Clinical trials consultation
UK clinical trials regulation is due for a refresh. Following its departure from the EU, the UK has not taken on the changes brought in by the EU Clinical Trials Regulation, leaving its law aligned with the old EU Directive. Taking this opportunity to update in a manner that tracks international norms while making the most of the flexibility offered by Brexit, the UK Government has carried out a consultation process on a set of proposed reforms. Most of these are set to be taken forward through changes to law and guidance following positive feedback. We discuss some of the main changes.
Patient and public involvement
The proposal to introduce a mandatory requirement to involve patients and others with relevant experience in the design, management, conduct and dissemination of a trial proposal received strong support. However, concerns were raised as to the possible administrative and cost burden, and overly prescriptive obligations, as well as introducing a disincentive to carry out research in the UK. The current intention is to address this through detailed guidance, with sufficient flexibility to adapt to different situations. Legislative requirements may be added at a later date.
A clear international trend towards research transparency was reflected in the consultation responses. As a result, proposals to register trials, require publication of summary results and share findings with participants are expected to be taken forward.
- The current “best practice” approach of registration will become a legal requirement to register a trial in a World Health Organization compliant public register, unless a deferral has been agreed with the Research Ethics Committee. Guidance will be available on what registers are acceptable.
- New rules will require publication of a summary of trial results within 12 months of completion, unless a deferral has been agreed
- Proposed changes will require sponsors to share trial findings with participants, or explain why this is not possible. Some flexibility is expected around adapting to different types of trials and international expectations, as well as ensuring compliance with data protection laws.
The approval process
Simplification and streamlining of the approval process is widely recognised as a priority. We can expect to see a number of changes, including the following.
- A combined MHRA and ethics review will be the norm, taking a maximum of 30 days for the initial review, and 10 days for consideration of responses to requests for further information. Sponsors will have 60 days to respond to requests, although will be able to extend this period where necessary.
- An extended time frame for assessment will be possible if the trial may present greater risks, requiring expert advice
- Clinical trial approval will lapse after two years if no participants have been recruited, with provision for extensions where appropriate
- Documentation required to support an application for approval, currently set out in detail in the legislation, will be listed briefly, with the detail moved to guidance that can be updated more easily
Low Intervention Trials – notification scheme
Where a clinical trial does not introduce additional risk beyond that involved in standard medical care, a full regulatory assessment is not necessary to ensure patient safety. This might involve the use of an already marketed product either in accordance with the marketing authorisation, or with established medical practice. Currently a simpler approach is available through guidance, but a risk-averse approach amongst public sector trial sponsors means that take-up is low. To improve confidence, a notification scheme will be set out in legislation, and fleshed out in guidance. A research ethics committee review will be required, and the transparency obligations outlined above will apply. However, notification to the MHRA will replace the full assessment process.
Research Ethics Committee improvements
Research Ethics Committees (RECs) play a vital role in scrutinising clinical research. However, the current legislation sets out in detail how these are to be established and run. Greater agility and flexibility will be possible through removing the detailed rules and relying instead on guidance given by the Health Research Authority.
Improving diversity in clinical trial populations
For clinical trials to work well, they should reflect the wider population. Consultation responses were divided, however, on whether it would be appropriate to address this through legal changes. It can sometimes be difficult to ensure full diversity – for example risks to pregnant women might mean that it is not appropriate to include them in a trial. This issue will be addressed in guidance, aiming to ensure that clinical trial populations appropriately represent the affected groups, and to ensure safety and effectiveness for all patients who will ultimately receive the medicine.
Informed consent in cluster trials
Cluster trials are seen as a useful tool to enable comparisons between already approved medicines for a particular condition. These involve randomisation of patients to a certain treatment based on location – hospital by hospital for example. Proposed changes will enable flexibility around informed consent for these studies, which are seen as lower risk than a clinical trial of a new medicine.
The consultation proposed updates to the pharmacovigilance aspects of clinical trials, aimed at reducing administrative burden while maintaining high standards of participant safety. This included removing the requirements for sponsors to report individual Suspected Unexpected Serious Adverse Reactions (SUSARs) directly to all investigators and to RECs, and optional aggregate reporting of SUSARs. Also proposed were changes to extend the time for written notification of Urgent Safety Measures to seven days. Despite some concerns raised in consultation responses, these proposed changes will be progressed, with additional guidance to ensure that there is no reduction in participant safety.
Good clinical practice
The level of risk associated with different clinical trials varies considerably. Planned changes will aim to reflect this by introducing proportionality to the Good Clinical Practice (GCP) requirements, alongside an overarching expectation for sponsors to identify and document the risks to patient safety and the reliability of data and introduce proportionate controls. While welcoming this approach in principle, many consultation responses emphasised the need for alignment with international standards. Explicit requirements require electronic system providers managing clinical trial data to comply with GCP. Alignment with international principles (ICH GCP), currently being updated, will be required, although not compliance with the entire ICH guidance.
Sanctions and corrective measures
Planned changes to permit the regulator to take account of serious failures in relation to a sponsor’s previous clinical trials when considering a new application will not be progressed, although failure to comply with transparency requirements will be added as a ground for rejecting an application. Changes allowing action to be taken in relation to one part of a multi-arm trial will go forward. This promises to be helpful for advanced therapy medicinal product research, which can involve novel trial designs testing different products at different stages.
Manufacturing and assembly
A new definition of “non-investigational medicinal product” will be included, moving the existing concept from guidance. This is similar to the EU concept of “auxiliary medicinal product”. Some flexibilities around labelling of authorised medicinal products used in clinical trials will be introduced.
Definitions and terminology
Updating and modernisation of a number of definitions is planned. The term “substantial amendment” will become “substantial modification”, aligning with EU terminology. The term “subject” will be changed to “participant”, although this should not affect the terminology that may be used in multi-national trial documentation.
Greater flexibility around which healthcare professionals may act as investigator in a clinical trial will be introduced, with the potential for updating through guidance. Likewise, greater flexibility and proportionality around team members that are able to seek participant consent will be taken forward.
The proposed updates and refinements to clinical trials law and guidance are welcome, given the strong emphasis on streamlining procedures, introducing proportionality and improving international alignment. These changes, together with the current review by Lord James O’Shaughnessy on the UK as a location for clinical trials, demonstrate a commitment to providing a supportive environment for clinical research.
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