UK MHRA Guidance: Clinical Trials: How to Modify a Clinical Trial Approval

Clinical trials may need to be changed during their lifecycle because of developments in trial design, participant safety, medicines, scientific information, or trial administration. The Medicines and Healthcare products Regulatory Agency (MHRA) has published guidance, Clinical trials for medicines: modifying a clinical trial approval, explaining the different types of modifications that can be made to a clinical trial approval.

The amended Clinical Trials Regulations took full effect on 28 April 2026.

Types of Clinical Trial Modifications

Under the Clinical Trials Regulations, a clinical trial approval can be modified by the sponsor, licensing authority, or ethics committee.

Modifications are divided into three main categories:

• Substantial modifications

• Modifications of an important detail

• Minor modifications

Substantial modifications are further divided into Route A and Route B.

• Route A substantial modifications are changes that are likely to have a significant impact on participant safety or rights, or on the reliability or robustness of the data generated by the trial.

• Route B substantial modifications are defined under the Clinical Trials Regulations and the MHRA guidance.

Modifications of an Important Detail

A modification of an important detail does not significantly affect participant safety or rights, but the authorities need to be informed for administrative or oversight purposes.

Examples include changes to trial identification, certain changes to trial duration, sponsor or legal representative details, changes to investigators other than the chief investigator at a trial location in a multi-centre trial, and adding new trial locations where no additional documents are required.

The date when the first UK participant is recruited to the trial is also notified as a modification of an important detail.

Sponsors must notify the authorities when these changes are made. There are no fees associated with this notification process.

Minor Modifications

Minor modifications can be implemented without informing the licensing authority or ethics committee at the time of implementation.

However, other approvals may still be required, depending on the modification.

Sponsors must keep records of minor modifications and provide those records to the licensing authority or ethics committee if requested.

Examples of minor modifications include certain changes to exploratory or tertiary endpoints, some changes to participant numbers at individual trial locations, changes to record-keeping processes, protocol clarification letters, internal organisational changes, changes in sample storage or transportation arrangements, technical equipment changes, and the addition or deletion of a third country.

Determining the Correct Modification Type

The sponsor is responsible for determining whether a modification is substantial, a modification of an important detail, or minor.

This assessment should follow a risk-based approach.

If the modification is substantial, the sponsor must determine whether it qualifies as Route A or Route B. A Route B modification is eligible for automatic approval by the licensing authority when it meets the applicable criteria.

The justification for classifying a modification as Route B should be clearly documented.

Sponsors can generally include multiple modifications of different categories in a single application. However, certain modifications of an important detail cannot be submitted together with other modifications.

Where an application contains different types of modifications, the submission route should be based on the modification requiring the highest level of regulatory scrutiny.

Examples of Route A Substantial Modifications

Route A substantial modifications can include important changes to the clinical trial.

Examples include significant changes to primary or secondary endpoints, changes to the investigational medicinal product (IMP), changes to IMP dosing, and new toxicological or pharmacological information that affects the risk-benefit assessment.

Other examples include adding a trial arm or placebo group, significant changes in the number of trial participants, significant changes to diagnostic or medical monitoring procedures, changes to participant safety monitoring visits, withdrawal of an independent Data Safety Monitoring Committee, changes to contraceptive requirements, and changes to stopping rules.

Changes involving important safety information in the Investigator’s Brochure (IB), Summary of Product Characteristics (SmPC), or reference safety information (RSI) may also be considered substantial modifications.

A temporary halt or restart of a trial, resubmission of a previously unapproved modification, and certain changes resulting from safety or marketing authorisation developments may also require a Route A substantial modification.

Route B Substantial Modifications

Route B substantial modifications provide a streamlined and risk-proportionate approach for certain types of changes.

For a modification to qualify as Route B, the sponsor must not be aware of any new significant safety concerns with the investigational medicinal products that have arisen since the clinical trial was approved.

If new significant safety concerns are known, the modification cannot be treated as a Route B substantial modification even if it otherwise meets the criteria.

Where a Route B modification involves changes to quality documentation, such as the IMP dossier, Good Manufacturing Practice (GMP) documentation, or labelling documents, this should be clearly identified in the cover letter.

The licensing authority may decide to conduct a full review of a Route B modification.

Applying for Approval of a Substantial Modification

For trials approved through the combined review process, a single application containing the required documentation should be submitted through the Integrated Research Application System (IRAS).

