Guidance

Route B substantial modification pilot

Published 18 August 2025

A Route B substantial modification refers to a specific category of changes made to a clinical trial approval under the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025.

Although these modifications are considered “substantial,” they do not introduce significant new safety concerns and are subject to a risk-proportionate review instead of a full assessment. These modifications will be automatically approved unless the licensing authority intervenes within 14 calendar days from the application received effective date to inform the sponsor that a full assessment is being undertaken.

1. Criteria

Section 11B of the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 explicitly states the criteria for a route B substantial modification in full.

According to section 11B, a Route B substantial modification must meet the following criteria:

• the sponsor, having made reasonable enquiries, is confident that there are no significant safety concerns with the modification.

• no new significant safety concerns with any investigational medicinal products involved.

The modification must meet at least one of the following three conditions:

• Condition A: The trial does not involve a first-in-human investigational (FIH) product, and the modification has been approved by a recognised authority (EU, EEA, or USA).
• Condition B: limited to a specific set of changes to the trial protocol (e.g. study design, objectives, measurements).
• Condition C: limited to a specific set of changes to the investigator’s brochure or summary product characteristics (e.g. safety updates, adverse event frequencies).

2. Guidance

The draft guidance supporting the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 is available on The Clinical Trials Hub. The section on modifications to a clinical trial covers the Route B substantial modifications criteria and provides a flow chart for determining the correct modification type.

3. Join the Route B substantial modifications pilot

Ahead of the new regulations coming into force on 28 April 2026 we will open a pilot for Route B substantial modifications. Being part of the pilot will enable applicants to receive a response to their amendment/modification within 14 days while, at the same time, familiarising themselves with the new eligibility criteria.

Note that during the pilot the automatic approval process will not apply, instead we will contact sponsors within 14 days from the application received effective date to confirm approval or to inform them that a full assessment will be undertaken.

• We encourage organisations to take part in the pilot so we can fully test the processes and procedures before full implementation on 28 April 2026. Please be aware that the automated process will not be in place during the pilot and this may impact the speed we can process applications.

• We are committed to the 14-day delivery time so, in the event of oversubscription, we may perform a staged rollout - onboarding sponsors into the pilot in waves.

• We will provide the clinical trials community with updates on how the pilot is progressing.

4. Pilot details

4.1 Dates

• Submissions for the pilot will open on 1 October 2025.
• The planned end date is 31 March 2026.

4.2 Who the pilot is aimed at

The pilot is open to any sponsor who submits an amendment to a clinical trial application that meets the eligibility criteria defined in section 11B of the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025.

4.3 Benefits to sponsors

Participants will:

• receive a response from us within 14 days of the application received effective date.
• be able to provide feedback on the process and help shape the future of clinical trials in the UK.
• gain familiarity with the eligibility criteria listed in section 11B of the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025.

4.4 Trials that are eligible to participate

• Any modification that will be eligible under section 11B of the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 will be eligible to join the pilot.

5. How to register

• Interested sponsors should complete this registration form: Route B Pilot registration form

Sponsors will be contacted to confirm their registration and provided with more details about the pilot.

6. How the MHRA will communicate with sponsors

• We will directly communicate with interested sponsors via the email address they used to register for the pilot.
• An online form will be circulated to registered sponsors to provide feedback on the Route B substantial modification process.

7. How sponsors contact the MHRA about the Route B substantial modification process

• For submission queries and questions, please email CT‑NotificationScheme@mhra.gov.uk
• For general comments, we will provide an online form for registered sponsors to provide their feedback on the process.