Our response to the MHRA rare disease therapies regulatory framework consultation

We have responded to the Medicines and Healthcare products Regulatory Agency's (MHRA) consultation on a proposed regulatory framework for rare disease therapies.

The proposals aim to support the development of treatments for very rare conditions by creating a regulated pathway that enables earlier patient access while continuing to generate evidence on safety and effectiveness.

In our response, we support the principle of bringing more rare disease treatments into a regulated, evidence-generating pathway rather than relying on off-label use. We highlight that a regulated route can provide stronger safeguards for patients through ethical review, safety monitoring, transparency and structured evidence generation.

We also emphasise that public confidence in the framework will depend on maintaining strong participant protections, transparent reporting of evidence, and meaningful public involvement.

Section 1 – Overall aim and patient views

Question 1. In your view, is it desirable for more pharmaceutical treatments for rare diseases to be brought into a regulated pathway rather than used 'off-label' as many are at present?

The HRA supports, in principle, bringing more rare disease treatments into a regulated, evidence-generating pathway rather than relying on off-label use. A regulated route allows treatments to be developed and overseen within a framework of ethical review, structured evidence generation, safety monitoring and transparency. This protects patients better, and builds public confidence more effectively, than ad hoc off-label prescribing, where evidence is rarely captured systematically or shared.

The benefit depends on the research and oversight elements being genuinely rigorous and proportionate, so that earlier access does not come at the cost of participant protection or the quality of the evidence generated.

Question 2. The consultation sets out challenges associated with the development and regulation of treatments for rare diseases. Please identify any other challenges you are aware of that have not been considered or elaborate on those already identified.

Beyond those identified, we would highlight a number of further challenges:

• the pathway needs to integrate with existing research approvals, research ethics review, combined review and the UK Clinical Trials Regulations, so that sponsors experience one consistent process rather than a parallel or duplicative pathway
• 5.5.4 Ethics Considerations references the requirement within the pathway to secure a favourable opinion from a recognised Research Ethics Committee. The HRA is a member of the United Kingdom Ethics Committee Authority (UKECA) under section 116 of the Care Act 2014. UKECA recognises RECs across the UK for the purposes of ethics review under the Clinical Trials Regulations. A favourable opinion from an HRA-appointed REC applies in other nations, as would the same opinion be recognised within England where it is given by a REC in Scotland, Wales or Northern Ireland. Proposals should clarify the suggested involvement of RECs UK wide in discussion with research ethics leads in each country
• it is possible that the nature of evidence generation in rare diseases would alter the ethical profile of activity carried out under an IMA in terms of balancing known risk and benefits, and information which informs the ongoing, active consent for treatment with the IMP. Further consideration is needed on an appropriate, proportionate ethics review pathway within this framework, which can take account in the understanding of the treatment in a timely way, and ensure that an independent assessment of the ethical acceptability of treatment under an IMA remains in place. For example, this could be on the basis of enhanced notifications to the approving REC on effectiveness and safety matters
• support to Recognised RECs in approaching this novel framework and applying existing nationally agreed ethics review considerations to it will be important
• the data-governance and confidentiality considerations that arise where platform data, registries and real-world data are relied upon. These include clarity about whether data collection and use form part of research, care or post-market surveillance; the respective responsibilities of sponsors, healthcare organisations, registry operators and other parties; the lawful and confidential basis for accessing and linking identifiable information; and appropriate expectations for transparency, data minimisation, retention, onward use and international access

Question 3. Patient engagement is a key feature of the framework. How can patients and their families and carers contribute most effectively to the regulatory process?

Patients, families and carers contribute most effectively when they are involved meaningfully and throughout, from the earliest design of each development programme through to the sharing of results, rather than consulted at isolated moments. This reflects the HRA’s belief that research should be done ‘with’ or ‘by’ the public, not only 'to', 'for' or 'about' them.

Involvement should be built into the pathway’s expectations rather than left optional. In the NHS, research ethics committees will not normally give a favourable ethics opinion where participant-facing information has been developed without public involvement appropriate to the study and population. The framework could adopt comparable expectations, drawing on the HRA’s best-practice principles for public involvement and the wider people-centred clinical research principles and hallmarks.

