Clinical trials for medicines: guidance on compliance with ICH E6 good clinical practice (GCP) in the United Kingdom
Information on how ICH E6(R3) good clinical practice (GCP) principles are implemented and enforced in UK clinical trial legislation.
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Background
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is an organisation comprised of regulatory authorities from ICH Regions and the pharmaceutical industry to discuss scientific and technical aspects relating to the authorisation of medicinal products.
The mission of ICH is to achieve greater harmonisation worldwide to ensure that safe, effective, and high-quality medicines are developed and registered. Harmonisation is achieved through the development of ICH guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side.
Key to the success of this process is the commitment of the ICH regulators to implement the final guidelines.
As the UK sovereign medicines regulator, following the UK departure from the European Union (EU), the MHRA became a full member of ICH in May 2022.
ICH E6 GCP is an international guideline that has been developed to facilitate the harmonisation of the quality of the conduct of clinical trials that are intended to be submitted to a regulatory authority in one or more ICH regions to gain a marketing authorisation approval (MAA) for a medicinal product.
The ICH GCP guideline is also applicable to other interventional clinical trials of investigational medicinal products that are not intended to support marketing authorisation applications.
The (ICH) Expert Working Group for ICH E6 (R3) (EWG) updated the ICH E6 (R2) GCP guideline. The UK Medicines and Healthcare products Regulatory Agency (MHRA) represented the Pharmaceutical Inspection Co-operation Scheme (PIC/s) in the EWG. The EWG involved stakeholders during the revision process, and the guideline was subject to public consultation which the MHRA facilitated for the UK.
ICH E6 (R3) GCP consists of the GCP principles, two annexes, appendices A, B and C and a glossary.
Compliance with ICH E6 GCP in the United Kingdom
The Medicines for Human Use (Clinical Trials) Regulations 2004 (‘UK CT Regulations’) have been updated following United Kingdom’s departure from the EU and the proposed changes to the legislation were subject to public consultation.
The government response to the consultation on legislative proposals for clinical trials confirmed that the principles of GCP, as set out in ICH E6 GCP, would replace the current GCP principles in the UK legislation that were based primarily on outdated EU legislation.
Compliance with the ICH E6 GCP Principles (as amended from time to time) and not the entirety of the guideline becomes a legal requirement in the UK on 28 April 2026. This is set out in Regulation 28 of the amended UK CT Regulations, which states that:
“(1) No person shall (a) conduct a clinical trial, or (b) perform the functions of the sponsor of a clinical trial (whether that person is the sponsor or is acting under arrangements made with that sponsor), otherwise than in accordance with the conditions and principles of good clinical practice.”
“(1A) The conditions and principles of good clinical practice include those 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.”
“(1B) (a) For the avoidance of doubt the functions of the sponsor include functions in relation to (i) the development and maintenance of trial specific computerised systems, and (ii) the selection and oversight of a laboratory in relation to the analysis or evaluation of human samples collected as part of the clinical trial; and (b) conducting a trial.”
Training in ICH E6 GCP
In addition to writing the guidance, the EWG also developed training materials for the E6 (R3) GCP guideline. These training materials are available on the ICH website.
Training in ICH E6 GCP and the UK legislation should be proportionate to each individual’s role in a clinical trial based on their delegated activities.
Sponsors, service providers and investigator s/institutions should use or consider the training materials provided by the E6 (R3) EWG in their training provision. ICH E6 GCP training should be documented.
United Kingdom-specific GCP principles
Within the Medicines for Human Use (Clinical Trials) Regulations 2004 (“UK CT Regulations”), three UK specific principles have been retained by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 (Regulation 37 (which amends Schedule 1, Part 2 of the UK CT Regulations)).
One requiring compliance with the Declaration of Helsinki (see guidance on Declaration of Helsinki and Clinical Trial Regulations alignment), a second relating to the provision of insurance, and a third one as follows:
“The investigator and sponsor must have regard to all relevant guidance with respect to commencing and conducting a clinical trial.”
This means that the annexes to ICH E6 (R3) GCP cannot be ignored as they are relevant guidance. As the principles of ICH E6 GCP are high level, the annexes provide more detailed guidance on how compliance with the principles could be achieved.
The sponsor and investigator must give due regard to the Annexes when commencing or conducting a clinical trial.
Disapplication and interpretation of aspects of the guidance contained in the ICH E6 GCP annexes for trials not intended for marketing authorisation applications
ICH E6 (R3) GCP introduction and structure contains the following text:
“This guideline applies to interventional clinical trials of investigational 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.”
“The Annexes provide the basis for the appropriate interpretation and application of the principles and should therefore be appropriately considered; however, various approaches to the provisions in the Annexes may be considered provided they are justified and achieve the intended purpose of the application of the principles.”
“The principles outlined in this guideline may be satisfied using differing approaches and should be applied to fit the intended purpose of the clinical trial.”
As a result, for trials that are not related to a MAA, disapplication and specific interpretation of some aspects of the Annexes may occur or be required. Clinical trials of medicines that are not used for marketing authorisation purposes may nevertheless impact on public health, for example, the publication of the trial results may impact prescribing practice.
It is important such trials generate reliable results when used for decision making and that trial participants’ rights, safety and well-being are protected. In accordance with the UK-specific principle outlined above, which requires the sponsor and investigator have regard to all relevant guidance when commencing and conducting a clinical trial, a robust rationale must be provided for any such disapplication or alternative methods used to satisfy the ICH E6 GCP principles.
