Head of Regulatory Consultancy (Europe) for Precision for Medicine

Chris Ingram, Bsc (Hons)

On Jan. 17, 2022, the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) issued proposals for revision of the current Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, to improve and strengthen clinical trials regulation in the UK.

 The proposals have been developed by the MHRA and Health Research Authority (HRA), in collaboration with an Expert Working Group of stakeholders from across the clinical research sector, including patient representation. Further, the proposals as issued are open for public consultation until March 14, 2022 and consequently the timeline for implementation of these proposals remains unknown at this time.

The underlying rationale for the proposed revisions is to create a “world-class sovereign regulatory environment for clinical trials” with the UK now more than one year on from leaving the European Union following the conclusion of Brexit. Key objectives for the proposed revisions include:

Promote public health and ensure protection of participants remains at the heart of legislation

Remove obstacles to innovation, whilst maintaining robust oversight of the safety of trials

Streamline the regulation of clinical trials and reduce unnecessary burden to those running trials by embedding risk proportionality into the framework

Facilitate the evaluation and development of new or better medicines to reduce the burden of disease on patients and society

Ensure the legislation builds international interoperability so that the UK remains a preferred site to conduct multi-national trials

At present the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, transpose the requirements of the EU Clinical Trials Directive 2001/20/EC into UK law, and consequently worth noting that the EU Clinical Trials Directive will be retired on Jan. 31, 2025 following implementation of the EU Clinical Trials Regulation (Regulation (EU) 536/2014) on Jan. 31, 2022.

The proposed revisions of the current UK regulations for clinical trials focus on the following key areas:

The revised legislation will include a requirement for the involvement of people with relevant lived experience in the design, management, conduct and dissemination of clinical trials, to improve quality and relevance to participants and embed patient engagement in the development pathway for medicine. This is consistent with the current expectations of UK Research Ethics Committees (REC) whereby researchers are expected to involve patients and the public in the design, management, conduct and dissemination of research, however, is not stipulated in the current Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. It is further proposed that clear guidance will be issued in tandem to ensured unified messaging across funders and regulators and consistent review by RECs.

The revised legislation will include a requirement to register a trial in a World Health Organization (WHO) compliant public register prior to its start. Further, it will also include a requirement to publish a summary of results within 12 months of the end of the trial and that clinical trial findings are further shared with participants in a suitable format. Registration of a study in a WHO compliant registry is consistent with current expectations of UK RECs when a positive opinion for a clinical trial is given, however also notable that for any clinical trial application progressed in accordance with the Combined Review process shall automatically be registered in the ISRCTN registry. Publication of trial results within 12 months of the end of trial is also consistent with the process as has been observed under the Clinical Trials Directive. The publication of results in lay language is a new requirement however considered consistent with the revision to the European framework for clinical trials under the newly implemented Clinical Trials Regulation.

Further to the implementation of the Combined Review process on Jan. 1, 2022, the proposed revisions to the legislation will account for this process cognizant that in the current format separate regulatory and ethical approvals are implied. It is however noteworthy that the revised legislation will continue to permit separate applications as an exception.

The requirement for a EudraCT number will no longer apply under the proposed revisions, consequently a UK specific trial reference number will be assigned (IRAS number) automatically at the time of preparation of an application. It is proposed that the maximum timeframe for a study to obtain approval would be 30 calendar days from acknowledgment, with a proposal to allow sponsor organizations up to 60 calendar days to respond to any request for further information, with a final decision being given in 10 calendar days from receipt of responses. Within the current Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, the timeline for approval where there is a request for further information is 60 calendar days with a period of 14 calendar days given to respond to queries. It is therefore notable that the proposals afford Sponsor organization greater flexibility for addressing any review remarks that may be raised. It is also noteworthy that these timelines may be extended by a further 60 calendar days for higher risk investigational products, e.g. advanced therapy medicinal products.

The revised legislation will be further permit sponsor organizations the opportunity to withdraw an application from review, thereby negating the potential for study rejections. In the case of requests for further information it is also noteworthy that it is proposed that questions on individual parts of an application can be issued when ready, consequently quality, non-clinical and clinical questions may filter through at different rates during assessment. Of further note is the proposal to implement a sunset provision on clinical trial approvals, whereby if no participants are enrolled to a given study within a specified time period that the trial approval will lapse unless an extension is sought by the trial sponsor.

With regards to amending a study approval it is proposed that the legislation shall be updated to allow for request for information to be issued to reduce chances of such applications being rejected, based on the current provisions within the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. It is also noteworthy that the UK will continue to permit parallel amendment submissions under the proposed revisions. It is also of note that the UK will continue to maintain the categorization of “substantial amendment” and conversely will not adopt the “substantial modification” terminology being adopted in the EU under the Clinical Trials Regulation.

