Policy paper

Rare therapies and UK regulatory considerations

Published 2 November 2025

Introduction

The UK is well-positioned to become a global leader in developing, regulating, and integrating rare therapies into national healthcare pathways. This position paper outlines the current approach by UK regulators and partners to design a forward-looking framework that meets the needs of patients with rare diseases, while ensuring robust evidence generation, system sustainability, and international convergence. Our programme of work will look at the full lifecycle of rare therapies - from early scientific engagement with developers, to a proportionate and adaptable licensing process, to post-market surveillance. Ongoing dialogue with relevant decision makers will help ensure that any the new framework aligns with Health Technology Assessment (HTA) and National Health Service (NHS) processes, which is important to maximise uptake. Consultation on this framework will begin in early 2026, with the objective of establishing a refined and implementable model by late 2026.

For this programme, rare therapies are defined as medicinal products intended to treat rare diseases – specifically, conditions with a prevalence of no more than 5 in 10,000, where significant barriers exist to conducting standard clinical development programmes or regulatory approvals.

Conventional regulatory pathways are designed for common diseases and assume the availability of large patient populations, validated clinical endpoints, and multiple confirmatory trials. Rare diseases challenge these assumptions because:

• Small, heterogeneous populations make large, randomized trials unfeasible and potentially unethical.
• Limited natural history data means endpoints are often unclear or not validated.
• Urgent unmet needs conflict with lengthy development timelines.
• Advanced modalities, such as gene and cell therapies raise unique manufacturing and long-term safety questions.

The UK has established a strong legacy through its prior participation in the European Medicines Agency (EMA) framework and continues to foster pioneering innovation through domestic initiatives, such as the Innovative Licensing and Access Pathway (ILAP).

The MHRA recognises that a patient-focused regulatory framework is essential to address the unique challenges of rare diseases and to support timely access to innovative therapies.

The Problem Statement

More than 3.5 million people in the UK live with a rare disease – affecting 1 in 17 people, including carers. Only 5% of rare diseases have had medicinal products approved through the regulatory procedures, but there are 10,000 rare diseases that remain without satisfactory treatment options. Many patients face long diagnostic journeys (average 5.6 years), with 30% of affected children dying before the age of five. There are some genetic diseases that are caused by private variants only seen in individuals or their families.  Access to bespoke therapies in these scenarios is challenging in the current regulatory frameworks. The number of patients with actionable mutations suitable for therapies such as oligonucleotides and gene editing is rapidly increasing, highlighting the need for an appropriate regulatory pathway.

Current regulatory pathways assume large populations, standard endpoints, and multiple trials. Rare disease therapies, however, need flexibility, adaptable trial designs, real-world evidence, and expedited review – needs that existing frameworks do not adequately support.

The MHRA acknowledges this shifting paradigm and the great opportunity to help patients with rare genetic diseases. In response, the MHRA is committed to broadening a product-based principle to a more flexible licensing approach in this area – where, for example, a single marketing authorisation could be granted for a therapy even where there is a variable component tailored to an individual’s characteristics. This change aims to establish a novel pathway for individualised medicines at scale, enabling rather than impeding access to potentially life-saving technologies.

To address these challenges, regulatory systems are evolving to allow greater flexibility in evidence generation while maintaining strict safety oversight:

• Adaptive trial designs (e.g., Bayesian, N-of-1, platform trials) maximize the value of small patient samples without lowering scientific rigor.
• Natural history and real-world data provide acceptable comparators when randomised controlled trials (RCTs) are not feasible.
• Surrogate endpoints can accelerate approval but require regulatory qualification and post-marketing confirmatory studies.
• Conditional and stepwise approvals allow earlier access while obliging sponsors to collect long-term safety and efficacy data.
• Mandatory long-term follow-up ensure ongoing efficacy and enhanced safety monitoring continuously after approval, especially for advanced therapies.
• International collaborations can act to pool scarce data across jurisdictions to strengthen evidence quality.

