GCP Snippets: Is ICH GCP applicable in the European Union (and elsewhere)?
ICH GCP IS ALIVE AND KICKING
“When designing, conducting, recording and reporting clinical trials, detailed questions may arise as to the appropriate quality standard. In such a case, the 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.” >> Recital 43 of Regulation (EU) No 536/2014 (the “EU Clinical Trials Regulation”, “CTR”) sets this tone.
And although recital (80) assures: “This Regulation is in line with […] good clinical practice […]”, the EU Clinical Trials Regulation Questions & Answers document of the Clinical Trials Coordination and Advisory Group leaves no doubt about the EU’s claim to power:
“The CTR […] takes precedence over conflicting rules in guidelines, albeit ICH or other guidelines. Documents or data that are not foreseen by the Regulation … shall not be requested or submitted based on recommendations in different guidelines.”
A representative of the German competent authority BfArM boiled it down to: “CTR beats ICH GCP.” However, ICH GCP is not dead, even in Germany it is alive and kicking. In 2024, the inspection reports of a German authority for a clinical trial that is subject to the CTR made numerous references to ICH E6, but none to the CTR (!). One can assume that they will continue this practice for all types of clinical trials that are subject to the CTR.
How does ICH E6 (R3) itself think about this issue?
While previous versions were ignorant about the scope of applicability, the new version of ICH GCP states in the introduction:
- “This guideline applies to interventional clinical trials of investigational products [in a footnote explained as synonymous with drugs, medicines, medicinal products, vaccines and biological products] that are intended to be submitted to regulatory authorities. The Principles of GCP in this guideline may also be applicable to other interventional clinical trials of investigational products that are not intended to support marketing authorisation applications in accordance with local requirements.”
Let’s dissect this as far as possible:
The sentence “clinical trials of investigational products that are intended to be submitted to regulatory authorities” probably refers to applications for authorisations, but is it about applications for clinical trials or applications for the authorisation of medicinal products? The second sentence gives a hint that ICH E6 (R3) sees itself only mandatory for clinical trials that would be used “to support marketing authorisation applications”. This would exclude many Phase IV trials and perhaps some Phase I trials.
This interpretation is supported by a statement from an MHRA GCP Inspector on the 2023 draft of ICH E6 (R3): “For the UK, the MHRA would expect clinical trials of investigational medicinal products (IMP) with a MHRA Clinical Trial Authorisation that are intended for marketing authorisation submissions to comply with the entire guideline and ALL trials involving an IMP, irrespective of marketing authorisation status of the IMP, to comply with the principles [of ICH GCP] in section II [of ICH E6 (R3) or of Schedule 1 of “The Medicines for Human Use (Clinical Trials) Regulations 2004”?] as a minimum legal requirement.”
The new reference to and explanation of “investigational products” excludes the application of ICH E6 (R3) to clinical investigations with medical devices, while the US American FDA regards ICH GCP as applicable for such types of studies (see the FDA links below).
Another element of the definition of the scope of ICH E6 (R3) is the term “interventional”. ICH E6 (R3) does not say what it is but in the glossary it defines
- “Clinical Trial” as “Any interventional investigation in human participants …”.
This makes the reference to “interventional clinical trials” in the introduction a pleonasm and shows that ICH GCP practices a quite “easy-going” approach to definitions.
The CTR is not so sloppy: The definition in CTR Article 2 (2) pushes an otherwise non-interventional clinical study into the playing field of a clinical trial that is subject to the CTR if it applies “diagnostic or monitoring procedures in addition to normal clinical practice”. This could be the use of a simple questionnaire that is not an element of normal clinical practice.
One might wonder whether the forthcoming Annex 2 of ICH E6(R3) does not open ICH GCP to non-interventional studies, because the draft version of 2024 announces: “Annex 2 provides additional GCP considerations, focusing on examples of trials that incorporate […] real-world data (RWD).” Although an universally accepted definition of real-world data is not available, a common concept is that real-world data is collected from marketed products, i.e. rather from a non-interventional setting. However, the draft of Annex 2 of ICH E6(R3) does not cover pure real world data studies, but real word data used by clinical trials: “RWD incorporated in clinical trials include the use of data relating to patient health status collected from a variety of sources outside of clinical trials (e.g., electronic health records (EHRs), registries, claims data). These data from RWD sources may be used in various ways, including, but not limited to, ascertaining endpoints or outcomes or serving as an external control.”
Apart from the EU, is ICH GCP applicable in other major European study countries?
UK: The forthcoming “The Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2024” in the United Kingdom plans to amend Schedule 1, Part 2 (Conditions and principles which apply to all clinical trials” of “The Medicines for Human Use (Clinical Trials) Regulations 2004” as follows:
“1. Clinical trials must be conducted in accordance with the principles of good clinical practice set out in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, as amended from time to time.
2. Except where it would be a contravention of these Regulations, clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki.”
(Note that ICH GCP is supposed to apply without limitation, while the Declaration of Helsinki might be overruled by Statutory Instruments 2004 No. 1031.)
Switzerland: The Swiss “Ordinance on Clinical Trials with the exception of Clinical Trials of Medical Devices” provides in Annex 1: “The applicable rules of Good Clinical Practice are: 1. for clinical trials of medicinal products and transplant products: the Guideline for Good Clinical Practice issued by the International Conference on Harmonisation […]”
ICH has collected information about the worldwide implementation of its guidelines, including ICH E6 (https://www.ich.org/page/ich-guideline-implementation). But although you see ICH E6 (R2) flagged as “Implemented” in quite a few countries and regions, and find, for example, a copy of ICH E6 (R3) on the EMA website with the reassuring EMA logo in EU blue, this does not mean that the whole ICH GCP guideline is implemented as a mandatory norm.
Links and further reading:
https://mhrainspectorate.blog.gov.uk/2023/05/26/ich-e6-r3-good-clinical-practice/
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-clinical-data-support-medical-device-applications-and-submissions-frequently-asked
https://www.govinfo.gov/content/pkg/FR-2018-02-21/pdf/2018-03244.pdf
https://www.fda.gov/medical-devices/investigational-device-exemption-ide/acceptance-data-clinical-investigations-medical-devices
https://www.fedlex.admin.ch/eli/cc/2013/643/en
https://www.legislation.gov.uk/uksi/2004/1031/contents
https://www.legislation.gov.uk/ukdsi/2024/9780348267167/contents
