On 2 November 2025, MHRA published a pivotal position paper outlining a comprehensive overhaul of the regulatory framework for rare disease therapies in the UK.
The initiative forms a cornerstone of the MHRA’s will to leverage genomics, real-world data (RWD), and digital infrastructure to position the UK as a global leader in orphan medicine development. This reform directly impacts marketing authorisation holders (MAHs), biotech sponsors, and regulatory teams preparing orphan designation applications—a core service offered by Pharma Design Limited.
Below is a structured summary of the framework, key changes, timelines, and actionable steps for industry. Special emphasis is placed on the orphan designation process, diverging current EU and UK procedures and addressing whether the new framework signals shifts in the UK’s approach.
Background: Why Now?
The UK currently lags behind the EU and US in orphan drug approvals per capita, despite a strong academic and clinical base. Post-Brexit divergence from EMA’s Orphan Medicinal Product (OMP) Regulation has created both challenges and opportunities. The MHRA’s 2025 paper responds to:
- Stakeholder feedback from the 2024 Rare Diseases Framework consultation.
- ILAP success in accelerating transformative therapies.
- Genomics England and NHS Genomic Medicine Service data maturity.
- Global competition (e.g., FDA’s 40+ orphan approvals in 2024 vs. UK’s 12).
The goal: reduce time-to-patient by 6–12 months for rare disease therapies without compromising evidence standards.
Current EU vs. UK Procedures: Key Differences in Orphan Designation
A core divergence between the EU and UK lies in the timing and integration of orphan designation with the Marketing Authorisation Application (MAA). This affects strategic planning for sponsors pursuing dual EU/UK filings. Below is a highlighted comparison:
| Aspect | EU (EMA/COMP Process) ema.europa.eu +1 | UK (MHRA/CHM Process) gov.uk +2 |
| Timing Relative to MAA | Pre-MAA requirement: Apply for orphan designation before filing the MAA. COMP reviews within 90 days; designation must be granted prior to MAA submission to unlock incentives (e.g., protocol assistance, fee reductions). | Integrated with MAA: No standalone pre-MAA designation. Submit orphan application simultaneously with MAA (via eCTD Module 1.2). CHM evaluates during MAA review; designation is granted as part of the MA decision. |
| Application Process | – Standalone submission via EMA IRIS portal. – Criteria: Prevalence <5/10,000; significant benefit; medical plausibility. – Annual maintenance reports required post-designation. | – Bundled with MAA cover letter and UK Orphan Drug Form. – Similar criteria (prevalence <5/10,000; significant clinical benefit). – No pre-MAA step; appeals to CHM during MAA if criteria unmet. |
| Incentives Unlock | Early access to scientific advice, market exclusivity (10 years +2 for paediatrics), fee waivers—tied to designation grant. | Same incentives (10-year exclusivity from MA grant date; +2 paediatric), but unlocked only upon MA approval. No maintenance reports needed. |
| Pros/Cons for Sponsors | Pros: Early certainty; supports EU-wide trials. Cons: Adds 90+ day delay before MAA; higher upfront evidence burden. | Pros: Streamlined (no separate process); faster overall if MAA aligns. Cons: Risk of MA rejection cascading to lost designation; less early guidance. |
Key Highlight: In the EU, the pre-MAA orphan designation acts as a “gateway” for incentives and trial optimization, allowing sponsors to refine development with EMA input early. In contrast, the UK’s integrated approach embeds designation within the MAA, reducing steps but tying orphan status to full MA success—potentially risking delays if MAA issues arise.