Our scope is comprehensive, spanning:

• Risk appropriate evidence generation for non-clinical and clinical studies, quality, and GxP compliance.
• Licensing and regulatory assessment, including ongoing patient access.
• Enhanced post-market data collection and surveillance.

Development of this new pathway is driven by the principle of enabling a risk-benefit assessment to be appropriate for the target disease and target patient population.

Defining Scope and Criteria for Rare Disease Regulatory Pathway

Defining the scope and entry criteria for a new regulatory pathway for rare diseases is essential to facilitate development. Considerations include whether to use fixed patient number thresholds, commercial viability, or other flexible criteria, and alignment with international standards. Our starting point is rare conditions with a prevalence of less than or equal to 5 in 10,000, where quantifiable barriers exist to conducting standard clinical development programmes or gaining regulatory approvals. This is a starting point for consultation, not an exclusion criterion, and the underpinning principle is to drive new therapies for patients.

Developing pragmatic entry criteria and decision tools will be important to enable therapies to utilise the new pathway. This includes the use of decision trees, identification of challenges, and the need for flexibility to accommodate both individualised and small population therapies.

This approach will guide the regulator, aiming to simplify evidence requirements and facilitate discussion with HTA assessment methodologies or NHS commissioning and reimbursement frameworks to facilitate ultimate patient access.

The UK’s ambition is to enable prompt access to these therapies, while safeguarding patient safety, evidence credibility, and affordability.

 Key considerations which are being developed to enable a new pathway for rare disease therapies include:

• Defining eligibility for a new rare disease pathway, focusing on prevalence thresholds and recognising the challenges posed by conditions that transition from rare to more common. Separate definitions may be required to aid any designation conversations and a degree of flexibility may be required to ensure the framework can accommodate future changes to functional delineations and definitions within traditional disease groups.
• Development of a clear decision tree to guide entry, with attention to global alignment to ensure industry engagement.
• Addressing the complexity of defining rare diseases in the context of personalized medicine and platform technologies, with scalable evidence requirements based on patient benefit, disease prognosis and population size.

Prior Knowledge

The UK currently accepts evidence to support licence applications from a diverse range of sources. The MHRA is actively exploring how real-world data and innovative methodologies, such as in-silico trials and artificial intelligence (AI) and machine learning (ML) models, can be used to generate evidence for regulatory decision-making.

Through this work the aim is to focus on how evidence from related products or technologies can be leveraged to meet the evidence requirement for new treatments. The MHRA is considering how clinical evidence requirements can be applied across different circumstances, and how both safety and efficacy can be determined.

Innovation in rare disease therapy requires proposals to develop regulatory guidance for the use of prior knowledge, source files, and demonstrating on case-based scenarios. This guidance will cover:

• Defining What Prior Knowledge: Establish what constitutes prior knowledge across quality, clinical, non-clinical and statistical aspects. This includes balancing internal (proprietary) and external (published) knowledge and proposing a framework to guide how different data sources can be weighed in evidence generation to support regulatory submissions.
• Addressing Platform Definition Challenges:  Platforms may be used in three main contexts: disease area, non-clinical, and manufacturing. Guidance is needed on interpreting these definitions, with built-in flexibility to adapt as new evidence emerges. Clarity on terminology and expectations is essential.
• Risk-Based and Stage-Appropriate Application: Acceptance of prior knowledge and platform approaches should be based on a balance of benefits and risks, considering disease severity, patient population size, and stage of product development. A sliding scale or decision tree could help operationalise this.
• Tiered Approach: A tiered framework is envisioned, based on the type of rare disease according to the difficulty or challenges in generating sufficient data to support a study. This could include fixed, variable elements and cases where new and or bridging data may be required at appropriate stages of the product lifecycle.
• Guidance on referencing of prior knowledge sources: MHRA guidance should support the inclusion of prior knowledge in regulatory dossiers, define platform technologies, appropriate use of master files, and provide direction on how such data should be weighed in evidence generation to support regulatory decisions. Practical case studies will be included to illustrate these concepts.

