Guidance

UK-specific annotations to ICH E6(R3)

Published 12 January 2026

Please note that “the Clinical Trials Regulations” refers to the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025.

ICH E6(R3) TEXT	ANNOTATION
Introduction (I) 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. See also Annex 1 3.8.1.	Under regulation 12 of the Clinical Trials Regulations, a clinical trial of an IMP cannot be started in the UK without authorisation from the licensing authority and a positive opinion from the ethics committee (i.e. a clinical trial approval). All clinical trials of an IMP must therefore be submitted to the regulatory authorities. In addition, under Schedule 1, Part 2 of the Clinical Trials Regulations, all clinical trials of an IMP “must be conducted in accordance with the principles of GCP set out in the ICH Guideline for Good Clinical Practice”. This applies whether or not the trial is intended to support an application for an MA.
Principles of ICH GCP (II) 1.5 A qualified physician or, when appropriate, a qualified dentist (or other qualified healthcare professionals in accordance with local regulatory requirements) should have the overall responsibility for the trial-related medical care given to and medical decisions made on behalf of participants; however, the practical interactions and the delivery of medical care and decisions can be carried out by appropriately qualified healthcare professionals in accordance with applicable regulatory requirements. See also: Annex 1 2.7.1 (a) and Annex 1 2.7.1 (b) and Annex 1 3.4.	The definitions of both “health care professional” and “investigator” are given in Regulation 2(1) of the Clinical Trials Regulations. In the UK, a person with a role included in the definition of health care professional can act as an investigator for a clinical trial. However, per the guidance on collection, verification, & reporting of safety events, a qualified physician (or, where appropriate, a qualified dentist) who is an investigator for the trial should have the overall responsibility for trial-related medical care and decisions on behalf of participants.
Principles of ICH GCP (II) 1.6 The confidentiality of information that could identify participants should be protected in accordance with applicable privacy and data protection requirements. See also: Annex 1 2.8.10 (o) and Annex 1 2.12.7 and Annex 1 3.11.4 and Annex 1 3.16.1 (t) and Appendix C C.2.11.	The applicable data protection requirements for the UK are set out in the UK General Data Protection Regulation and the Data Protection Act 2018. The Health Research Authority has further guidance available on UK GDPR for both researchers and study co-ordinators and for data protection officers, information governance officers and research governance managers.
Annex 1 2.8.10 (n) The informed consent discussion and the informed consent materials to be provided to participants should explain […] the process by which the participant’s data will be handled, including in the event of the withdrawal or discontinuation of participation in accordance with applicable regulatory requirements. See also: Annex 1 2.9.1 and Annex 1 3.16.1 (u) and Annex B B.6 (b) [p.60].	The applicable data protection requirements for the UK are set out in the UK General Data Protection Regulation and the Data Protection Act 2018. The Health Research Authority has further guidance available on data handling in the event of participant withdrawal here.
Principles of ICH GCP (II) 2.4 In emergency situations, where consent cannot be obtained prior to trial participation, consent should be obtained from the participant or their legally acceptable representative as soon as possible in accordance with applicable regulatory requirements and the processes approved by the institutional review board/independent ethics committee (IRB/IEC). See also: Annex 1 1.2.6 and Annex 1 2.8.8.	The applicable regulatory requirements are given in Schedule 1, Part 1, regulations 1(6) and 1(7) of the Clinical Trials Regulations and regulation 51 of the Adults with Incapacity (Scotland) Act 2000. The Health Research Authority has further guidance available on research in emergency settings.
Principles of ICH GCP (II) 3.2 Periodic review of the trial by the IRB/IEC should also be conducted in accordance with applicable regulatory requirements. See also: Annex 1 2.3.5 and Annex 1 2.4.5 and Annex 1 3.6.3 (d) and Annex 1 3.16.4 (a) and Appendix B B.11 and Appendix C C.1.3.	There is no legal requirement in the UK for the ethics committee to undertake periodic reviews of a clinical trial once approved. However, the ethics committee will review documentation relating to an ongoing trial under specific circumstances, such as in the event of an urgent safety measure or serious breach, or as part of their review of an application to make a substantial modification, etc.
Principles of ICH GCP (II) 9.5 Essential records should be retained securely by sponsors and investigators for the required period in accordance with applicable regulatory requirements. See also: Annex 1 2.12.11 and Annex 1 2.12.12 and Annex 1 3.6.3 (c) and Annex 1 3.16.3 (a) and Annex 1 3.16.3 (b) and Annex 1 4.2.8 and Appendix B B.14.3 and Appendix C C.1.3.	The regulatory requirements applicable to retention of the trial master file are given in regulation 31A of the Clinical Trials Regulations, or, where the trial was submitted to the authorities for approval before 28 April 2026, in regulation 4 of Schedule 14. Further detail is available in the guidance on transitional arrangements for Good Clinical Practice.