Key Pillars of the Overhaul
The framework proposes enhancements across designation, assessment, and post-approval, with a patient-centered lens via the new Rare Disease Consortium (MHRA, NICE, NHS England, industry, patients).
| Pillar | Current State (2025) | Proposed Change (2026+) | Benefit for Sponsors |
| Orphan Designation Pathway | Integrated with MAA; no pre-MAA option. | New UK Orphan Designation (UK-OD) with pre-MAA application possible; streamlined criteria and fee waivers for SMEs. Automatic ILAP eligibility. | Standalone early status; aligns closer to EU model for dual filings. |
| Accelerated Assessment | Standard 150-day review; ILAP offers rolling review. | 90-day targeted review for UK-OD + ILAP products; conditional MAs expanded. | Earlier revenue; reduced capital burn. |
| Manufacturing Flexibility | Full GMP compliance pre-approval. | Risk-based GMP for Phase III/ATMPs; decentralised manufacturing nodes. | Lower CMC costs; scalable production. |
| Real-World Evidence (RWE) | Limited acceptance in orphan settings. | Formal RWE framework via CPRD, HES, and Genomics England; precedents for single-arm trials. | Smaller, faster trials; post-auth evidence generation. |
| NICE Integration | Sequential HTA post-MHRA. | Parallel MHRA-NICE review under Aligned Pathway Pilot (expanded to orphan drugs). | Simultaneous approval + reimbursement. |
Does the New Framework Signal Changes to the UK’s Orphan Designation Process?
Yes—significantly. The overhaul explicitly signals a shift toward pre-MAA orphan designation, introducing a formal UK-OD pathway that allows applications prior to MAA filing (opening July 1, 2026).
This moves away from the current integrated model, addressing post-Brexit criticisms of lacking early incentives. Key changes:
- Pre-MAA Option: Sponsors can seek UK-OD independently, unlocking early scientific advice and ILAP entry—mirroring EU’s structure but with UK-specific flex (e.g., NHS RWD focus).
- No Full Flip: Existing MAA-integrated applications remain viable as a “fast-track” alternative, but the new pathway offers choice.
- Rationale: Enables earlier trial optimization for small populations; aligns with global standards (e.g., FDA’s pre-IND orphan requests).
This evolution reduces EU/UK divergence, easing dual strategies while preserving UK’s agility.
Timeline for Implementation
| Milestone | Date |
| Stakeholder consultation closes | Q1 2026 |
| Final guidance publication | Q2 2026 |
| First UK-OD applications open | 1 July 2026 |
| Full framework live | 1 January 2027 |
Implications for Orphan Designation Applicants
- Dual Filing Strategy (EU + UK)
- Retain EMA pre-MAA for EU27 access.
- New: Opt for pre-MAA UK-OD to parallel EU, minimizing timeline gaps.
- ILAP as Gateway
- UK-OD will automatically qualify products for ILAP Innovation Passport.
- Early TDP (Target Development Profile) meetings will define RWE acceptability.
- CMC & Manufacturing
- Expect comparability protocols for decentralised sites.
- ATMPs: hospital exemption pathways clarified for early access.
- NICE & Reimbursement
- Highly specialised technologies route expanded.
- Managed access agreements (MAAs) with RWE collection mandatory.
Action Steps for Sponsors (Start Now)
| Action | Deadline |
| Audit pipeline for UK-OD eligibility | Dec 2025 |
| Engage MHRA pre-submission (via ILAP or direct) | Q1 2026 |
| Align EU/UK dossiers (prevalence, significant benefit) | Ongoing |
| Build RWE strategy (CPRD/Genomics England access) | Q2 2026 |
| Prepare for parallel MHRA-NICE submission | Mid-2026 |
Conclusion: A New Era for UK Orphan Drug Development
The MHRA’s rare disease framework overhaul is not incremental—it is transformative. For the first time, the UK will offer a bespoke pre-MAA orphan pathway with regulatory, manufacturing, and reimbursement acceleration in one package. Sponsors who prepare now will gain first-mover advantage in a market projected to see 30% more orphan launches by 2030.
Pharma Design Limited is already supporting clients with UK-OD strategy, ILAP entry applications, and EU-UK dossier harmonisation. Contact us to future-proof your rare disease pipeline.
Reference: MHRA Position Paper, 2 November 2025 – GOV.UK