For example, the Collaborative’s submission (a letter with an Appendix) to the U.S. Food and Drug Administration (FDA), on behalf of leading voices in the U.S. clinical trials sector, can be viewed publicly here and is reproduced below.
The comment periods for regulators in the European Union, Singapore, Canada, Japan and Switzerland remain open. If you would like to support our response as a co-signatory, please contact us at [email protected].
Commentary on E6(R3) Good Clinical Practice (GCP) Draft Guidance (FDA-2023-D-1955)
Response submitted by the Good Clinical Trials Collaborative on behalf of signatories
Tuesday, 5 September, 2023
Thank you for the opportunity to review and provide feedback on the draft ICH E6 (R3) guideline.
The new revision is a substantial improvement on previous versions. It is very positive to see the focus on Principles rather than operational details. This is in line with the recommendations made in the G7 100 Days Mission to Respond to Future Pandemic Threats, which stated that, “We should refocus regulatory guidelines on the fundamental scientific and ethical principles… whilst embracing flexibility and innovation… The Good Clinical Practice for clinical trials guidance should be revised to focus on what matters for the generation of actionable information about effects of an intervention, rather than what is easy to check but less relevant, placing an emphasis on principles and purpose rather than process.”
However, further improvements are essential if the ICH E6 (R3) guideline is to have the intended beneficial impact on clinical trials.
Principles are the Priority
The introductory text on Principles of ICH GCP (lines 35-77) is very strong, setting out exactly the right tone and emphasis. The principles themselves (lines 78-265) are generally good, although would be improved by some presentational changes and modifications.
Guidance is Guidance
It needs to be made much clearer that Guidance is Guidance, rather than binding requirements or ‘rules’, and that the Annexes (just 1 in this version) are to be used as implementation guides rather than as detailed requirements. It should be emphasised (e.g. in section I. Introduction) that it is acceptable to use an alternative approach to those specified in the Annex(es) providing that it satisfies the Principles of GCP (lines 35-265) and the applicable laws. Doing so will help ensure that the document lasts the test of time – advances in drug development, innovations in communications and information systems technology, novel or changing diseases and health conditions, and varying healthcare and societal contexts. It will foster innovation in trial methodology to the benefit of trial participants and the efficient generation of reliable clinical trial results.
Enabling adaptation for context, emphasising proportionality, and addressing the dangers of over-interpretation
There is a serious danger that for all the good intent of the authors of this revision, those charged with implementing it (including sponsors, investigators, auditors and inspectors) will fail to appreciate the context set by the Principles (lines 35-265) and apply the details set out in the Annex and associated Appendices rigidly ‘reading from the back’. The most extreme examples of such over-interpretation are likely to be an excessive focus on Records, Data and Computer Systems (multiple pages) in the Investigator and Sponsor sections (sections 2 and 3) and on the Essential Records (the last 6 pages of the document) rather than on the much more thoughtful, balanced and risk proportionate approaches set out at the beginning (pages 1-6). Some fairly simple but essential changes would substantially reduce the risk of over-interpretation.
We have identified a number of topics where major improvements are needed, in many cases these span several sections (Sponsor, Investigator, etc) and/or several individual clauses. We have grouped these into the following themes:
Document structure and layout: Some simple changes are required to better orientate the reader and avoid confusion.
Improvements to and Emphasis on the Principles: There is a need for some re-organisation and grouping of the existing principles (Section II) to improve comprehension and impact; some further improvements to the Principles themselves (lines 78-265) such as the benefits of involving the perspectives of patients, healthcare providers and professionals in trial design; and consistent reference to the ‘Principles of GCP’ (rather than ‘GCP’) in the Annex(es). The Principles might be further improved by text explaining the rationale (we are happy to provide examples).
Records, Data & Computerised Systems: The new draft has substantially increased text relating to records, data and computerised systems. The new Section 4 (lines 1813-2029) is largely helpful in providing guidance, emphasising proportionality and fitness-for-purpose, and enabling flexibility to the context of the specific trial and changes in information technology in the future. However, the sections for Investigator (Section 2) and Sponsor (Section 3) are unjustifiably rigid and specific. They also fail to take account of the substantial expertise in developing and maintaining high quality information systems in other contexts (e.g. communications technology, banking and commerce sectors).Given that development of information systems is a well-established endeavour with its own standards and guidelines, one sensible option might be to delete the sections on data in the Investigator (Section 2) and Sponsor (Section 3) sections, to retain the new Section 4 and add to it that development of Information Systems for Clinical Trials should follow the principles of relevant, well-established international standards and guidelines (perhaps giving a few examples, such as GAMP, ISO 27001 [quality management systems], ISO 9001 [information security]).
Essential Records: Substantial improvements are needed to encourage proportionality, reduce rigidity, and discourage a tendency of documentation for documentation’s sake that may distract attention from other activities that may be more fundamental to trial quality.
Roles & Responsibilities: Modifications are needed to avoid undue rigidity that may restrict sensible arrangements being put in place or which may impose unreasonable / unworkable oversight obligations on individuals /organisations for activities or data sources beyond their control.
Other issues: We have suggested a range of corrections and clarifications that will help improve the document and the way that it is interpreted and implemented.
We have provided details for each of these in the Appendix in the hope that they may lead to further improvements in the E6 document and in turn facilitate high quality clinical trials that lead to improvements in individual and public health.
Please write to [email protected] if we can answer questions or provide additional detail.
Professor John H. Alexander, MD, MHS
Professor of Medicine/Cardiology
Clinical Trials Transformation Initiative (CoChair)
(reflects my individual views and not an
official CTTI position)
Population Health Partners
Duke Clinical Research Institute, Duke
Senior Project Manager
Clinical Trials Transformation Initiative
(reflects my individual views and not an
official CTTI position)
Executive Vice President, Health
Professor Sir Martin Landray FMedSci
Lead, Good Clinical Trials Collaborative
Chief Executive Officer, Protas
Professor of Medicine & Epidemiology,
University of Oxford
Mark McClellan, MD, PhD
Duke-Margolis Center for Health Policy
Durham, NC and Washington, DC
Clive Meanwell, MD
Executive Chairman, Population Health
Dr. Amrit Ray
Visiting Professor of Practice, Newcastle
Chief Executive Officer, Principled Impact LLC
Janet Wittes, PhD
Brian Anderson, MD
Chief Digital Health Physician