In January 2025, the ICH made its finalised, updated GCP Principles and ‘Annex 1’ available to the public, due to become effective in Summer 2025. The ICH also consulted on a new ‘Annex 2’ with additional advice on trials using decentralised or pragmatic elements and/or real-world data (RWD). The Collaborative coordinated an expert response to the Annex 2 public consultation. Here we reflect on our work to influence the ICH GCP guidelines and promote rational guidance that makes it easier to do informative, ethical and efficient clinical trials.

GCP Principles and Annex 1

The finalised guideline is the third major revision (R3) of GCP since its introduction in 1996, with the other update published in 2016 (R2). The finalised Principles of GCP in R3, while retaining the same general focus, are significantly changed from R2 and help to advance priority advocacy objectives of the Good Clinical Trials Collaborative.

Principles are the Priority

The eleven numbered Principles are each supported by sub-bullets providing subsidiary stipulations or clarification. Major changes include the introduction of new principles of GCP, including:

• Principle #6: Quality should be built into the scientific and operational design and conduct of clinical trials.

Additional text emphasises quality must be managed prospectively by identifying and focusing on factors critical to the quality of the trial.

• Principle #7: Clinical trial processes, measures and approaches should be implemented in a way that is proportionate to the risks to participants and to the importance of the data collected and that avoids unnecessary burden on participants and investigators.

Emphasises that “the focus should be on risks that go beyond those associated with usual medical care.”

• Principle #9: Clinical trials should generate reliable results.

Emphasises the value of fitness-for-purpose, efficiency, sufficiency, and proportionality in ensuring the integrity and reliability of trial results and supporting good decision making.

Further additions and edits contribute to an overall shift in the emphasis of the guideline from a defensive, rules-based framework to one that is more enabling, flexible and proportionate. For example:

• Principle 1 of R3 includes explicit direction (at point 1.4) to avoid unnecessarily excluding particular participant populations. This point is not addressed in R2 at all.
• Principle 2.5 of R2 required that “Clinical trials should be scientifically sound, and described in a clear, detailed protocol.” In R3, this has been revised (at Principle 8) to read “Clinical trials should be described in a clear, concise, scientifically sound and operationally feasible”
• Principle 2 of R3 significantly expands the key considerations in relation to informed consent, principally ensuring that the principle is focused on the objective of informing participants (rather than obtaining consent records) but also addressing issues where informed consent may be challenging e.g. emergency situations.

Successes

These changes align with goals established at the outset of the Good Clinical Trials Collaborative project and represent important successes for our work.

A newly introduced preamble to the Principles explicitly states that they are “designed to be flexible” and “support efficient approaches to trial design and conduct”, and that each clinical trial can differ in terms of “factors relevant to ensuring trial quality”, requiring “thoughtful consideration”.

This is backed up by statements encouraging the implementation of Quality by Design approaches, and engagement with patients and their communities, patient advocacy groups and healthcare professionals, seeking their input to “reduce unnecessary complexity, improve feasibility and increase the likelihood of meaningful trial outcomes.”

Challenges for the future

However, weak language on transparency (particularly in relation to publishing results) and the absence of text emphasising involvement of patients, public, or the community in trial design and conduct among the eleven principles are notable and disappointing.

It remains to be seen whether these valuable statements will have a material impact on users’ implementation of the guideline. However, their inclusion is important as a globally-agreed articulation of the value of focusing on fitness-for-purpose in trial design, conduct and effective quality management.

Text relating to sponsor and investigator roles (both in Principle 10 and various sections of Annex 1) is outmoded, despite examples of more appropriate, efficient, and higher quality alternative solutions. This is a topic we returned to in our response to the Annex 2 consultation.

On Annex 1, during the public consultation phase, the Collaborative made recommendations to improve text we perceived as unduly specific, detailed, limiting, erroneous or duplicative.

In some cases, these recommendations have been implemented but overall Annex 1 remains vulnerable to over-interpretation and rigid implementation, where users (including sponsors, investigators, funders, trial and clinical operations staff, trainers, monitors, auditors, and inspectors) are directed too narrowly by its text, rather than be guided to the most appropriate interpretation and application by the principles.

Annex 2

The Collaborative coordinated an expert response to the Annex 2 public consultation, making recommendations to:

• Strengthen reference to the Principles of GCP
• Improve text to support Sponsor and Investigator roles and responsibilities to be assigned flexibly
• Promote established best practices of engaging patients, patient advocacy groups and their communities
• Improve text on involving Healthcare Professionals in trials to set proportionate expectations
• Set more pragmatic expectations on accessing RWD sources
• Adapt text to promote informative, actionable safety reporting

The response was developed with input from more than 30 global experts, representing diverse expertise and backgrounds, and was subsequently endorsed by over 100 individuals, and relevant specialist and international organisations including the UKCRC Registered Clinical Trials Unit (CTU) Network, the Clinical Data Interchange Standards Consortium (CDISC), the Faculty of Pharmaceutical Medicine (FPM), the Biomedical Alliance in Europe (BioMed Alliance), and the Decentralized Trials & Research Alliance (DTRA).

You can read the response, as submitted to the U.S. FDA, here: https://www.regulations.gov/comment/FDA-2024-D-5601-0012