Principles of ICH GCP (II) 11.1 Investigational products used in a clinical trial should be manufactured in accordance with applicable GMP standards.	The legal basis for GMP is 2003/94/EC in Great Britain and EU Delegated Regulation 2017/1569 in Northern Ireland.
Principles of ICH GCP (II) 11.5 Investigational product labelling should follow applicable regulatory requirements.	The applicable regulatory requirements for labelling of investigational medicinal products used in clinical trials in the UK are set out in Part 6 of the Clinical Trials Regulations. Additional guidance on labelling of investigational medicinal products and noninvestigational medicinal products, including guidance protecting the blinding can be found at Clinical trials for medicines: labelling.
Annex 1 IRB/IEC The requirements for the IRB/IEC in this guideline should be read in conjunction with local regulatory requirements. See also Annex 1 1.3.2.	The applicable regulatory requirements for the IRB/IEC are set out in Part 2 of the Clinical Trials Regulations. For further context, the Standard Operating Procedures for Research Ethics Committees are also available on the HRA website. This will be updated to align with the amended Clinical Trial Regulations in due course.
Annex 1 1.1 For the submission to or communication with the IRB/IEC, in most regions where there is also a requirement to make a submission to the relevant regulatory authority, these may be combined in a single submission in accordance with applicable regulatory requirements.	Per regulation 16(1) of the Clinical Trials Regulations, the request for authorisation from the licensing authority and the application for an ethics committee opinion must be made by way of a single application dossier known as a ‘request for approval’. Per regulation 16(5) of the Clinical Trials Regulations, in exceptional circumstances, the request for authorisation from the licensing authority and the application for an ethics committee opinion may be made separately if agreed in advance by the licensing authority or the ethics committee.
Annex 1 1.1 Submissions and communications with the IRB/IEC and regulatory authorities are made in some regions by the investigator/institution and by the sponsor in other regions in accordance with applicable regulatory requirements. See also Annex 1 2.4.1 and Annex 1 3.8.2 (a).	Per regulations 14 and 15 of the Clinical Trials Regulations, the sponsor must make the request to the licensing authority for authorisation to conduct a clinical and the application to the ethics committee for an opinion in relation to the clinical trial. The sponsor may delegate this function but, per regulation 3(12), any such arrangement does not affect the responsibility of the sponsor.
Principles of ICH GCP (II) 2.1 In the event that a minor is a participant, assent should be collected from that minor, as appropriate, and in accordance with local regulatory requirements. See also Annex 1 1.2.7 and Glossary – “Legally Acceptable Representative”.	The applicable regulatory requirements regarding participation of minors in a clinical trial are set out in Schedule 1, Part 4 of the Clinical Trials Regulations.
Annex 1 1.4.5 The IRB/IEC should establish, document and follow its procedures, which should include providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC. See also Annex 1 1.4.7.	Standard Operating Procedures for Research Ethics Committees are available on the HRA website. The specific regulatory requirements applicable to modification of a clinical trial approval by the sponsor are given in regulations 22, 22A, 22B and 22C of the Clinical Trials Regulations. See detailed guidance on making modifications to a clinical trial approval.
Annex 1 1.4.8 (c) The IRB/IEC should establish, document and follow its procedures, which should include specifying that the investigator/institution should promptly report to the IRB/IEC All suspected unexpected serious adverse reactions (SUSARs) in accordance with applicable regulatory requirements. See also Annex 1 3.12.2 (d).	In the UK, there is no legal requirement to report individual SUSARs to the investigators or the ethics committee. Individual SUSARs must be reported to the MHRA, which is the authority responsible for safety. Please also see the MHRA’s detailed guidance on reporting SUSARs.
Annex 1 1.5.1 The IRB/IEC should retain all relevant records (e.g. documented procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings and correspondence) in accordance with applicable regulatory requirements and make them available upon request from the regulatory authority(ies).	Section 15 of the Standard Operating Procedures for Research Ethics Committees covers retention of records by the ethics committee. This document will be updated to align with the amended Clinical Trial Regulations in due course.
