New Clinical Trials Regulations will bring UK closer to EU regime

Applying for a clinical trial approval

Part 4, Regulations 12 and 14

Under the EU Regulations a sponsor typically only has 12 days to respond to initial RFIs. The overall timeline may be extended if RFIs are raised.

A notification scheme for initial applications will be introduced for low-intervention/ lower-risk clinical trials.

There is a similar scheme currently in place in the guidance for initial applications, however, the new regulations mean that clinical trials that meet the criteria for notification will now receive an automatic authorisation from the licensing authority.

Initial applications for the lowest-risk Phase 3 and 4 trials will be processed by the MHRA within 14 days instead of the statutory 30 days, provided the sponsor can demonstrate that the trial meets the MHRA criteria and that there are no significant safety concerns with the product.  

Part 3, Regulation 9 amends the provisions on the operation and constitution of the ethics committee 

Part 12, Regulation 38 removes Schedule 2 (additional provisions relating to ethics committees)

Restrictive requirements concerning the make-up, proceedings, support staff, premises and facilities relating to ethics committees are removed and replaced with new provisions on how the ethics committee should be constituted.

The Ethics Committees Authority also has an expanded power to establish and abolish ethics committees.

Applying to Modify a clinical trial approval

Introduction of ‘Route B substantial modifications’, which are eligible for automatic approval by MHRA.

Ending a clinical trial

Safety and pharmacovigilance

Sponsors of clinical trials need to identify Suspected Unexpected Serious Adverse Reactions (“SUSARs”). These are serious adverse events suspected to be caused by the medicinal product under investigation.

These must be reported to the MHRA on an individual basis. If they are fatal or life-threatening then the SUSAR must be reported as soon as possible to licensing authority and no later than 7 days after the sponsor first became aware of the reaction.

The requirement for sponsors to directly report SUSARs to investigators and to ethics committees will also be removed. The rationale behind this is to remove duplicative legislative requirements.

Sponsors will also be able to review cumulative data rather than single occurrences and so can assess the causality of serious adverse events. 

Development Safety Reports no longer have to be sent to ethics committees, but they must now include appropriate evaluation of SAEs and SARs (serious adverse events and serious adverse reactions). Current reports submitted to regulators are not transparent enough as they fail to describe how these events and reactions have been evaluated/interpreted.

The content is further updated so that sponsors should ensure that they set out any signals/risks associated with the use of the medicinal product and any mitigation actions that have been taken.

Sponsors must submit the report annually within 60 days from the end of the reporting year.

This aligns with the EU regulations which require sponsors to submit annual safety reports for each medicinal product used in a clinical trial via CTIS. 

Radiopharmaceuticals used for diagnostic purposes in a clinical trial require a specific Manufacturing Authorisation for an Investigational Medicinal Product (“MA IMP”).

Radiopharmaceuticals which are used exclusively at a trial location (in a hospital or health centre), will still require a valid manufacturing licence, but it will not need to be specific to IMPs.

Article 61(5) provides an exemption from the requirement to hold a manufacturer’s authorisation for the preparation of radiopharmaceuticals used as diagnostic investigational medicinal products (IMPs)

This exemption applies to radiopharmaceuticals prepared in hospitals, health centres, or clinics participating in the clinical trial.

Where a medicine is labelled according to its marketing authorisation (“MA”), and certain conditions are met, the legislation will allow for medicines to be used with just their MA labelling, rather than specific clinical trial labelling.

This will reduce duplicative labelling in certain circumstances and the information already on the licensed packaging will still be required in the majority of cases.

Annex VI of the regulation provides detailed requirements for the labelling of IMPs, allowing for some flexibility depending on the trial phase and the risk associated with the IMP.

Essential information such as the trial reference code, the name of the sponsor, and the storage conditions must be included. The regulation allows for reduced labelling requirements for certain low-intervention trials.

Transparency

There will be a legal requirement to register clinical trials in a WHO recognised public register before the recruitment of the first participant or within 90 days (whichever is sooner). This is unless an exemption or deferral is agreed.

The Sponsor will also be required to publish a summary of results on the same public registry within 12 months of the trial ending (unless an exemption or deferral is agreed).

Introduces a requirement to offer a summary of the results to participants in a suitable format within 12 months of the trial end (unless an exemption or deferral is agreed). This must be in a way that is understandable to laypersons.

Sponsors can request to defer these transparency requirements for up to 30 months from the end of the clinical trial, for example to protect commercially confidential information. Phase I trials may receive an automatic deferral from transparency requirements, provided that certain essential information is registered. However, the cumulative deferral period must not exceed 10 years from the conclusion of the clinical trial.

A waiver may also be requested in exceptional circumstances, for example, in matters relating to national defence and security.

There are similar provisions including sharing results on CTIS and that these must be accompanied by a summary written in a manner that is understandable to laypersons.

Miscellaneous

A number of areas of good practice in clinical trials are now identified as better supported through guidance rather than legislative change.

These include new guidance for public involvement ‘which is expected and possible for all clinical trials.’

MHRA will issue guidance on the processes and changes resulting from the new regulations. HRA guidance will address ethics related matters and areas that fall outside the scope of MHRA and will include information regarding combined processes. Both sets will be released simultaneously and continue to be updated on ongoing basis with stakeholders.

MHRA is planning further UK-specific guidance on pharmacovigilance aspects that remain unchanged under the new clinical trial regulations. 

This extends the power of the licensing authority to issue infringement notices to facilitate compliance with the regulations.

Both the UK MHRA and EU national competent authorities have the power to enforce compliance

Both sets of regulations impose penalties for non-compliance, ensuring that sponsors and investigators adhere to regulatory requirements.