Modifying Clinical Trial Approvals for Medicines in the UK

Overview

This guidance accompanies the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended by the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025. Amendments come into force on 28 April 2026. Until then, this is draft guidance for preparation. Refer to existing guidance for current processes. Published 25 June 2025; last updated 17 February 2026. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Part 2 of Schedule 1 to the Clinical Trials Regulations requires investigators and sponsors to consider all relevant guidance for commencing and conducting trials. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Types of Modification

Per regulation 20, approvals may be modified by sponsor, licensing authority, or ethics committee. Categorized as substantial, important detail, or minor.

Substantial Modifications

• Route A: Likely substantial impact on safety/rights or data reliability/robustness.
• Route B: Defined in regulation 11B and examples. Require approval before implementation (except urgent safety measures). Assess if modification creates new trial; if so, new application needed. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Modifications of an Important Detail

Do not significantly impact safety/rights but authorities need awareness for admin/oversight. Notification instructions from modification tool. Examples: Changes to identification, duration (no treatment extension), contact details, principal investigator at non-NHS/HSC, new locations (no docs), sponsor changes, protocol alignment to new regs, recruitment date. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Minor Modifications

Implement anytime without informing; record and provide if requested. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Determining Modification Type

Sponsor's responsibility: Risk-based assessment. For substantial, determine Route A/B; Route B eligible for auto-approval. Justification documented. Route B based on nature, independent of original authorisation. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Decision tree: https://assets.publishing.service.gov.uk/media/68dbc85949e17d00a56ffc13/Fig1._Modification_types.pdf Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Examples of Modifications

Route B Substantial Modifications

Table: All current Route B. Note: No new safety concerns since approval. Examples include adding/deleting trial arms (no IMP change), changing dosing (no safety impact), new toxicology data (no risk/benefit change), participant number changes (no safety impact), etc. Full table: https://assets.publishing.service.gov.uk/media/68dbc859ef1c2f72bc1e4c33/Tab1._Route_B_substantial_modifications.pdf Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

For quality doc changes: Highlight in cover letter for potential full review. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Modifications of an Important Detail

As listed.

Route A Substantial Modifications and Minor Modifications

Tables for protocol, IB/SmPC, other changes. Examples: Endpoint changes (Route A vs minor), IMP changes (Route A), dosing (Route A), new data (Route A vs minor), etc. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Applying for Approval of a Substantial Modification

Submitting an Application

For combined review trials: Single via IRAS (HRA guidance: https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/step-step-guide-using-iras-combined-ways-working-cwow/#making). Non-combined: Separate to MHRA (MHRA Submissions: https://www.gov.uk/guidance/register-to-make-submissions-to-the-mhra#gaining-access-to-mhra-submissions) and ethics (IRAS portal: https://www.myresearchproject.org.uk/help/hlpamendments.aspx#Online-Submission).

Fees: https://www.gov.uk/government/publications/mhra-fees/current-mhra-fees#clinical-trials-application-fees. Payment: https://www.gov.uk/guidance/make-a-payment-to-mhra. Parallel submissions possible (HRA: https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/clinical-trials-investigational-medicinal-products-ctimps/combined-ways-working-pilot/step-step-guide-using-iras-combined-ways-working-cwow/#amendment). Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Validation of Applications

Validation within 7 days by email/IRAS. Deficiencies notified ASAP (by day 5); resolve by day 7 or invalid. Resubmit corrected. Common invalids: https://www.gov.uk/government/publications/common-issues-identified-during-clinical-trial-applications/common-issues-validation. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Initial Review of Applications by the Authorities

For Route B: Auto-approval. Valid apps reviewed by authorities depending on nature; joint decision within 35 days (Route A), 14 days (Route B). Clock stops for queries (14 days response). Outcomes: Approval, conditional, non-approval. Non-approval response: 14 days. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Automatic Approval of Route B Substantial Modifications by the Licensing Authority

Valid Route B: Auto-approved 14 days post-validation unless MHRA notifies full review (within 7 days). Ethics separate. If full review, 35 days. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Implementation of Substantial Modifications

Implement after approval (joint email/IRAS). Urgent: Implement then notify. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval

Updates

17 February 2026: Clarified auto-approval, implementation. 12 January 2026: Added modification tool. 1 October 2025: Added examples, decision tree. 21 August 2025: Removed feedback. 25 June 2025: First published. Source: https://www.gov.uk/guidance/clinical-trials-for-medicines-modifying-a-clinical-trial-approval