For trials that were not originally approved through combined review, applications must be submitted to both the licensing authority through MHRA Submissions and the ethics committee through the relevant IRAS process.

Fees apply to applications for modification of a clinical trial approval.

Once submitted, applications undergo validation checks to confirm that the required documentation has been provided. The outcome of validation is communicated within 7 calendar days.

If deficiencies are identified, the applicant may be given an opportunity to address them. If the deficiencies are not resolved within the required period, the application will be invalidated and must be resubmitted after the deficiencies are corrected.

Review of Route A Modifications

Valid Route A substantial modification applications are reviewed by the relevant licensing authority or ethics committee, or both, depending on the nature of the modification.

A joint decision is normally issued within 35 calendar days of the validation date.

The authorities may:

• Approve the modification

• Approve the modification subject to conditions

• Not approve the modification and provide the reasons

When approval is subject to conditions, the sponsor must meet the specified conditions before implementing the modification in most cases.

Sponsors should maintain records showing how the conditions have been met.

Automatic Approval of Route B Modifications

Eligible Route B substantial modifications can receive automatic approval from the licensing authority.

Sponsors must identify the modification as Route B in the cover letter and provide the required confirmation form along with the application.

If the application meets the Route B eligibility criteria, confirmation of automatic approval from the licensing authority is issued within 14 calendar days of validation.

However, the modification cannot be implemented until the required combined approval decision has been received.

Where the licensing authority determines that the modification does not meet the Route B criteria, the application will proceed as a Route A substantial modification without requiring the sponsor to resubmit the application.

The licensing authority may also decide to conduct a full review of a Route B application.

Documents Required for a Substantial Modification

The cover letter should contain key trial and submission information, including the trial title, protocol number, relevant identification numbers, and the reason the modification is considered Route A or Route B.

It should also describe the proposed substantial modification, provide justification for the changes, identify minor changes being submitted at the same time, and highlight changes made following a previous submission where applicable.

A table listing all submitted documents, including version numbers and dates, should also be included.

Depending on the modification, additional documents may be required. These can include an updated medicines form, revised protocol, Investigator’s Brochure, IMP dossier, updated data summaries, risk-benefit assessments, and documents showing both marked-up and clean versions of revised documents.

Withdrawing a Modification Application

An applicant can withdraw an application for a substantial modification before a decision is issued or before a request for further information is raised.

For applications submitted through IRAS, the relevant withdrawal process should be followed.

For applications submitted separately to the licensing authority and ethics committee, the applicant should contact the relevant authorities.

The withdrawal request should include a brief explanation of why the application is being withdrawn.

Depending on how much of the review has already been completed, part of the application fee may be refunded.

Requests for Further Information and Appeals

If a substantial modification is not approved, the applicant may have one opportunity to provide further information and request reconsideration.

The requested information must normally be submitted within 60 calendar days from the date of the decision letter. If the deadline is not met, the application will be treated as rejected.

A decision following the response is issued within 10 calendar days. If the modification remains unapproved, a new application is required if the applicant wants to continue seeking approval.

Applicants can also appeal certain decisions. Notice of an intention to appeal must generally be provided within 28 calendar days of receiving the decision.

Modifications Required by the Authorities

The licensing authority or ethics committee may require a sponsor to modify a clinical trial to protect participant safety, maintain scientific validity, or ensure compliance with Good Clinical Practice.

The sponsor will receive notification of the proposed modification and the reason for it at least 7 calendar days before the modification is intended to take effect.

The sponsor can accept the proposal or submit written representations against it within 7 calendar days.

Following consideration of the sponsor's representations, the authority will issue a final decision. Where applicable, the sponsor may also have a right to appeal the decision.

Clinical Trial Modifications Throughout the Trial Lifecycle

The MHRA guidance provides a structured approach for managing changes to clinical trials after approval.

Sponsors are responsible for assessing the type of modification, selecting the appropriate submission route, preparing the required documentation, and ensuring that changes are implemented only when the necessary approvals or notifications have been completed.

The guidance therefore provides an important framework for maintaining participant safety, scientific validity, regulatory compliance, and appropriate oversight throughout the clinical trial lifecycle.

References

• MHRA Guidance: Clinical trials for medicines: modifying a clinical trial approval — published 25 June 2025 and last updated 19 August 2026.