ICH has taken the best modifications and suggestions from these versions and created a clear and concise protocol design. The goal, of course, is that no matter in what region or by which sponsor a protocol is developed, international regulatory agencies and clinical research sites will know where to find important protocol elements and instructions. With this standard approach in mind, we agree it will certainly be easier to navigate online protocols, such as those on agency websites, and find specific information more quickly.

While the GCP guidance covers the content of a clinical protocol, the CeSHarP guidance, associated template, and technical specifications documents cover the format and organization of a protocol down to the headings and fonts. Level 1 and 2 headings are to remain in all protocols so that the sequence (heading numbers) of all sections will become well-known. For example, trial design will always be in Section 4, start and end of trial in Section 4.4, inclusion/exclusion criteria in Sections 5.4 and 5.5, and trial stopping rules in Section 7.4. This specific information may be difficult to locate without a standard format since sponsors may include them in different sections of the protocol. Specific sections are now also allocated for items such as pregnancy, medical devices, pharmacokinetics, genetics, biomarkers, immunogenicity assessments, medical resource utilization, and health economics. Without specific guidance, sponsors were making various decisions as to where best to locate these topics.

Of particular interest is the new information to be included in the protocol and on the protocol cover sheet. requests that each protocol entered into this system include a short title in plain language, and the CeSHarP template includes this requirement. In addition, regulatory approval information is required such as the IND or EudraCt number and the NCT number (if entered on the website). Amendment details are on the cover sheet and include a list of amendments, the sponsor approval date, and the approximate enrollment under the previous amendments when the newest amendment was instituted. This information is helpful in completing EudraCT results information as a list of substantial amendments is required. For a new amendment, a summary of the amendment is required as well as a statement regarding whether the amendment is likely to have a substantial impact on safety or the rights of the participants, or on the reliability and robustness of the data generated in the clinical trial.

Although the new format has not yet been finalized by ICH (completed Step 4), PROMETRIKA has engaged in a mock protocol writing exercise to become familiar with the new outline. During this testing, questions arose as to how to populate certain sections, and, in some instances, there appeared to be redundancies in the information required among sections. When ICH updates the guidance and instructions, these issues will likely be resolved.

The protocol synopsis requires primary and secondary objectives, endpoints and estimands. The inclusion of the estimand, a systematic description of the treatment effect to be quantified in order to answer the trial’s research objective, is a new requirement. To keep the synopsis focused on the most important objectives of the research, tertiary and exploratory objectives are not listed in the synopsis, but are covered later in the protocol. In the section of the synopsis describing study blinding, blinding status (blinded, not blinded) of participants and investigators is indicated; sponsor blinding status is included in another section of the protocol. In PROMETRIKA’s exercise of building a mock protocol, we felt this particular separation of information a bit unsettling. As soon as one reads the blinding information in the synopsis, it immediately raises the question of, “What about the sponsor?” We wonder if ICH will amend this instruction or industry practice will adapt it over time.

One of the more interesting changes is the information required in the Introduction section. This guideline specifically states that information in the Investigator Brochure (IB) should not be repeated here. This, to us, is a good change as we will no longer feel the need to provide detailed descriptions of the investigational product, non-clinical research, and previously conducted clinical studies that are currently summarized in the IB. On the other hand, this requirement forces sponsors to update IBs in advance of/alongside new studies rather than adding the newest information to the introduction section of the protocol.

The introduction section now focusses on the purpose of the study, the benefits and risks of administering the therapy, trial intervention, and trial procedures, and the overall benefit risk conclusion as it pertains to this particular study and participant group. As the focus is on the study not the overall benefit risk assessment of the product being tested, this section must address benefits and risks to individual participants and needs to address those who receive the investigational product as well as those on the control arm or placebo, if it is a controlled study. As some of these concepts are new to protocol writers, it is hoped that with the final guidance, more detail of what is expected in these sections will be provided.

Section 8.4 provides an overview of Adverse Events and Serious Adverse Events, handling and reporting. Section 12 also covers these items, but in more detail. It would be better to consolidate the information in these two sections into one section unless the expectation is to provide different information in each of these sections. If the expectation is the latter, we hope that more guidance will be provided regarding the appropriate information to be included in each of these sections.

While this is a new format to which we will need to adjust, in the end, it will be a benefit to sponsors, regulators and individuals accessing study results whether in a publication or on a public website. One standard format all protocols enhances ease of use and clarity of activities for all parties in the clinical research sector.

When my colleagues and I first saw this guidance, we were pleased that ICH had finally provided an updated, considered protocol format for the industry.

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