It is further proposed to introduce a notification scheme for low-intervention trials, whereby only ethical approval would be required to initiate such a study. The proposal defines a low-intervention trial as, “

Trials where the risk is similar to that of standard medical care, e.g. they involve marketed product(s) either used in accordance with the marketing authorization or supported by (nationally accepted) published evidence and/or guidance and /or established medical practice

”, which is broadly consistent with the definition as given by the Organization for Economic Co-operation and Development (OECD) and that given in the EU Clinical Trials Regulation. It is however noteworthy that in the case of marketed products, these must be licensed in the UK.

It is proposed to streamline requirements for the make-up of ethics committee with updates to the minimum number of members and definitions of lay and expert members in line with international standards, retaining the need for a mix of lay and expert members. Further it proposed that Schedule 2 of the current Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, will be deleted, and replaced by guidance and/or Health Research Authority (HRA) policy to allow for greater agility in decision making.

It is also suggested that legislative requirements may be introduced concerning the inclusion of underserved populations and increase diversity in clinical research.

It is proposed to streamline requirements by introducing a simplified/low burden means of seeking consent from participants for low-intervention clinical trials where the investigational medicinal product is pre-determined based on location and are used in accordance with the terms of the marketing authorization i.e. “cluster trials”. Simplifying the approach for consent in these large-scale randomized studies is perceived as supporting heir use and facilitating the gathering of real-world evidence and consequently support wider uptake into such lower risk trials.

It is proposed to remove reporting requirements that add burden to investigators but do not contribute to participant safety whilst maintaining the highest standards of participant safety. Included within the suggestions are removal of the requirement for individual SUSARs to be reported to all investigators, remove the requirement to report SUSARs and annual safety reports to RECs, introduce flexibility in the reporting of SUSARs an allowing for reporting in an aggregate manner, introduce a legal requirement for Sponsors to have a pharmacovigilance system aimed at periodically reviewing accumulated safety data for signal detection, remove the requirement to have listings of serious adverse events and serious adverse reaction in annual safety reports, and to extend the notification period for urgent safety measures from 3 days to 7 days.

Compliance with the broad principles of GCP to protect the right and well-being of trial participants and the reliability of trial results is to be maintained, however UK principles will be clarified within the legislation. The proposal centers on ensuring that UK GCP principles are flexible and applicable to a broad range of clinical trials and will include identification of critical to quality factors, risk proportionality, and will support more efficient approaches to trial design and conduct. Specific changes referenced in the MHRA publication include risk proportionality and regulators taking a proportionate approach throughout the clinical trial life cycle, future proofing GCP principles for electronic systems by introducing clarity over the design and control of such systems that impact on safety and results, trial master files, and clarifications regarding participants not bearing any financial cost to take part in a clinical trial.

It is proposed to expand the current Enforcement and Related provisions given in Part 8 of the current Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, by introducing the ability for the regulators to refuse to approve a new study based on ongoing serious non-compliance with the legislation where there could be significant harm to participants. It is further stipulated that in respect of suspension or termination of a clinical trial by the regulators that proportionate actions shall be taken and therefore a whole trial may not need to stop as is the current case. It is also noteworthy that the proposals indicate further legislation being introduced to address the right to appeal of any decisions taken.

It is noteworthy that the MHRA are stipulating that there is no intent to align with the EU Clinical Trials Regulation in respect of investigational medicinal product labelling requirements nor the adoption of the definition of an auxiliary medicinal product. It is proposed that the legislation will be updated to include the term “non-investigational medicinal product” (NIMP) to extend the concept to non-medicinal products that may currently be unregulated. It is further proposed that risk-proportionate requirements to labelling of investigational products will be applied.

It is also further proposed to make an exemption from the need to hold a Manufacturers Authorization for IMPs (MIA(IMP)) for the preparation of radiopharmaceuticals used as diagnostic IMPs where the process is carried out in hospitals, health centers or clinics, thereby expanding the current exemptions permitted under the current Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. It would however remain a requirement that any radiopharmaceutical used in a clinical trial would still need to be manufactured to an appropriate level of GMP and consequently facilities will still need to hold a manufacturing specials license.

The revisions to the UK legislation are accompanied by a number of proposed changes to definitions to promote international harmonization. Of note in the proposals published are clarifications on the role of sponsors and the ability to co-sponsor trials, that informed consent may be sought by any member of the investigator’s team when qualified by education, training or experience, expanding the professional groups who can be an Investigator, permit data collection after MHRA early access approval without need for Clinical Trial Authorization, and to permit non-interventional long term follow up information to be collected after intervention end without the need for regulatory approval.

The proposed revisions to the UK regulatory framework for the approval and conduct of clinical trials are far ranging and to a certain extent will enshrine current working practices of the UK MHRA and RECs. It is notable that the proposed revisions to the review and approval process may further streamline the time taken to attain approvals to initiate a study. It is however equally notable that there is an emerging divergence from the framework adopted by the European Union with its implementation of the Clinical Trials Regulation.

