The long-awaited Government response to the consultation on reforming clinical trials regulation has been published. The changes represent the biggest shift in clinical trial regulation in 20 years. The MHRA say they will “help to make the UK one of the best countries in the world to conduct clinical research for patients and researchers”.

Broadly speaking, the proposals focus on trying to make the UK an attractive destination for clinical trials, by reforming a regulatory regime which is still based on the 2001 EU Directive to make if faster and easier to gain approval and to run clinical trials in the UK. 

While the MHRA played a key role in shaping the EU’s new Clinical Trials Regulation, the timing of Brexit meant that the new EU regime was never implemented in the UK, leaving the UK with a framework based on law that was generally accepted to be in need of an overhaul.

Changes include implementing a maximum 30 days for completing an application (subject to some exceptions), with 10 days for the regulator to make a decision once it has received all information, and an integration of the regulatory and ethics reviews for applications, which has been shown to significantly reduce the time from application to recruiting patients.

There are a large number of proposed reforms. We have summarised these in the table below and the full response can be read here.

We will need to wait and see the detail of the new law and guidance before understanding exactly what all the reforms mean in practice. If you would like to discuss how the current regulatory regime or future changes might impact you or your business, please contact our Healthcare team.

Consultation proposal

New legislation or guidance?

Further detail 

Requirement for the involvement of people who have relevant experience as a patient, family member or carer, in the design, management, conduct and dissemination of a trial

No new legislation, to be addressed through guidance

MHRA recognise clear benefit of public involvement in trial, but also flag concern that any legal requirement may undermine the key objective of making UK a go-to destination for trials: “detailed guidance will provide the necessary flexibility to make clear our expectations but prevent additional legal burdens on Sponsors”.

Requirement to register a trial

New legislation with accompanying guidance

While may Sponsors will do this anyway as part of best practice, requirement will be to register a trial in a World Health Organization compliant public register, subject to certain exceptions where justified and agreed on a case-by-case basis.

Requirement to publish a summary of results within 12 months of the end of the trial unless a deferral has been agreed

New legislation with accompanying guidance

While may Sponsors will do this anyway as part of best practice, this will become mandatory, subject to certain exceptions where justified and agreed on a case-by-case basis.

Requirement to share trial findings with participants in a suitable format

New legislation with accompanying guidance

Unclear what “suitable format” will mean in practice in terms of level of detail or manner of delivery. Guidance will also need to address data protection issues.

Combined MHRA and ethics review with initial review of application by 30 days post validation of the application, as standard

Introduce a combined regulatory and ethics approval process into legislation, but keep the option for independent submissions available to allow exceptions

Shorter timescales than under the EU regime, with timeline for completion of an application review 30 calendar days, with 10 calendar days for a decision to be granted once the regulator has received responses to any Request for Further Information.

Nominal max 60 days to respond to RFI (Requests for Information)

New legislation with accompanying guidance

Intention to reduce multiple rounds of RFIs and will permit extensions in accordance with guidance to be published.

MHRA and ethics review have 10 days to provide final decision after RFI response received

New legislation with accompanying guidance

MHRA says it has met this timescale in pilots, but will be provisions allowing further time for complex cases.

Extended timeframe for assessment of an application, where independent expert advice is required

New legislation with accompanying guidance

Ability for the regulators to extend the timeframe for review of a trial application, where the risks to the participants may be greater, so that independent expert advice may be sought, noting concerns that this extension should be in line with other international schemes.

Trial approval to lapse if no recruitment occurs within 2 years

Introduce in legislation, but with consideration of exceptions and a clear process for those exemptions

The detail of the exceptions will be important here, especially for those working on trials where participant recruitment is more challenging.

Detail currently outlined in schedule 3 (documents to support application) better placed in the form of guidance rather than legislation

Amend legislation to keep core requirements but move detail to guidance

Core documentation (e.g., the trial protocol, IMP (Investigational Medicinal Product) dossier and investigators brochure) will be specified in legislation but the current granularity in schedule 3 will be removed to allow ‘futureproofing’ and agility to respond to innovation.

Trial sponsor can have sight of RFI per discipline as they are ready

Ensure the legislation does not restrict ability to do so (rather than introduce a specific provision)

This would allow Sponsors to have visibility of RFIs as each discipline (ethics, medical, pharmaceutical or non-clinical) finalises their initial assessment of the application.

Ability to receive an RFI during the review of a substantial amendment

New legislation with accompanying guidance and clear timelines

The legislation will also allow an outright rejection of an unacceptable amendment without an RFI step and the ability for regulators to reject a proposed amendment outright, where it is clear no further information would allow an approval.

Introduction of a notification scheme for low intervention trials

New legislation with accompanying guidance

MHRA say that providing a clear legislative basis for the scheme will increase confidence in the use of the scheme, particularly within the academic community, reduce risk adverse culture among the public sector sponsors, and reduce regulatory burden.

Membership or constitution of Research Ethics Committees (including update/deletion to Schedule 2)

Amend in legislation with accompanying guidance

Level of detail in Schedule 2 is to be removed, with reference to HRA policy and guidance.

Requirements to support diversity

No new legislation, to be addressed through guidance

MHRA say taking this approach through guidance rather than legislation will ensure the flexibility necessary to reflect the many different types of clinical trials and participant populations, and avoid any unnecessary risks or constraints related to unforeseen disease burden, evolving views on how to define diversity and new technologies and trial designs.