Disapplication of aspects of annex guidance may be on a trial or a quality system level; the latter therefore applies to all the trials conducted using the quality system. Rationale for the departure and details of any mitigation or other means to ensure that the relevant principle(s) are met should be documented.
It is recommended that such considerations are made proactively and early in the trial lifecycle and could be part of a trial risk assessment and accompany the consideration of critical to quality factors.
A line-by-line assessment of Annex 1 is not required to be documented. Documentation should be retained that demonstrates that consideration of the Annexes was undertaken and that any disapplication that could potentially impact on compliance with ICH E6 GCP principles was mitigated or how compliance was maintained by other means. This then would demonstrate that this UK principle had been complied with respect to GCP.
The MHRA may conduct a GCP inspection of a trial conducted in the United Kingdom against the UK legislative requirements including the ICH E6 GCP principles. For trials conducted to support marketing authorisations and/or where the sponsor organisation claims compliance with ICH E6 GCP for its clinical trials, compliance with the Annexes in addition to the principles would be expected.
Proportional application of aspects of the guidance contained in the ICH E6 GCP Annexes
ICH E6 (R3) GCP Principles contains the following text:
“The Principles of GCP are designed to be flexible and applicable to a broad range of clinical trials. This guideline, along with ICH E8(R1), encourages thoughtful consideration and planning to address specific and potentially unique aspects of an individual clinical trial. This includes evaluation of trial characteristics, such as the design elements, the investigational product being evaluated, the medical condition being addressed, the characteristics of the participants, the setting in which the clinical trial is being conducted, and the type of data being collected. Careful consideration of factors relevant to ensuring trial quality is needed for each clinical trial.”
“Clinical trial processes and risk mitigation strategies implemented to support the conduct of the trial should be proportionate to the importance of the data being collected and the risks to trial participant and the reliability of trial results.”
Amendments to the UK CT Regulations (made by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025), implemented on 28 April 2026, contains the following top-level principle from ICH E6 (R3) GCP:
“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.”
This means that a risk proportionate approach to how the trial is designed, set-up, conducted and reported must be implemented.
The ICH E6 (R3) GCP principles include further proportionate requirements in relation to processes and systems for ensuring the quality of the information from the trial and for computerised systems being fit for purpose as follows:
“9.2 Systems and processes that aid in data capture, management and analyses, as well as those that help ensure the quality of the information generated from the trial, should be fit for purpose, should capture the data required by the protocol and should be implemented in a way that is proportionate to the risks to participants and the importance of acquired data.”
“9.3 Computerised systems used in clinical trials should be fit for purpose (e.g., through risk-based validation, if appropriate), and factors critical to their quality should be addressed in their design or adaptation for clinical trial purposes to ensure the integrity of relevant trial data.”
The MHRA therefore expects sponsors to have undertaken a robust risk assessment to facilitate the implementation of a risk-based approach. Additionally, the annex guidance specifically requires sponsors to implement implementation of risk-proportionate approaches and an appropriate risk-based quality management system (see ICH E6 (R3) Introduction to section 3 and section 3.10).
Further guidance is available for this in Clinical Trials for Medicines: Guidance on Quality & Risk Proportionality.
All aspects of the guidance should be interpreted in the context of the risks to the reliability of the trial results and to the rights, safety and well-being of trial participants. As a result of the flexibility afforded in ICH E6 (R3) GCP it is expected that specific processes applied during the trial will vary from trial to trial and how aspects of the guidance were implemented would vary as a result.
It is expected that the sponsor’s interpretation of compliance with the guidance would be traceable to a robust justification in a risk assessment.
Sponsors should understand that MHRA GCP Inspectors aim to evaluate compliance with the Annexes proportionately and pragmatically in relation to the risks to the reliability of the trial results and the protection of the participants’ rights, safety and well-being and will make use of the sponsor’s risk assessment as part of this process.
The responses to the ICH E6 R3 consultation identified a need for consistency of approach and assessment of risk proportionality across regulators. The MHRA collaborates via the Pharmaceutical Cooperation Inspection Scheme (PIC/S) to enhance consistency across regulators and to discuss differences in approach and interpretation
Implementation of ICH E6 (R3) GCP for ongoing trials on 28 April 2026
Updating the Medicines for Human Use (Clinical Trials) Regulations2004 (“UK CT Regulations”) to implement the ICH E6 GCP principles has been a known intention for some time.
It was stated in the government response to consultation on legislative proposals for clinical trials which published on 21 March 2023) and contained in the legislation that was laid before parliament on 12 December 2024 (that amended the UK CT Regulations).
The ICH E6 (R3) GCP principles and Annexe 1 reached Step 4 on 06 January 2025 and the date for implementation of the updated legislation of 12 months after the legislation came into law became clear on 10 April 2025.
It is expected that sponsors should have assessed ICH E6 (R3) GCP principles and Annexe 1 to determine necessary changes to their quality management system to ensure compliance from 28 April 2026. This assessment should be documented, and it could be examined during MHRA GCP inspections.
For trials that commenced prior to 28 April 2026, there should be a documented impact assessment of the GCP updates on the trial. During this assessment consideration should be given to the status of the trial when the implementation date was announced and the expected duration of the trial after 28 April 2026.
It is understood that for some aspects of the updated guidance it would be inappropriate to apply updated procedures to the trial, and such justifications should be part of the assessment.
This would be dependent upon the trial and its timing, for example, trials that were being set up and started between dates 10 April 2025 and 28 April 2026 and anticipated to continue after that date would be expected to have fewer required deviations than those trials started a lot earlier and continuing only for a short period of time after 28 April 2026.
Such prospective deviations from the updated quality management system should be documented and should be limited to the affected trials.