With the public consultation period scheduled to run until 14th March 2022 it remains to be seen as to which of these proposals will be adopted in the final version of the revised UK regulations when released.

, Bsc (Hons), Head of Regulatory Consultancy (Europe) for

MHRA, Clinical Trials and Investigations, Open Consultation, 

https://www.gov.uk/government/consultations/consultation-on-proposals-for-legislative-changes-for-clinical-trials

MHRA, Consultation on Proposals for Legislative Changes for Clinical Trials, 

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1046680/Clinical_trial_consultation_proposals_final.pdf

MHRA, Annex A - Legal basis and the assessment of the matters set out in section 2 of the Medicines and Medical Devices Act 2021, 

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1046710/Annex_A_-_legal_basis_final.pdf

Articles

New proposals aim to create higher standards for trial regulation.

Evolution of the UK Legislative Framework for Clinical Trials

Following the United Kingdom’s exit from the European Union on Jan. 31, 2020, revisions were applied to the regulations concerning clinical trials, and which have ramifications for sponsors of clinical trials run in the UK. The following article aims to address key aspects around the importation of investigational medicinal products to the UK, sponsors of clinical trials, registration of a clinical trial in a publicly accessible database and requests for authorization of a clinical trial.

Per regulation 3 of The Medicines for Human Use (Clinical Trials) Regulations 2004

as amended by The Medicines for Human Use (Clinical Trials) (Amendment)(EU Exit) Regulations 2019

, a sponsor of a clinical trial is defined as the person who takes responsibility for the initiation, management and financing (or arranging the financing) of that trial. A sponsor of a clinical trial must further be established in the United Kingdom or a country that is included in an approved country list

 or have a legal representative who is so established. Those countries on the current approved list are summarized below. The regulation permits for co-sponsorship of a given clinical trial if two or more persons take responsibility for a given trial.

For sponsor organizations that are not established entities in the UK or in a country listed in Table 1 there shall remain the requirement to appoint a legal representative to serve on their behalf. It is however not implicit that a legal representative need be established in the UK if the nominated individual/entity is established in one of the approved countries.

Requests for clinical trial authorization

On Oct. 21, 2021 the MHRA announced that the pilot Combined Ways of Working (CWoW) review service, in operation since March 2018, will become the new standard approach for seeking clinical trial authorizations in the UK from Jan. 1, 2022. With its announcement the name of the process has been revised to “Combined Review” and will apply to both investigational medicinal products and medical devices.

Through the Combined Review service applicants for clinical trial approval will have a single application route and coordinated review by MHRA, HRA and REC leading to a single opinion for a UK trial. Applications are managed electronically via the Integrated Research Application System (IRAS), for which sponsor organizations should register.

Timelines for review under the combined review service are consistent with those as stipulated in regulations 15, 18, 19 and 20 of The Medicines for Human Use (Clinical Trials) Regulations 2004

 as amended by The Medicines for Human Use (Clinical Trials) (Amendment)(EU Exit) Regulations 2019.

 As such an opinion can be expected in 60 days from the date of valid receipt of an application in the case of general medicinal products or medicinal products with special characteristics, or 90 days in the case of gene therapy, somatic cell therapy (including xenogenic cell therapy) or products containing genetically modified organisms. In the case of medical device investigations the timeline for review will be 60 days from the date of valid receipt of an application. In all cases an initial assessment can be expected within 30 days of a submission being validated with a deadline for responses to any grounds for non-acceptance expected within 14 days (30 days in the case of gene/cell therapy or GMO products).

Although the combined review service will be mandatory from Jan. 1, 2022 it is noteworthy that both MHRA and HRA recommend that any sponsors wishing to seek approval for a clinical trial prior to the formal implementation date should do so through the combined review service.

From the changes implemented to regulation 36 of The Medicines for Human Use (Clinical Trials) Regulations 2004

 by The Medicines for Human Use (Clinical Trials) (Amendment)(EU Exit) Regulations 2019

 it is a requirement of sponsors of clinical trials being conducted that a UK Manufacturing and Import Authorization (MIA(IMP)) holder, with an appropriate qualified person, be employed to implement an assurance system that verifies that investigational product batches are appropriately certified before these are distributed to sites for use in a given clinical trial. Sponsor organizations who are holders of a UK MIA(IMP) may perform the verification process themselves assuming that the MIA(IMP) held appropriately covers the required activities. Alternatively, this responsibility can be outsourced to a third party who is a UK MIA(IMP) holder. In the case of the latter, it will be important to ensure that written agreements describing the assigned responsibilities and provision of relevant information between sponsor and the third party(ies) are in place. This requirement will formally apply from Jan. 1, 2022.

