On October 15, 2025, the Medicines and Healthcare products Regulatory Agency (MHRA) released draft guidance on non-standard Clinical Trials of Investigational Medicinal Products (CTIMPs), marking a pivotal step in modernizing the UK’s clinical research framework.
Open for consultation until December 15, 2025, the guidance clarifies submission requirements for innovative trial designs—such as basket, umbrella, and platform trials – and integrates real-world data (RWD) to support adaptive protocols. Building on the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 and the Route B Notification Pilot (launched October 1), this initiative responds to stakeholder demands for flexibility in designing trials for complex therapies like advanced therapy medicinal products (ATMPs) and precision medicines. It aims to position the UK as a global leader in innovative trial methodologies while ensuring participant safety and data integrity.
Background and Objectives
Non-standard trial designs deviate from traditional randomized controlled trials, enabling adaptive or multi-arm studies that accelerate evidence generation for unmet needs (e.g., rare diseases, oncology). The MHRA’s guidance, developed with the Health Research Authority (HRA), addresses gaps in the 2004 regulations exposed by COVID-era platform trials (e.g., RECOVERY). Objectives include streamlining submissions for adaptive protocols, clarifying RWD use (e.g., electronic health records via CPRD), and aligning with global standards like ICH E6(R3). The draft supports the broader 2025 reforms, including Route B’s 14-day approvals for low-risk modifications, to boost UK trial starts by an estimated 20–30% (per HRA projections).
Key Features of the Guidance
- Supported Designs: Covers basket trials (single drug, multiple indications), umbrella trials (multiple drugs, single disease), and platform trials (ongoing arms with shared controls). Also includes adaptive designs with pre-specified decision rules (e.g., dropping ineffective arms).
- Submission Requirements: Sponsors must provide clear protocols via the Integrated Research Application System (IRAS), including statistical justifications, RWD integration plans, and risk mitigation strategies. Combined MHRA/REC review ensures ethical alignment within 60 days (30 for low-risk).
- RWD Integration: Guidance endorses RWD (e.g., NHS data) for secondary endpoints or long-term follow-up, with emphasis on data integrity (aligned with ICH E8). Sponsors must validate sources per MHRA’s 2024 RWD framework.
- Consultation Process: Feedback via MHRA’s online survey shapes final guidance by Q2 2026. Key questions address adaptive protocol clarity and RWD governance.
Implications for Sponsors
The guidance empowers sponsors to design agile trials, reducing timelines by 6–12 months for complex therapies (e.g., ATMPs). It complements Route B’s streamlined modifications, enabling mid-trial tweaks without delays. However, robust statistical plans and RWD validation demand upfront investment – Sponsors should audit protocols now to meet IRAS standards. Non-compliance risks rejection, especially for multinational trials needing EU/FDA harmonization. The UK’s flexibility enhances its appeal as a trial hub, particularly for SMEs leveraging ILAP’s Innovation Passport.
Next Steps
Sponsors should review protocols against the draft guidance, engage in the consultation (submit by Dec 15), and attend HRA’s November 2025 webinars for IRAS training. Cross-reference with EMA’s complex trial guidelines for EU-UK alignment. For full details, visit MHRA’s Clinical Trials Hub.
Also reference our full article on MHRA’s new Guidance on route B trial notification here https://pharmadesign.firecask.dev/articles/1287/