DE

GCP Snippets: Compliance with the unknown

Do you know your way through the jungle of clinical trial regulations and requirements to comply with? FGK does. - Picture by FGK generated with AI

HOW ARE SPONSORS AND INVESTIGATORS ABLE TO comply with ICH GCP?

ICH E6 (R3) requires that clinical trial protocols contain

  • “A statement that the trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory requirement(s)” (Annex 1, Appendix B, B.2.5).

Usually sponsors and investigators confirm compliance by signing on a dotted line beneath this very statement. But do they actually comply with ICH GCP, are they enabled to comply, and could they know how to comply?

We’ll show you why for clinical trials that are subject to the Regulation (EU) No 536/2014 (the “EU Clinical Trials Regulation”, CTR) the response is “no”. Triple “no”.

Let us start with Recital 43 of the CTR again: “[…] ICH guidelines on good clinical practice should be taken appropriately into account for the application of the rules set out in this Regulation, provided that there is no other specific guidance issued by the Commission and that those guidelines are compatible with this Regulation.”

This recital suggests to check ICH GCP rules for clinical trials that are subject to the CTR this way:

A. If the CTR has a similar rule, follow the CTR and ICH GCP.
B. If the CTR has a rule for a topic that differs from the rule of ICH GCP for the same topic follow the CTR.
C. If the CTR has no rule for the same topic as the ICH GCP rule, follow ICH GCP.

While it is already quite burdensome to follow this procedure for each of the hundreds rules of ICH E6 (R3), it is also futile, since the official Q&A document for the CTR does not agree to principle C of this approach when it states: “Documents or data that are not foreseen by the Regulation (e.g. the progress report as defined in the ICH E.6 guidance [in ICH E6 (R3) this is gone] shall not be requested or submitted based on recommendations in different guidelines. This approach reflects also recital 24, stating that the content of the application dossier should be harmonised to simplify the application process for clinical trials.”

The justification is somewhat wry since the progress report is not part of the application dossier at all. In addition, the CTR and the EU Commission allow or tolerate for the EU member states a colourful diversity in various aspects of the application procedure and the conduct of clinical trials. At this point you come to the question: If the progress report is not required by the CTR but also not explicitly forbidden, what other requirements of ICH E6 (R3) that are also not required by the CTR but also not explicitly forbidden are regarded as non-compliances to the CTR by the EU Commission and the EU member states?

For reasons that will probably remain unknown forever, the following one does not fall into that category: The official Q&A document on the CTR answers the question “Should sponsors also send SUSARs to investigators of a clinical trial?” with a reference to ICH E6, quoting some wording of the rules 5.16.2 and 5.17.1 (in ICH E6 (R3) this is Annex 1, 3.13.2, in which the rule of ICH E6 (R2) is modified):

“The sponsor should promptly notify all concerned investigators/institutions of findings that could adversely affect the safety of the subjects and should expedite the reporting of all SUSARs to all concerned investigators/institutions”.

These rules are not contained in the CTR. Why does the Q&A document introduce them via reference to ICH GCP? At this point you might wonder what exact criteria qualify rules of ICH E6 that are not featured by the EU CTR as compliant to the CTR. The author of these lines is clueless.

Some rules of ICH E6 (R3) are easier to handle. Different from previous versions of ICH GCP, ICH E6 (R3) allows adaptation of its rules to the rules of the venue of a clinical trial. As an example, Annex 1, section 3.8.1. reads like this:

  • “In accordance with applicable regulatory requirement(s), before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator) should submit any required application(s) to the appropriate regulatory authority(ies) for review […].”

The flexibility here ensures that this rule does not get into conflict with legal requirements like the EU CTR. Good job, ICH!
However, there are also rules like that of Annex 1, section 2.4.6 :

  • “The investigator or the sponsor should promptly communicate to the IRB/IEC […] changes significantly affecting the conduct of the trial and/or increasing the risk to participants.”

Would this rule constitute a conflict with the EU CTR? The EU CTR does not have provisions for reporting to ethics committees at all and it has no provisions for reporting “any changes significantly affecting the conduct of the trial” if they do not qualify as urgent safety measures or
serious breaches of the EU CTR or the study protocol. Would the investigator or the sponsor be obliged to report, e.g., supply delays, to the ethics committee because they have signed an agreement to comply with ICH GCP?

And now hold on to your seats: If not, because, as the argument goes, the EU CTR does not demand such reports, would the sponsor and the investigator still be obliged (as an example) to adhere to Annex I, section 4 of ICH E6 (R3) about data governance, although the EU CTR does not requires this?

These ambiguities are utilised by EU ethics committees for clinical trials that are subject to the EU CTR to gain some more liberty. E.g. the essential records table of ICH E6 (R3) lists the “IRB/IEC composition”. In line with this, Annex 1, section 1.5.2 of ICH E6 (R3) provides:

  • “The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its documented procedures and membership lists.”

However, for EU CTR studies, most EU ethics committees just say no. Some justify this with data protection issues (which is bizarre, since you find the names of the member on the ethics committee websites anyway), while the National Ethics Committee for Clinical Research in Portugal recites the arguments of the official Q&A document for the CTR: “It has been requested by several sponsors to identify the members of the ethics committee who evaluated the clinical trial dossier, in accordance with the recommendation of ICH-GCP (2). […] Documents or data that are not foreseen by the CTR cannot be requested or submitted based on the recommendations in different guidelines. […]” (https://www.ceic.pt/regulamento-ec, accessed on 27 February 2025)

In spite of such explicit refusal of adherence, the ethics committees of the EU still confirm compliance to ICH GCP in their charters and on their websites.
With the knowledge collected, we can modify the ICH GCP compliance for CTR trials as follows:

A. If the CTR has a similar rule, follow the CTR and ICH GCP.

B. If the CTR has a rule for a topic that differs from the rule of ICH GCP for the same topic follow the CTR.

C. If the CTR has no rule for the same topic as the ICH GCP rule, it is not clear what to do. Ask the EU commission, but do not expect a response that will help and accept that you are lost.

D. If you are an ethics committee, you have to follow the CTR and you are free to choose whether you follow ICH GCP or not.