The MHRA’s Proposed Rare Disease Therapies Regulatory Framework: A New Era for Rare Disease Innovation in the UK?
The UK Medicines and Healthcare products Regulatory Agency (MHRA) launched a public consultation this spring on its proposed Draft rare disease therapies regulatory framework, signalling one of the most significant potential reforms to the regulation of rare disease medicines in recent years.
For developers working in orphan diseases, advanced therapies, gene therapies and highly personalised medicines, the proposal represents an ambitious attempt to address a longstanding challenge: how can innovative therapies be developed and approved when traditional drug development models are simply not feasible?
With more than 3.5 million people in the UK affected by a rare disease, yet only around 5% of rare diseases having an approved medicinal treatment, there is growing recognition that conventional regulatory approaches designed for common diseases do not always work for very small patient populations.
The draft framework seeks to address this gap through a more flexible, patient-centred, and iterative regulatory model. It is designed for therapies for traditionally described rare conditions with a prevalence of typically 1 in 50,000 or less in the UK.
While the framework is primarily intended for rare diseases, certain elements, together with the accompanying guidance, may also be relevant to conditions with higher prevalence where randomised controlled trials are infeasible or impractical.
Why Change is Needed
Traditional medicine development relies heavily on large clinical trials, validated endpoints and extensive datasets to demonstrate safety and efficacy. While this approach remains appropriate for many therapies, rare disease developers often face significant barriers, including:
- Extremely small patient populations
- Limited natural history data
- Challenges establishing suitable control arms
- Difficulties validating clinical endpoints
- Urgent unmet medical needs
- Increasing development of highly personalised therapies
The MHRA acknowledges that for some ultra-rare diseases, conventional development pathways may be impractical or even impossible. The proposed framework is intended to provide an alternative route where these challenges can be appropriately addressed while maintaining regulatory standards for safety, quality and efficacy.
The Centerpiece: The Investigational Marketing Authorisation (IMA)
Perhaps the most novel aspect of the proposal is the introduction of an Investigational Marketing Authorisation (IMA).
The IMA is envisaged as a hybrid regulatory mechanism that combines elements of a traditional clinical trial authorisation with aspects of a marketing authorisation.
Under the proposal, developers could obtain an authorisation that:
- Permits ongoing clinical investigation
- Allows controlled patient access
- Enables rigorous safety assessment
- Supports iterative regulatory review
- Enables rolling evidence generation
- Facilitates progression towards a full marketing authorisation
Rather than requiring complete data packages before patient access can begin, developers would operate within a continuously monitored lifecycle framework where additional evidence is generated and reviewed over time.
If introduced, this could represent a major departure from the traditional sequential progression of clinical development followed by marketing authorisation.
Earlier Engagement with Regulators
A notable feature of the framework is its emphasis on much earlier and more frequent dialogue between developers and regulators.
The proposed pathway includes:
- Early Engagement Meeting
- Rare Disease Designation
- Additional Scientific Advice
- IMA Application
- Ongoing Clinical Monitoring
- Transition to Post-Authorisation Oversight
- Conversion to a conventional Marketing Authorisation
This approach aims to reduce uncertainty, provide earlier regulatory clarity, and ensure evidence-generation strategies are aligned with regulatory expectations from the outset.
For emerging biotechnology companies and academic developers, this could significantly reduce development risk at an earlier stage.
Greater Acceptance of Innovative Evidence Generation
The draft framework recognises that traditional randomised controlled trials may not always be feasible in rare diseases.
Consequently, the MHRA proposes a more flexible approach to evidence generation, potentially incorporating:
- Real-world evidence (RWE)
- Natural history studies
- External control arms
- Adaptive trial designs
- Basket and umbrella studies
- Bayesian statistical approaches
- Patient-reported outcomes
- Video-based assessments
- Digital health technologies
- In silico modelling and computational evidence
The framework also places substantial emphasis on the concepts of prior knowledge and predictive knowledge. Existing platform data, previous clinical experience, manufacturing knowledge and mechanistic understanding could all contribute towards a proportionate evidence package.
For developers leveraging platform technologies, including gene therapies, mRNA-based medicines and antisense oligonucleotide platforms, this recognition of prior knowledge could prove particularly valuable.
Opportunities for Developers of Personalised Therapies
The framework has also been designed to accommodate emerging treatment paradigms, including highly personalised and potentially individualised medicines.
The MHRA notes that some rare diseases may be caused by unique or “private” genetic mutations affecting only one patient or family. Such cases present significant regulatory challenges under existing systems.
The proposed framework complements the Agency’s broader work on individualised medicines and may provide a pathway for increasingly personalised therapeutic approaches, including:
- Gene editing therapies
- Antisense oligonucleotides
- Individualised genetic medicines
- Advanced therapy medicinal products (ATMPs)
This reflects a growing recognition that future innovation may increasingly target highly specific patient populations rather than broad disease groups.
Patient-Centred Regulation at the Forefront
One of the strongest themes throughout the consultation is patient engagement.
The MHRA proposes that patients, caregivers and patient organisations should play a more active role throughout the development and regulatory process.
Importantly, informed consent is described not as a one-off event but as an ongoing process reflecting the evolving nature of evidence generation and understanding of benefit-risk profiles.
The framework also highlights the importance of transparent communication regarding uncertainty, long-term follow-up and emerging evidence.
This patient-focused approach aligns closely with wider trends in regulatory science, where patient perspectives increasingly inform benefit-risk assessments and development strategies.
Key Considerations and Challenges
While the framework offers significant opportunities, several questions remain.
The consultation acknowledges that some elements, particularly the full implementation of an Investigational Marketing Authorisation, may require legislative change before they can be fully realised.
Developers will also need clarity on:
- Designation criteria
- Evidence thresholds
- Monitoring requirements
- Fee structures
- Interaction with existing orphan incentives
- Reimbursement considerations
- International regulatory acceptance
The success of the framework will ultimately depend on achieving an appropriate balance between flexibility and regulatory rigor.
What Could This Mean for the UK?
The MHRA’s proposal reflects an ambition to position the UK as a global leader in rare disease innovation. The consultation highlights the UK’s strengths, including its academic research base, genomics infrastructure and NHS datasets.
If implemented effectively, the framework could:
- Accelerate patient access to innovative therapies
- Improve the commercial viability of ultra-rare disease programmes
- Encourage investment in rare disease development
- Support academic and non-commercial innovation
- Enhance the UK’s attractiveness as a development and regulatory environment
The proposal is therefore more than a new regulatory pathway. It represents a broader vision for how the UK might support the development of therapies for some of the most underserved patient populations.
Conclusion
The MHRA’s proposed Rare Disease Therapies Regulatory Framework is a bold and innovative attempt to address longstanding barriers in rare disease development. By introducing a more flexible, lifecycle-based regulatory approach centred on early engagement, iterative evidence generation and patient involvement, the framework has the potential to transform how rare disease therapies are developed and licensed in the UK.
Although many details remain subject to consultation and potential legislative change, the direction of travel is clear. Regulators are increasingly recognising that innovative therapies for rare diseases require innovative regulatory approaches.
For developers, investors, patient organisations and healthcare stakeholders, this consultation represents an important opportunity to help shape what could become one of the most progressive rare disease regulatory frameworks globally.
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While the information in this article is considered to be true and correct at the date of publication, changes in guidance and/or experience may impact on the accuracy of the information. Please refer to the relevant guidance for the latest information.