UK MHRA Guidance: Modifying Clinical Trial Approvals in the UK

With the 2025 amendments to the Medicines for Human Use (Clinical Trials) Regulations taking effect on 28 April 2026, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has provided comprehensive guidance “Clinical trials for medicines: modifying a clinical trial approval”  for sponsors and investigators which outlines how to manage changes to an approved clinical trial of a medicinal product.

Types of Modification

Modifications to a clinical trial approval fall into three main categories:​

Substantial modification: A change to approved trial which is likely to impact participant safety or rights, or the robustness of the data.

• Route A: Changes with a significant impact on the safety or rights of participants or the reliability/robustness of the data (e.g., changes to endpoints, dosing, protocol amendments).

• Route B: Defined by regulation and listed examples; eligible for automatic approval unless new significant safety concerns are present.

  Both require pre-approval from the licensing authority and ethics committee, except urgent safety issues.

Modifications of an Important Detail

Impact is administrative, not affecting participant safety or trial integrity; must be notified to authorities for record-keeping and oversight.

Minor Modifications

Can be implemented without prior notification or approval, but must be documented and made available during inspections. Other approvals may be necessary depending on the change. Applying for Approval of a Substantial Modification

Submission Process

• Applications for Route A or Route B substantial modifications are submitted via the Integrated Research Application System (IRAS) for combined reviews or via MHRA Submissions and ethics committee portals for others.

• Fees apply and must be paid using MHRA payment guidance.

• Multiple substantial modifications may sometimes be submitted in parallel.​

Validation & Review

• Applications are validated within seven calendar days, with deficiencies communicated by day five to be resolved promptly.

• Valid Route A modifications are jointly reviewed by the licensing authority and/or ethics committee within 35 calendar days.

Possible outcomes

• Approval, approval with conditions, non-approval (with specific grounds).

• Conditions for approval must be met—timing for fulfilling them (before/after implementation) will be specified in the notice.

• Non-approval allows one opportunity for additional information submission, with a 60-day response window. Final non-approval requires a fresh application if changes remain desired.

Automatic Approval for Route B Modifications

• Route B modifications are eligible for automatic approval from the licensing authority within 14 days, provided the eligibility criteria and required documentation are met.

• Where any modification in a group does not qualify as Route B, the whole application is reassigned to Route A processing.

• The licensing authority reserves the right to audit or conduct full review even for Route B applications.

Appeals

Applicants have 28 days from decision receipt to initiate an appeal via the Commission on Human Medicines (CHM), with detailed written/oral submissions allowed within 6 to 12 months.

Public hearings may be requested, and the final decision by the licensing authority follows CHM’s report.

Withdrawing a Modification Application

Applications may be withdrawn anytime before decision or further information request.

Withdrawal instructions differ based on the submission route (IRAS or direct email); partial fee refunds may be possible depending on review stage.

Documentation Requirements

Applications must include:

• Comprehensive cover letter (identifiers, statement of modification type, outline of changes, document list with versions and dates, PO number for invoicing).

• Output of the modification tool (to classify change and identify required approvals).

• Updated documents impacted by the modification—protocols, IB, IMP dossier—with tracked changes and full justification.

• For substantial changes affecting multiple non-combined review trials, a consolidated application is allowed.

For important-detail modifications, sponsors must use the online modification tool (or other MHRA-specified route).

Key requirements:

• Notify before or shortly after implementation depending on nature of change.

• Provide the date of first participant recruitment post-modification (for trial registration tracking).

• Submit the summary of change plus any updated documents (protocol excerpts, PIS, etc).The authorities will review but may not require as full an assessment as for substantial modifications.

For more details, please refer to the guidance provided Clinical trials for medicines: modifying a clinical trial approval on GOV.UK.