Annex 1 2.4.3 If the Investigator’s Brochure or basic product information brochure is updated during the trial, the IRB/IEC should receive the current version in accordance with applicable regulatory requirements. See also Annex 1 2.4.4 and Annex 1 3.13.2 (a).	If the change to the document is considered to be substantial per regulation 11 of the Clinical Trial Regulations, it must be submitted to the authorities for approval before the change made. If the change to the document is not substantial, the updated version does not need to be submitted to the authorities.
Annex 1 2.5.5 The investigator should follow the protocol and deviate only where necessary to eliminate an immediate hazard(s) to trial participants. The investigator should report information on the immediate hazard, the implemented change and the subsequent proposed protocol amendment, if any, to the IRB/IEC and, where applicable, regulatory authorities (see section 1.1). See also Annex 1 3.13.2 (e) and Annex 1 3.13.3.	The regulatory requirements applicable to urgent safety measures are given in regulation 30 of the Clinical Trials Regulations. See the guidance on urgent safety measures for further detail.
Annex 1 2.6.2 Where the investigator terminates or suspends their involvement in a trial without prior agreement by the sponsor, the investigator should promptly inform the institution, where applicable, the sponsor, the IRB/IEC and the regulatory authorities in accordance with applicable regulatory requirements and should provide a detailed explanation of the reasons.	There is no regulatory requirement for an investigator to inform the authorities that they are withdrawing from a trial. However, depending on the circumstances of the investigator’s withdrawal, the sponsor may need to temporarily halt the trial or report a serious breach to the MHRA in accordance with regulation 29A of the Clinical Trials Regulations. Further guidance on temporary halts and serious breaches is available at Clinical trials for medicines: collection, verification, & reporting of safety events.. In addition, if the investigator that has withdrawn from the trial is the chief investigator, then the sponsor will need to submit a substantial modification to the authorities with the details of the new chief investigator.
Annex 1 2.6.3 If the sponsor terminates or suspends a trial, the investigator/institution or the sponsor, in accordance with applicable regulatory requirement(s), should promptly inform the IRB/IEC and the regulatory authorities and should provide an appropriate explanation (see section 3.17.1). See also Annex 1 3.17.1.	The regulatory requirements applicable to termination of a clinical prior to the date or event specified in the protocol are given in regulations 27(2) and 27(3) of the Clinical Trials Regulations. See the guidance on notifying the authorities about the end of a clinical trial for further detail. A temporary halt can also be part of an urgent safety measure. In this case, the notification of the temporary halt of a trial should be done via the usual process and following the usual timelines for reporting urgent safety measures given in regulation 30 of the Clinical Trials Regulations and the guidance on urgent safety measures.
Annex 1 2.7.2 (b) In accordance with applicable regulatory requirements, the protocol may identify SAEs not requiring immediate reporting; for example, deaths or other events that are endpoints. See also Annex 1 3.11.4.5.2 (e).	The applicable regulatory requirements for the reporting of adverse events (including serious adverse events) are given in regulation 32 of the Clinical Trials Regulations. Please also see the MHRA’s detailed guidance on reporting adverse events and serious adverse events.
Annex 1 2.8.1 In obtaining and documenting informed consent (paper or electronic format), the investigator should comply with the applicable regulatory requirement(s) and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. See also Annex 1 2.8.5 and Annex 1 2.8.1 and Glossary – “Legally Acceptable Representative”.	The applicable regulatory requirements for obtaining and documenting informed consent are set out in Part 1 of Schedule 1 of the Clinical Trials Regulations.
Annex 1 2.8.1 (e) Whether the informed consent process takes place in person or remotely, the investigator should assure themselves of the identity of the participant (or legally acceptable representative) in accordance with applicable regulatory requirements.	The Clinical Trials Regulations do not specify how the investigator should assure themselves of the identity of the participant, however, the MHRA and HRA have released a joint statement on seeking consent using electronic methods that includes guidance on identity verification.
Annex 1 2.8.10 (p) The informed consent discussion and the informed consent materials to be provided to participants should explain […] the trial may be registered on publicly accessible and recognised databases, per applicable regulatory requirements.	Per regulatory requirements applicable to the registration of clinical trials are given in regulation 25(1) of the Clinical Trial Regulations.
Annex 1 2.8.12 A process for consent should be considered if, during the course of the trial, the minor reaches the age of legal consent, in accordance with applicable regulatory requirements.	Per regulation 2(1) of the Clinical Trial Regulations, a minor is defined as a person under the age of 16 years. See the HRA’s guidance on research involving children for further detail.
Annex 1 2.10.5 The investigational product(s) should be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s). See also Annex 1 2.10.9 and Annex 1 3.15.3 (a) and Annex 1 3.15.3 (b)	Storage and management arrangements for the investigational products should be specified in the trial protocol. Per regulation 29 of the Clinical Trial Regulations, no person shall conduct a clinical trial otherwise than in accordance with the protocol relating to that trial.
