The UK’s clinical trials framework is set for a major update with the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 coming into full effect on 28 April 2026.
This represents the most significant reform in over two decades, introducing a more agile, risk-proportionate, and sponsor-friendly system.
Among the changes, the introduction of automatic approval for certain substantial modifications stands out as particularly innovative and practical. These are handled via the new Route B pathway — a streamlined process designed to eliminate unnecessary delays for low-risk changes while keeping patient safety at the forefront.
This article zooms in on Route B automatic approvals for substantial modifications, explaining what qualifies, how the process works, and why it’s one of the most welcome features for biotech and pharma sponsors running trials in the UK.
Goodbye “Amendments,” Hello “Modifications”
The new rules replace the old terminology of “substantial amendments” with “substantial modifications.” These are changes that could significantly affect participant safety, scientific validity, trial conduct, or IMP quality/safety.
Substantial modifications now fall into two clear routes:
- Route A — Full MHRA (and ethics, where applicable) review — the default for higher-impact or safety-related changes.
- Route B — Automatic approval by the licensing authority (MHRA) for qualifying low-risk substantial modifications.
If a modification meets the strict Route B criteria (set out in Regulation 11B of the amended regulations), it must follow the Route B process from 28 April 2026 — sponsors cannot choose the slower Route A route.
The Key to Automatic Approval: Route B Eligibility Criteria
A substantial modification qualifies for Route B only if both of the following are satisfied:
- No new significant safety concerns
After reasonable enquiries, the sponsor confirms there are no new major safety issues with the investigational medicinal product(s) (IMPs) since the original trial authorisation (or last relevant update). - The modification fits one (or more) of the three specific conditions defined in the legislation:
Condition A: International harmonisation alignment
The trial is not first-in-human, and the exact same modification (with identical supporting documents, no UK-specific differences) has already been approved by a recognised regulatory authority in the EU, EEA, or USA.
Condition B: Specific protocol-level changes
The modification is restricted to certain protocol updates, including (but not limited to):
- Changes to the primary objective
- Addition of new primary endpoint measurements
- Significant design or statistical changes
- Updates to trial stopping rules
- Changes in safety monitoring visit frequency (only for authorised IMPs, and not prompted by new safety signals)
- Additions/removals from lists of permitted/prohibited concomitant medicines
- Alignment of a global protocol to UK-specific requirements (without altering safety reporting obligations)
Condition C: Investigator’s Brochure (IB) or SmPC updates
The change is limited to updates in the IB or Summary of Product Characteristics (SmPC), such as:
- Addition of new non-clinical (toxicological/pharmacological) data without triggering protocol changes due to safety concerns
- Increased frequency of known adverse reactions (without new expected reactions)
- Other IB updates that do not change the overall risk-benefit profile or introduce new safety signals
- Modifications to the “undesirable effects” section of the SmPC
If a submission includes multiple changes, every single one must independently qualify under Route B for the whole application to use automatic approval.
How Route B Automatic Approval Actually Works
- Sponsors perform a risk-based assessment and document their Route B justification clearly.
- Submit via the Integrated Research Application System (IRAS) (for combined review) or as required.
- Explicitly state in the cover letter that this is a Route B substantial modification.
- For Condition A cases, include proof of the foreign approval(s).
- MHRA validates the submission (typically within ~7 days).
- From validation, the MHRA has 14 calendar days to intervene and pull it into full assessment. If they do not, the modification receives automatic approval from the licensing authority.
- Ethics committee review (if needed) still follows its own timeline (up to 35 days total for combined decisions).
- Sponsors can implement the change once they receive confirmation of automatic approval (or after 14 days with no intervention).
Patient safety safeguards remain strong: the “no new significant safety concerns” threshold is non-negotiable, and MHRA retains the right to step in or audit at any point.
Preparation Opportunity: The Route B Pilot (Closed October 2025 – March 2026)
To smooth the transition, MHRA ran a Route B substantial modification pilot from 1 October 2025 to 31 March 2026. During the pilot, qualifying submissions received rapid feedback (within 14 days) on eligibility — though full automatic approval only applies post-28 April 2026.Even though the pilot has now ended (as of February 2026), the lessons learned are directly transferable: refined justification templates, better risk assessments, and smoother cover-letter wording will give early adopters a real edge when the mandatory regime begins in late April.
Why Route B Is a Game-Changer for Sponsors
- Faster implementation — Eligible changes (protocol tweaks, global alignment, routine IB/SmPC updates) can go live in weeks rather than months.
- Reduced regulatory burden — Frees teams to focus on truly high-risk activities.
- Global programme synergy — Condition A rewards companies running parallel submissions in major markets.
- UK as a preferred trial location — Demonstrates MHRA’s commitment to pragmatic, innovation-friendly regulation post-Brexit.
In an era of complex, adaptive, and multi-country trials, this intelligent risk-based approach helps keep the UK competitive while maintaining world-class safety standards.
Next Steps for Your Team
- Review ongoing trials for potential future Route B-eligible modifications.
- Update SOPs, risk-assessment tools, and submission templates to incorporate the new criteria.
- Train regulatory and clinical operations staff on Regulation 11B and justification requirements.
- For global studies, coordinate submission timing to leverage Condition A wherever possible.
- Check the latest official guidance on the MHRA Clinical Trials Hub.
The Route B automatic approval pathway is one of the clearest signals that the new regulations are built for efficiency without compromising protection. If you’d like help assessing specific trial changes, drafting justifications, or preparing for 28 April 2026 go-live, our team is here to support.