Novel Registration and Licence Structure

The MHRA is developing a flexible, proportionate licensing and registration model tailored to the unique challenges of rare diseases. Product development could be aided with a regulatory process which bridges clinical trials and marketing authorisations, including:

• Investigative Licensing Pathways: Preliminary approvals may be granted based on appropriate, albeit limited, evidence such as mechanism hypothesis, with iterative reassessment throughout the process.
• Open Methodologies and Endpoint discussion: Assessing the validity and appropriateness of surrogate endpoints, natural history comparators, and real-world data to support evidence generation when conventional approaches are unfeasible.
• Pre-designation discussion: Before entering this pathway, developers will be required to participate in a mandatory discussion to clarify product components and requirements. This will detail the evidence requirements, planned application, and ongoing lifecycle management from the outset. Subsequent reviews may be needed to ensure continued appropriateness.

This new licensing structure permits speed and flexibility in the approval process, while ensuring rigorous regulatory requirements and obligations throughout. This includes necessary legislation, applicable standards both for clinical conduct and generation of data, regulatory powers and capabilities along with post-approval obligations.

The MHRA is exploring the use of source files for internal use, sharing, and licensing, while identifying commercial and regulatory challenges and potential solutions to increase accessibility. Allowing a system of interrogating existing dossiers and source files will enable broader use of prior knowledge across quality, non-clinical, and clinical data and will subsequently reduce regulatory burden. In addition to enabling the use of  prior knowledge through source files, collaborative evidence sharing could further support innovation. Data sharing between developers is recognised as potentially beneficial to enable product development. This would require safeguards for intellectual property protection and public safety, and ongoing regulatory oversight similar to clinical trials. A flexible, scalable, and risk-proportionate approach is proposed, including process-level approvals to enable development of therapies, such as platform-based technologies and individualised medicines.

To support this, a structured pathway should be outlined, beginning with a formal designation step. This step would involve early multi-agency and system partners to agree on use of prior knowledge, trial design for evidence generation, ethical considerations and access strategy. This would help define eligibility, clarify expectations, and align stakeholders on the requirements for progression through this pathway. Patient engagement and transparency in decision-making would be essential to build trust across the system.

Defining the boundaries of any platform or use of prior knowledge is essential. Considerations will be given on how to manage changes with appropriate controls, should newly generated knowledge subsequently necessitate a change (e.g., either a reduction or an increase) of the demonstrated scope.

The pathway could use an Investigational Marketing Authorisation, with modular data packages, iterative checkpoints, and real-world evidence collection. Regular reviews would be conducted, which could, if appropriate lead to conditional or full marketing authorization.

As part of this pathway, manufacturing and supply considerations will also be addressed. Clarity options for industry regarding supply of therapies need to be considered, potentially with a derivative of the MHRA Investigational Manufacturing Licence (MIA(IMP)), with proportional requirements for manufacturing and quality. Accreditation may be applied to centres with expertise in preparation and administration of these therapies, ensuring effective management of patient safety risk along with access to novel treatments.

Post-Market Surveillance

The safety and long-term effectiveness of rare disease therapies will be supported by appropriate post-market monitoring, including:

• National Rare Disease Registries: Real-time data collection capturing longitudinal patient outcomes.
• Risk Management Plans: Reclassification of safety concerns as new evidence emerges and potentially structured/bespoke studies to clarify and further define risks.
• International Data Sharing: Development of global rare disease registries and international initiatives to supplement potentially small UK cohort sizes and provide a broader overview of patients and outcomes. This could include sharing of reporting requirements and follow-up information.

Further considerations include evolving approaches to data generation, registry use, and proportional pharmacovigilance for rare products overlaying the ongoing clinical monitoring which would be required. Key priorities are ensuring registries are fit for purpose, achieving international harmonisation, and balancing the data collection burden with the needs of patients and the healthcare system. Real-world evidence, patient follow-up, and leveraging existing healthcare systems for long-term monitoring are also identified as priorities.