Annex 1 2.13 The investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome and, if applicable, the regulatory authority(ies) with any required reports. See also Annex 1 3.17.2 (a) and Annex 3.17.2 (c).	Per regulation 25(2), within 12 months from the day after the conclusion of the trial, the sponsor must publish a summary of the results in the same public registry that the trial was registered in (unless an exemption or deferral has been agreed with the authorities). The sponsor is expected to provide details of where the results have been published to the authorities. See the guidance on Ending a clinical trial for more detail.
Annex 3.6.6 A sponsor may transfer any or all of the sponsor’s trial-related activities to a service provider in accordance with applicable regulatory requirements; however, the ultimate responsibility for the sponsor’s trialrelated activities, including protection of participants’ rights, safety and well-being and reliability of the trial data, resides with the sponsor.	Per regulation 3(12) of the Clinical Trials Regulations, a sponsor may delegate any or all functions under the regulations to any person, but any such arrangement does not affect the responsibility of the sponsor.
Annex 1 3.6.11 A clinical trial may have one or several sponsors where permitted in accordance with applicable regulatory requirements. In trials with more than one sponsor, the sponsors should have a documented agreement that sets out their respective responsibilities, in accordance with local regulatory requirements and/or practice. See also Glossary – “Sponsor”.	Per regulation 3(2) of the Clinical Trials Regulations, it is acceptable for a clinical trial to have multiple sponsors. The regulatory requirements applicable in these cases are given in regulations 3(2) to 3(10) of the Clinical Trials Regulations.
Annex 1 3.11.2.2 (e) When required by applicable regulatory requirements, the sponsor should provide an audit certificate.	Per regulation 31A(2) of the Clinical Trials Regulations, the sponsor must ensure that the trial master file is readily available at all reasonable times for inspection by the licensing authority. Per regulation 31A(7)(a), the sponsor and the chief investigator must ensure that all documents that have been included in the trial master file are readily available to the licensing authority on request.
Annex 1 3.11.4.5.3 (a) (vi) Monitoring in accordance with the sponsor’s requirements and monitoring plan should generally include […] a statement confirming for the investigational product(s) that the disposition of unused investigational product(s) complies with applicable regulatory requirement(s) and is in accordance with the sponsor requirements.	The protocol (or subsequent open-access protocol) may specify the processes for disposition of unused investigational medicinal product, e.g. permitting longer-term supply until the product is licensed. Per regulation 29 of the Clinical Trial Regulations, no person shall conduct a clinical trial otherwise than in accordance with the protocol relating to that trial. See Supply unlicensed medicinal products for further guidance on manufacturing, importing, distributing or supplying unlicensed medicines for human use in the UK.
Annex 1 3.12.2 Where the sponsor identifies issues that are likely to significantly impact the rights, safety or well-being of the trial participant(s) or the reliability of trial results (i.e., serious noncompliance), the sponsor should notify the regulatory authority and/or IRB/IEC, in accordance with applicable regulatory requirements, and/or investigator, as appropriate.	The regulations applicable to the reporting of serious breaches are given in regulation 29A of the Clinical Trials Regulations.
Annex 1 3.13.2 (a) The sponsor should submit to the regulatory authority(ies) safety updates and periodic reports, including changes to the Investigator’s Brochure, as required by applicable regulatory requirements. See also Annex 1 3.13.2 (d) (regarding line listings).	The applicable regulatory requirements for the timing and content of annual safety reporting are given in regulation 35 of the Clinical Trials Regulations. Please also see the MHRA’s detailed guidance on annual safety reporting
Annex 1 3.13.2 (b) The sponsor should, in accordance with the applicable regulatory requirement(s) and with ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, expedite the reporting to the regulatory authority(ies) of all suspected, unexpected and serious adverse reactions (i.e., SUSARs). See also Appendix A A.1.2.	The applicable regulatory requirements for reporting of SUSARs to the licensing authority are given in regulation 33 of the Clinical Trials Regulations. Please also see the MHRA’s detailed guidance on reporting SUSARs.