It should, however, be noted that there is no expectation that a UK QP recertifies IMP that has already been batch released in an approved country. For any IMP that is being shipped directly to the UK from a non-approved country for import will require QP certification in the UK by a MIA(IMP) holder. In the case of comparator products that are imported from outside the UK and subject to a marketing authorization granted by a country on the approved country for import list or Northern Ireland, no recertification will be required by a UK QP however there must be evidence to demonstrate that the comparator product has been appropriately QP certified in a country on the approved list. Those countries on the current approved list are summarized below.

The MHRA foresees two routes for IMPs to be imported for use in UK clinical trials when coming from a country on the approved list, namely direct to site or alternatively via a storage and distribution hub in the UK. In both cases the oversight of a UK MIA(IMP) folder and QP is required and must ensure the following:

IMPs are not made available for use at UK clinical trial sites until QP certification in a country on the approved list has been verified

Written evidence should be available to demonstrate that each batch of IMP imported from a listed approved country has been QP certified

The clinical trial is approved by the MHRA before IMP is made available to Investigators

IMPs are shipped only to those UK clinical trial sites that are subject to approval within the UK clinical trial application

Sponsor provides up-to-date information and documentation in relation to the clinical trial and an associated product specification file.

In the case of non-investigational medicinal products importation from a listed approved country should be performed under a wholesale dealer’s license (WDA(H)) and overseen by a Responsible Person (import) (RPi).

 Responsibilities of the RPi include implementing a system to confirm that required QP certification has taken place and/or that the required independent batch release certificate for biological products is available. This approach would also apply in the case of unmodified comparators (marketed products) to be labelled in the UK prior to QP certification and release to a given clinical trial.

In addition to the requirements around MIA(IMP), QP and WDA(H) it should also be noted that for the purposes of importing goods into the United Kingdom the responsible party must be in possession of an Economic Operators Registration and Identification number.

In accordance with paragraph 35 of the World Medical Association Declaration of Helsinki

, every research study involving human subjects must be registered in a publicly accessible database

before recruitment of the first subject. Consequently, registration of a clinical trial is a formal condition of any favorable opinion issued by a UK Research Ethics Committee (REC).

The present expectation of Health Research Authority (HRA)

 is that registration should occur before the first participant is recruited and no later than six weeks after recruitment of the first participant. As such it is important factor in trial registration as part of overall study start up planning for any trial that may be conducted in the UK.

Recognized registries include the International Standard Randomized Controlled Trial Number (ISRCTN), ClinicalTrials.gov, EU Clinical Trials Register, or those cited on the World Health Organization (WHO) list of primary registries or the International Committee of Medical Journal Editors (ICMJE) list of registries.

Of note, should a given clinical trial involve sites in both the UK and EU a record in the EU Clinical Trials Register will satisfy the favorable opinion condition. It is however important to recognize that the EU Clinical Trials Register does not include adult Phase I studies and consequently for these trials an alternative registry must be considered.

HRA have further recently announced a partnership with ISRCTN to automatically register new clinical trials following a favorable REC opinion being issued. Whilst targeted towards improving visibility of UK-based research the automatic registration of trials within the ISRCTN registry will negate any specific actions on the side of study sponsors to ensure registration in accordance with the time limits set. Automatic registration of trials is expected to apply from the point of implementation of the Combined Review process on Jan. 1, 2022.

, Bsc(Hons), Head of Regulatory Consultancy (Europe) for 

The Medicines for Human Use (Clinical Trials) Regulations 2004, Statutory Instrument 2004 No. 1031, 

The Medicines for Human Use (Clinical Trials) Regulations 2004 (legislation.gov.uk)

The Medicines for Human Use (Clinical Trials)(Amendment)(EU Exit) Regulations 2019, Statutory Instrument 2019 No. 744, 

https://www.legislation.gov.uk/uksi/2019/744/contents

MHRA Guidance on list of approved countries for clinical trials and investigational medicinal products, 

https://www.gov.uk/government/publications/importing-investigational-medicinal-products-into-great-britain-from-approved-countries/list-of-approved-countries-for-clinical-trials-and-investigational-medicinal-products

MHRA Guidance on Acting as a Responsible Person (import), 

https://www.gov.uk/guidance/acting-as-a-responsible-person-import

World Medical Association Declaration of Helsinki, 

https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/

HRA Guidance on research registration and research project identifiers, 

https://www.hra.nhs.uk/planning-and-improving-research/research-planning/research-registration-research-project-identifiers/

Investigational medicinal products, trial sponsors, and registration all impacted by UK exit.

Chris Ingram, Bsc (Hons)

Articles

Evolution of the UK Legislative Framework for Clinical Trials

Key Aspects of Brexit in Play