As part of the ongoing management, regular mandated reviews of licence parameters and patient monitoring are being considered, similar to current practices for conditional marketing authorisations. These reviews could be triggered by either elapsed time or patient numbers.

A longer-term objective is to align, where possible, post-marketing data collection requirements for regulatory and HTA purposes (e.g., through managed access agreements), biomarker-based approvals, and the need for flexible, case-by-case approaches to post-marketing surveillance.

Patient and Patient Representative Involvement and Engagement

The MHRA is embedding patient expertise and experience at the heart of this programme, engaging with patient groups representing a wide range of rare diseases.

• Patient input will be incorporated into regulatory development sessions and licensing deliberations.
• Transparent communication will be maintained regarding uncertainties, investigational approvals, and ongoing monitoring.

The MHRA’s goal is to establish trust and transparency, with patients actively involved in the development of new regulatory principles.

It is crucial that the perspectives and experiences of rare disease patients and their representatives are integrated into all workstreams, supporting the drafting and review of guidance. Case studies for products within this new framework need to be ‘road-tested’ with meaningful patient involvement.  Patients and patient representatives bring a vast range of knowledge and expertise, including the practical, and real-life experience of working with companies, from clinical trial design to the day-to-day realities of engaging with the regulatory and HTA processes.  

The views of patients and patient representatives on benefit thresholds and risk ratios must be considered, particularly when a smaller burden of evidence or alternative forms of evidence are available and appropriate.  Guidance must be developed to better meets the needs of the rare disease community by making the regulatory process clearer, simpler, more transparent, flexible, with measurable indicators of success.  

Plans for the remainder of 2025 include ongoing input from patient representatives across all workstreams, contributions to key outputs, and a second in-person workshop.

Supporting the development of the reforms is a newly formed Rare Disease Consortium, which includes patients and their representatives, academics and industry. A comprehensive involvement project plan will also be developed to guide the Rare Disease Consortium’s efforts into 2026.

International Convergence

The UK recognises that no single country can address the challenges of rare therapies alone.  The MHRA is actively working to align appropriate regulatory pathways with our global peers to:

• Ensure similar approaches can be used for both academia and industry.
• Support scientific development in collaboration with academia, NHS providers and industry to accelerate development.

This work stream will be a focus during 2026 as the appropriate pathways are developed as part of this activity.

UK Health System Alignment

The MHRA is working with its system partners to build on the UK Government’s 10 Year Health Plan for cross-system collaboration, focusing on:

• Active involvement with devolved administrations to ensure consistent access to the framework for patients across the UK.
• Early alignment between MHRA, healthcare partners, to ensure regulatory and HTA processes run in parallel.
• Coordination with health care system organisations to support delivery of the England Rare Diseases Action Plan.

Planned Timeline

A draft of the framework is anticipated to be available by Spring 2026, followed by external review in the first half of 2026. Potential legislative or further development steps may also occur during this period. A public consultation will be conducted in 2026 to ensure all views are considered, maintaining patient interests and safety whilst supporting innovation of critical therapies.

Summary

The UK is advancing a comprehensive framework to ensure rare disease therapies are developed, licensed, and delivered in a way that balances patient needs, regulatory robustness, and system sustainability. Through international collaboration, strong patient engagement, and close alignment with the NHS, this initiative will position the UK as a leader in rare therapy regulation and patient access.

In developing this new pathway, the MHRA will ensure that safety standards are not weakened; instead, the balance of evidence generation will be adjusted. By combining flexible pre-approval requirements with robust post-approval monitoring, the UK can provide patients with rare diseases faster access to therapies without compromising safety or scientific integrity.

Acknowledgements

This work is the result of collaboration between the MHRA and many partners. Particular thanks are extended to all contributors.