Flexibility on consent provisions where the trial is considered to have lower risk

New legislation with accompanying guidance

Guidance will be developed in collaboration with stakeholders, including patients and the public, to ensure that any flexibility introduced into how consent is sought and documented does not compromise the ability of potential participants to provide adequately informed consent to taking part in clinical trials.

Simplified means of seeking agreement from participants for cluster trials using established medicines (existing treatments)

New legislation with accompanying guidance

MHRA say the proposal will comply with all UK data laws, with guidance explaining how simplified consent will work in practice.

Remove the requirement for individual SUSARs to be reported to all investigators

Remove from legislation, publish new guidance

Removing the legislative requirement for individual SUSARs to be reported to all investigators will not prevent sponsors from doing so if they choose to, but MHRA say it will remove a duplicative legislative requirement, because investigators will still receive safety information in other ways. For example, investigators receive updates about the safety profile of the medicine as part of the Investigator Brochure. Sponsors can also send Dear Investigator Letters to the investigators.

Remove the requirement to report SUSARs and annual safety reports to Research Ethics Committees (in addition to MHRA)

Remove from legislation, publish new guidance

The MHRA will continue to receive this information and will continue working closely with RECS to ensure that the appropriate information is shared where necessary.

SUSARs can be reported in an aggregate manner

Enable in legislation as an option, where justified and approved, publish new guidance

Aggregate SUSAR reporting will not be mandatory. The intent is for the legislation to enable the option of reviewing some serious adverse events in aggregate and this will only be acceptable if pre-specified criteria (which will be defined in guidance) are met.

Remove the requirement to include listings of serious adverse events and serious adverse reactions in annual safety reports and instead include an appropriate discussion

Enable in legislation as an option, where an appropriate discussion of the risks is provided instead

Sponsors will still have the option to include the listings in their annual safety reports if they chose to do so. The request to provide a discussion of the risks as well as the proposed mitigation strategies is consistent with the guideline already published jointly by the MHRA and Health Canada as well as expectations in the EU.

Extend the written notification for Urgent Safety Measures from no later than 3 days to no later than 7 days

New legislation with accompanying guidance

This is expected to bring the UK’s reporting requirements in line with the EU. Guidance will set out how to contact the MHRA and whether a phone call is still required.

Incorporate more elements on risk proportionality in legsilation

Introduce an overarching expectation for sponsors to identify and document the risks to patient safety and the reliability of the data and conduct the trial in a risk-proportionate manner

The legislation and guidance will encourage the adoption of risk proportionate approaches by both trial sponsors and regulators, which MHRA say will align with international approaches in this area.

Service providers of electronic systems that may impact on participant safety or reliability of results should also be required to follow the principles of GCP

Make explicit in legislation, with accompanying guidance

Guidance will help electronic vendors, investigators, laboratories and trial sponsors understand regulatory and best practice expectations regarding the complete lifecycle of electronic systems used in clinical trials.

Current GCP principles require updating to incorporate risk proportionality and GCP principles to be included in legislation

Legislation to reference ICH GCP principles, but not full ICH guidance

This will ensure that UK trials continue to be conducted to internationally accepted standards, and the data generated in the UK can be accepted globally.

Regulators permitted to take into account information on serious and ongoing non-compliance that would impact participant safety when considering an application for a new study

Not taken forward. However, non-compliance with new registration and reporting requirements to be grounds for non-acceptance of a request for authorisation

Despite 90% of respondents agreeing with this proposal, MHRA declined to take it forward, highlighting their goal of making the UK an attractive destination for Sponsors.  

Regulatory action to be taken against specific part of a trial where appropriate rather than the trial as a whole

Amend in legislation, with accompanying guidance

Existing powers on the ability of the regulator to amend, suspend or terminate a trial will remain in place. It is the intention of the legislation to enable regulatory action to be taken against both a specific part of a trial and/or the trial as a whole.

Introduce the term ‘non-investigational medicinal product’ into legislation

New legislation with accompanying guidance

NIMPs definition to be moved from guidance to legislation, in line with EU regulation.

Where a medicine is labelled according to its marketing authorisation (and no blinding is required) that specific clinical trial labelling may not be required

New legislation with accompanying guidance

This will introduce a risk-proportionate approach to the labelling of clinical trial medicines, such as removing the requirement for a specific clinical trial label where an authorised product in its marketed packaging can be used.

Radio pharmaceuticals used as diagnostics in a trial to be able to be exempted from the need to hold a Manufacturers Authorisation for IMPs

Introduce in legislation, as outlined in the consultation, with clarity that another valid type of authorisation will be required

Radiopharmaceuticals used as diagnostic IMPs to be exempt from an MIA(IMP). Manufacturers will need to hold a valid manufacturing licence and comply with Good Manufacturing Practice. The exemption will not apply to radiotherapeutics.

Updates to definitions

Amend legislation

The majority of these amendments are to align UK legislation with international regimes.

Expand the professional groups who can be an Investigator

Legislation to enable suitably trained and qualified individuals, and role of Investigator to be clearly defined

Guidance will set out the detail of professional roles that are suitable, so listings can be updated as professional practice changes.

Any appropriately trained and qualified member of the investigator’s team can seek consent

Amend legislation, with accompanying guidance

Guidance will set out the considerations for determining the suitability of the professional roles, qualifications and training under different circumstances, so that risk-proportionate approaches can be taken.

This articles was written by Rory Trust and Adam Reeves.