s part of the revision to the UK clinical trials legislation coming into force on 28 April 2026, the Medicines and Healthcare products Regulatory Agency (MHRA) undertook a review of requirements and timelines associated with safety management and reporting. As a regulator, we support a pragmatic and risk-proportionate approach, and the revised legislation encourages sponsors to embed risk proportionality within their operations. In today’s context of evolving clinical trials, technology, and innovative products, this revision places emphasis on the sponsor to review safety signals identified during product development and transparently describe to the regulator how these are being managed in the context of their ongoing clinical trials. Efforts have also been made to remove duplication in the reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs). While a risk-proportionate approach is encouraged throughout this regulatory reform, participant safety remains paramount. This article describes these changes, why they have been made, and what stakeholders can do to prepare.

Roles and Responsibilities

Within both the current and future UK clinical trials regulations, the sponsor remains responsible for overall safety of participants in the clinical trial through ongoing review of the benefit-risk profile of the product(s) and trial and complying with all safety requirements in the regulations, including expedited and aggregate reporting of safety events. The investigator retains responsibility for the medical care and decisions made on behalf of their participants. The MHRA has oversight of safety information received in relation to a clinical trial to review the ongoing risk-benefit of the trial.

Robust pharmacovigilance processes are essential for all parties to act promptly, ensure participant safety, and report safety events transparently. Since clinical trial participants face risks without the certainty of benefit, clearly communicating safety information to participants and investigators is crucial for informed consent, and for building trust in research participation. Following the clinical trial, transparently reporting safety information informs decisions on Marketing Authorisation applications or prescribing practice and can deepen scientific knowledge which can inspire further development or research.

Modifications and Pre-market Pharmacovigilance

The revised clinical trial legislation will introduce the term “modifications” to replace “amendments” used to denote an update or change to a clinical trial approval.

There will be two categories of substantial modifications:

• “Route A” is where the MHRA assessment is required because of a likely substantial impact on participant safety or to address new safety concerns, the rights of participants, or the data integrity.
• “Route B” is an automatic approval route without the MHRA assessment, as explained in the MHRA website guidance Clinical trials for medicines: modifying a clinical trial approval.

The categorization of substantial modifications (Route A or Route B) is not applicable to reviews conducted by the Research Ethics Committee (REC). All substantial modifications pertinent to the REC shall undergo the standard review and approval process.

Safety-related modifications which have an impact on the benefit-risk of the Investigational Medicinal Product (IMP) or trial will continue to be assessed to uphold the MHRA’s commitment to ensuring safety of UK clinical trial participants.

Urgent Safety Measures Due Dates Harmonized

The deadline for providing written notification of an Urgent Safety Measure (USM) will be extended from three to seven days. Contacting the MHRA within 24 hours of a USM taking place will still be required, but further time has been granted to allow the written notification to be provided. This is because USMs are reported to the MHRA and REC after they have been implemented, and actions have already been taken to protect the safety of trial participants. The additional time for written notification can be used to gather data that will facilitate the regulatory assessment of the measures. This change also supports international harmonization aligning the timeframe for reporting as stated in the European legislation.

More Flexible and Risk-Based Aggregate Reporting of Serious Adverse Events/Serious Adverse Reactions

The requirement to provide a mandatory list of Serious Adverse Events (SAEs)/Serious Adverse Reactions (SARs) to the MHRA will be removed. Instead, an appropriate and acceptable description (subject to MHRA’s discretion) of how any safety concerns have been assessed and managed will be required in aggregate reports such as the Development Safety Update Reports (DSUR). The sponsor can still include these listings as part of the DSUR, and the MHRA reserves the right to request these listings as required. This will enable flexibility for sponsors who prepare global reports that include individual listings to continue to submit those to the MHRA, while for other sponsors it may reduce the administrative burden.

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 to increase transparency when presenting safety data in the DSUR.

Removal of Duplicative Legislative Requirements for Reporting of Suspected Unexpected Serious Adverse Reactions and DSURs

The revised regulations will remove the mandatory duplicate reporting of the Annual Safety Reports (such as DSURs) and SUSARs to the REC, as these will be managed through information-exchange processes between the MHRA and HRA.

The legislation will also remove the requirement to inform investigators of SUSARs. Investigators will still receive safety information via Investigator Brochure updates and other means, while sponsors can inform investigators in a manner that reflects the urgency of action required and considers the evolving knowledge of the safety profile of the product utilizing alternative approaches such as Dear Investigator Letters.

What Can You Do to Prepare?

Prepare for these changes through appropriate change-control measures within your organization, ensuring that all relevant parties are aware of the changes to the legislation and guidance and the impact of these changes on your processes. Consult with your teams about implementation and opportunities for further updates to systems and processes. Ensure that revisions to processes look to minimize burden on investigators wherever possible so that their focus remains on the care of trial participants and the collection of accurate data.

MHRA Good Clinical Practice (GCP) inspection experience has highlighted critical findings in clinical trial pharmacovigilance, with many root cause(s). A common reason includes a lack of understanding of the differences and requirements for clinical trial pharmacovigilance compared to post-marketing activities. Further information on these findings can be found in GCP inspection metrics reports as well as MHRA Inspectorate blog posts.

Conclusion

Upcoming changes in the UK clinical trials regulation aim to make safety reporting processes more efficient, while keeping participant safety a priority. Sponsors must have strong pharmacovigilance systems for balanced risk assessment and continuous safety monitoring for clinical trials. Sponsors are responsible for detecting safety signals promptly, managing risks, and communicating clearly with the MHRA as required, including correct SUSAR reporting.

While the new clinical trials legislation offers different avenues for risk-proportionate modification, with “Route B” streamlining the approvals process, any safety-related changes that impact the benefit-risk of an IMP will still need review.

Trust, transparency, and robust pharmacovigilance processes are essential to ensure regulatory confidence and most importantly protect trial participants.