The UK’s Post-Brexit Orphan Drug Strategy

Understanding the Medicines and Healthcare Products Regulatory Agency (MHRA) independent approach to orphan drugs in the United Kingdom, and what this means for sponsors developing orphan medicines for rare diseases.

Post-Brexit Framework

As of January 1, 2021, the UK established its own orphan drug process after leaving the European Union (EU). The MHRA now grants orphan designation at the time of marketing authorisation application (MAA), with no separate pre-approval orphan designation step.¹

Sponsors submit an orphan application together with the MAA dossier, and the orphan status is assessed in parallel. This is a significant departure from the EU model (which has a standalone designation process earlier in development) and avoids the complexities and data generation associated with the orphan maintenance report required with an EU MAA.¹

UK Orphan Designation Criteria and Incentives

Although the MHRA’s orphan designation process may be different to that of the European Medicines Agency (EMA), the MHRA’s orphan designation criteria mirror the EUs. A product must address a life-threatening or chronically debilitating condition affecting ≤5 in 10,000 in the UK, or one with insufficient return on investment. Additionally, it must offer a significant benefit over existing methods, if any exist.¹

If approved with orphan status in the UK, the orphan medicine earns:¹

• 10 years of market exclusivity in Great Britain (England, Wales, Scotland),
• Extendable to 12 years if a Paediatric Investigation Plan (PIP) is completed.
• Like the EU, the UK can cut the exclusivity to 6 years if the mid-term review finds the criteria no longer met.
• The scope of exclusivity is defined by the orphan indication: during the exclusivity period, no “similar” product can be approved for the same indication.²

Orphan incentives include:

• Full or partial fee refunds for MA applications,
• Scientific advice fee waivers for UK based SMEs, and
• No fee for the orphan designation application itself.¹

Great Britain versus Northern Ireland

Between 2021 and 2024, the UK had to manage orphan applications differently in Great Britain (GB) versus Northern Ireland (NI).¹

Under the Northern Ireland Protocol (and later the Windsor Framework), EU pharmaceutical regulations (including orphan designations) continued to apply in NI.¹ If a product already held an active EU orphan designation, a UK-wide orphan MA could not be granted; instead, a GB-only orphan MA would be issued.¹ If the MHRA approved an orphan for the whole UK before the EU granted its designation, and later the product got EU orphan status, the MHRA would require converting the UK-wide orphan MA to a GB-only MA.¹

However, from 1 January 2025, under the Windsor Framework adjustments, any MHRA-granted orphan authorisation will be valid UK-wide (including NI) regardless of EU designation status.¹

MHRA’s Orphan Designation Evaluation

The MHRA does not maintain a committee like the EMA’s Committee for Orphan Medicinal Products (COMP). Instead, orphan assessments are carried out internally with possible referral to the Commission on Human Medicines (CHM) on appeal.¹ The MHRA also created a public Orphan Register listing all orphan-approved products, including those converted from EU authorisations and those approved by MHRA post-2021.  As orphan exclusivities expire, products are moved to an expired list.

The MHRA’s new rare therapies framework proposition

In a recent press release, the MHRA published considerations for a ‘forward-looking’ framework for rare diseases in the UK, with consultation on the framework in 2026. This patient-focused framework aims to create more flexible regulatory pathways and evidence generation requirements for orphan medicines. This includes new licensing options and robust post-market surveillance.

Considerations will include:

1. Defining eligibility for a new rare disease pathway.
2. Developing a decision tree to guide entry, bearing in mind global alignment to ensure industry engagement.
3. Addressing the complexity of defining rare diseases in the context of personalised medicine and platform technologies, including scalable evidence requirements based on patient benefit, disease prognosis and population size.

The MHRA accepts evidence to support approvals from several sources and is exploring how real-world data, in-silico trials,  artificial intelligence (AI) and machine learning can be used to support regulatory decision-making. The guidance will aim to clarify how prior knowledge can be used across regulatory submissions, defining platforms and evidentiary standards while balancing proprietary and published data. It proposes a flexible, risk- and stage-based, tiered evidence framework—supported by decision tools and case studies—to determine the level and type of evidence needed throughout the product lifecycle.

The MHRA proposes to develop a registrational model to bridge clinical trials and marketing authorisations, which includes:

• Investigative licensing pathways: preliminary approvals based on appropriate but limited evidence.
• Open methodologies and endpoints: assessing validity of surrogate endpoints, natural history comparators and real-world data to support evidence generation.
• Pre-designation discussion: Medicine developers will attend a mandatory discussion to clarify product components before entering the pathway.

Considerations also include using source files and a system of interrogating existing dossiers to utilise broader use of prior knowledge across quality, non-clinical and clinical data. It also proposes data sharing between developers supported by safeguards for intellectual property, public safety and ongoing regulatory oversight using a flexible, and risk-proportionate approach to support development.

The MHRA proposes a structured regulatory pathway that begins with an early formal designation step involving regulators, partners, and patients to agree on the use of prior knowledge, evidence generation, ethics, and access strategy, ensuring clarity, transparency, and stakeholder alignment. The pathway could use an Investigational Marketing Authorisation, with data submission in modules, iterative checkpoints, and collection of real-world evidence. Regular reviews by the MHRA, could lead to conditional or full marketing approval when appropriate.

The MHRA also addresses manufacturing and supply considerations. It may adapt the Investigational Manufacturing Licence (MIA(IMP)) to fit the needs of this pathway, applying proportionate quality and manufacturing requirements. The MHRA may also accredit centres with the expertise to prepare and administer these treatments, ensuring they manage patient safety risks effectively while expanding access to innovative therapies.

The framework will include a post-market monitoring approach for rare disease therapies that relies on national and international registries, real-world evidence, and proportionate pharmacovigilance to support long-term safety and effectiveness. It also proposes regular, mandated licence reviews and greater alignment of regulatory and HTA data requirements, using flexible, case-by-case approaches to post-marketing surveillance.

Patient and patient representative expertise is also important in defining this new framework. The MHRA proposes to include patient input into regulatory development sessions and licensing discussions, and involve patients in road testing case studies for products in this new framework. It is particularly important to obtain patient and patient representative views on benefit thresholds and risk ratios, and the MHRA has created a Rare Disease Consortium to include patients, patient representatives, academics and industry.

Summary

Following Brexit, the UK established an independent orphan drug framework managed by the MHRA, which assesses orphan designation in parallel with marketing authorisation applications, simplifying the process compared to the EU model. The criteria mirror those of the EU, and the UK similarly offers specific incentives such as up to 12 years of market exclusivity and fee waivers. Regulatory responsibilities differ between Great Britain and Northern Ireland, but from 1 January 2025, MHRA-granted orphan authorisations will apply UK-wide.

Looking ahead, the MHRA is designing a patient-focused framework focused on flexibility, scalable evidence standards, and better use of prior knowledge, real-world data, and platform technologies. The MHRA aims to support innovation while maintaining rigorous standards through a risk-proportionate approach, incorporating flexible pre-approval requirements with robust post-approval monitoring and patient perspectives to ensure the system meets the needs of the rare disease community.

How Somerville Development Partners can help

We have supported the development and approval of numerous orphan drugs across different therapeutic areas and rare diseases. We have an expert understanding of orphan drug development and regulatory science.

We can help you:

• Compile your orphan drug designation application.
• Address challenges and respond to questions often faced by orphan drug developers.
• Demonstrate that your medicine maintains its status as an orphan medicine by submitting an orphan maintenance report.
• Compile your similarity report in preparation for submitting your marketing authorisation application.