Annex 1 3.13.2 (c) Safety reporting to regulatory authorities should be undertaken by assessing the expectedness of the reaction in relation to the applicable product information (e.g., the reference safety information (RSI) contained within the Investigator’s Brochure or alternative documents) in accordance with applicable regulatory requirements. See also Glossary – “SUSAR” and Glossary – “RSI”.	The term “unexpected adverse event” is defined in regulation 2(1) of the Clinical Trials Regulations. See guidance on the reference safety information for an IMP and guidance on assessing expectedness of an adverse reaction
Annex 1 3.14.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial except for claims that arise from malpractice and/or negligence. See also Annex 1 3.14.2.	Per Schedule 1, Part 2 of the Clinical Trials Regulations, provision must be made for insurance or indemnity to cover all liabilities of the investigator and sponsor which may arise in relation to the clinical trial.
Annex 1 3.14.3 The approach to compensating trial participants should comply with applicable regulatory requirement(s).	Per Schedule 2, Parts 4 and 5 of the Clinical Trials Regulations, where the participant is a minor or incapacitated adult, no incentives or financial inducements can be given to the participant or their legal representative, except provision for compensation in the event of injury or loss. Annex D of the Standard Operating Procedures for Research Ethics Committees provides further guidance on how the ethics committee considers insurance, indemnity and compensation arrangements. This document will be updated to align with the amended Clinical Trial Regulations in due course. Please note that reimbursement cost queries can be referred to the ethics committee if not been resolved through initial discussion with the treating investigator or escalation to the sponsor. Failure to resolve claims, or issues associated with the process, may be considered a serious breach.
Annex 1 3.15.3 (a) The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s). Where appropriate, the sponsor may supply the investigational product(s) to the trial participants in accordance with applicable regulatory requirements. See also Annex 1 3.15.3 (c) (i).
Annex 1 3.15.3 (c) (vi) The sponsor should maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications should this become necessary and maintain records of batch sample analyses and characteristics. The samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period. The samples may not need to be kept by the sponsor in trials where an authorised medicinal product is used as an investigational product unmodified from its authorised state in accordance with local regulatory requirements. In this situation, samples are typically kept by the manufacturer	The regulatory requirements relating to retention periods for IMP samples are given in Article 11, Paragraph 4 of 2003/94/EC, which is the legal basis for GMP in the UK.
Annex 1 3.16.3 (c) The sponsor should report to the appropriate authority(ies) any transfer of ownership of the essential records as required by the applicable regulatory requirement(s).	Transfer of ownership of essential records must be documented by the sponsor but does not have to be reported to the UK authorities. If the transfer of ownership is related to a change in sponsor, this must be reported to the authorities as a modification of an important detail
Annex 1 3.17.2 (a) The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of ICH E3 or are otherwise in accordance with applicable regulatory requirements.	Schedule 8 of the Human Medicines Regulations 2012 describes the material that must accompany an application for a UK marketing authorisation. In addition, the UK has adopted ICH E3.
Annex 3.17.2 (c) Once the trial has been unblinded and relevant analyses/conclusions have been completed and finalised, the sponsor should generally, in accordance with applicable regulatory requirements: (ii) Provide the investigator with information about the treatment taken by their participants for blinded trials.	There is no specific regulatory requirement for the sponsor to provide the investigator with information about the treatment taken by participants for blinded trials. However, per Principle 1 of ICH GCP, clinical trials should be designed and conducted in ways that ensure the rights, safety and well-being of participants. This includes the post-trial transition back to standard of care, and to support this, it may be necessary to know which treatment the participant received.
Annex 3.17.2 (c) Once the trial has been unblinded and relevant analyses/conclusions have been completed and finalised, the sponsor should generally, in accordance with applicable regulatory requirements: […] (iii) Provide investigators with the trial results. Where a summary of trial results is provided to participants, this should have language that is non-technical, understandable to a layperson and nonpromotional.	Per regulation 25(2)(b) of the Clinical Trial Regulations, the sponsor must offer to all relevant persons a summary of the results written in a manner that is understandable to laypersons in (unless an exemption or deferral has been agreed with the authorities).
Glossary – “Legally Acceptable Representative” An individual or juridical or other body authorised under applicable law to consent, on behalf of a prospective participant, to the participant’s participation in the clinical trial.	The term “legal representative” in relation to a minor or to an adult unable by virtue of physical or mental incapacity to give informed consent is defined in paragraph 2 of Part 1 of Schedule 1 of the Clinical Trials Regulations.
Glossary – “Signature” A unique mark, symbol or entry executed, adopted or authorised by an individual, in accordance with applicable regulatory requirements and/or practice to show expression of will and allow authentication of the signatory (i.e., establish a high degree of certainty that a record was signed by the claimed signatory).	The MHRA and HRA have released a joint statement on seeking consent using electronic methods that includes guidance on electronic signatures. Further guidance is available in the MHRA’s ‘GXP’ Data Integrity Letter.