The letter can be read in full below, while the Appendix can be viewed here.
Commentary on E6(R3) Good Clinical Practice (GCP) Draft Guidance
Response submitted by the Good Clinical Trials Collaborative, on behalf of signatories.
Tuesday, 26 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 (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 following pages 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.
This submission has been developed and prepared by the Good Clinical Trials Collaborative, supported by the Coalition for Reducing Bureaucracy in Clinical Trials, and the Biomedical Alliance in Europe (BioMed Alliance), collectively representing more than 50 medical societies and patient advocacy and research organisations, and more than 400,000 researchers and healthcare professionals:
European Cancer Patient Coalition
European Society of Cardiology
European Society of Intensive Care Medicine
European Haematology Association
European Association of Urology
European Association for Clinical Pharmacology and Therapeutics
European Association for Haemophilia and Allied Disorders
European Association for the Study of the Liver
European League Against Rheumatism
European Academy of Allergy and Clinical Immunology
European Academy of Neurology
European Association for Cardio-Thoracic Surgery
European Association of Nuclear Medicine
European Atherosclerosis Society
European Cancer Organization
European Organisation for Research and Treatment of Cancer
European Renal Association
European Respiratory Society
European Society of Anaesthesiology and Intensive Care
European Society for Blood and Marrow Transplantation
European Society of Endocrinology
European Society of Human Reproduction and Embryology
European Society for Paediatric Gastroenterology Hepatology and Nutrition
Federation of European Biochemistry Societies
United European Gastroenterology
European Society for Paediatric Gastroenterology Hepatology and Nutrition
European Cancer Organisation Patient Advisory Committee
Belgian Society of Anesthesiology, Resuscitation, Perioperative Medicine and Pain Management
Cystic Fibrosis Europe
European Lymphoma Institute
Global Liver Institute
International Brain Tumour Alliance
International Kidney Cancer Coalition
Kidney Cancer Support Network
Kidney Cancer UK
Liver Patients International
Nordic Lymphoma Group
Österreichische Gesellschaft für Pneumologie
Respiratory Society of Serbia
Stichting Hemato-Oncologie voor Volwassenen Nederland
Thalassaemia International Federation
Belgian Respiratory Society
Croatian Cooperative Group for Hematologic Diseases
Czech Myeloma Group
Vall d’Hebron Institute of Oncology Experimental
World Duchenne Organization
VHL Family Alliance Greece
EHA Patient Advocacy Committee
European Society of Radiology
European Society of Clinical Microbiology and Infectious Diseases