The framework should also address the known gap in commercial-sector involvement. HRA analysis shows public involvement is now reported in around 84% of studies overall and 88% of clinical trials, but only around 69% of commercially sponsored studies. Rare disease development is largely commercial. For rare diseases specifically, established patient organisations, disease registries and family networks are particularly valuable partners; involvement must be resourced, accessible, and able to accommodate paediatric and family perspectives. We would encourage attention to the quality of involvement, not only whether it has taken place.

Section 2 – Elements of the framework

Question 4. A fundamental question is how much evidence is enough for a decision to be made on the use of a medicine? Using novel approaches to evidence generation the pathway aims to strike a balance between the nature and amount of data needed to support the safety and efficacy of a treatment before patients can access it and the time it takes to generate that data. Do you agree that the proposed approach has found the appropriate balance?

Answer: Agree.

The HRA’s comment is confined to the conditions for ethical acceptability and participant protection; the judgement of how much evidence is sufficient to support a marketing authorisation is a matter for the MHRA.

Within that scope, an adaptive approach using lower initial evidence may be ethically acceptable for very small populations where conventional trials are not feasible, provided appropriate safeguards are firmly in place such as robust ethics review proportionate to the degree of uncertainty; informed consent that is clear about residual uncertainty; and research transparency arrangements that ensure findings are publicly available.

Adaptive and novel evidence-generation study designs already come through the Research Ethics Service, so the system has relevant experience to draw on. The defensibility of a “less evidence upfront, more over time” model rests on thorough, ongoing data collection and reporting, supported by clear governance arrangements for who controls the data, who may access it, how long it will be retained and how patients will be informed about its continuing use.

Question 5. Defining rarity is a challenge due to the limitations of using a fixed prevalence (frequency) limit, changing disease classifications and the evolving nature of genetic and molecular disease definitions. Whilst retaining some flexibility, the framework is targeting diseases with a prevalence of around 1 in 50,000 of the UK population, which is deliberately distinct from the orphan designation threshold of 25 in 50,000. Do you consider that this threshold considered appropriate to encourage development of treatments for rare diseases ?

Answer: No response – outside the HRA’s remit.

The appropriateness of the prevalence threshold is a matter for the MHRA and falls outside the HRA’s statutory functions.

Question 6. Do the Scientific Opinion and Designation steps add a tangible incentive for research and development of rare therapies? Are they best delivered at predefined points or on a flexible basis depending on the the individual development?

From a research-system perspective, early and predictable regulatory engagement tends to support better-designed studies and smoother set-up; the principle underlying the combined review service. A balance between predefined engagement points, which give developers certainty, and flexibility to reflect the individual development programme is required; the two should not be mutually exclusive.

Question 7. Do you agree that open registration of all clinical trials which are linked to the pathway and transparent sharing of safety and efficacy data—especially from early-phase studies—will help in any of the following ways?

Answer: Select all four options — to foster public trust, to enhance scientific learning, to support sustainability of the framework, and to support development of treatments.

The HRA has a legal duty to promote research transparency, which means we have a responsibility to champion openness in research. Our vision is that trusted information from health and social care research studies is publicly available for the benefit of all.

We strongly support public registration of all trials linked to the pathway and transparent sharing of safety and efficacy data. Trials under this framework should meet the same transparency requirements as all other UK clinical trials i.e. registration before the first participant is recruited or within 90 days of approval, publication of a results summary within 12 months of completion, and an offer to share results with participants in an accessible format. The framework should align with these requirements rather than create exceptions to them.

On public trust specifically, HRA-commissioned public attitudes research found that around two-thirds of people feel more confident in research when it is registered before it starts and when results are published promptly. On early-phase data, we support transparency from the earliest phases while recognising legitimate commercial-confidentiality concerns; the existing deferral mechanism, requiring a minimal public record up front, with the full record published when the deferral ends, balances openness with respect for commercial confidentiality.

Transparency should also extend to how patient data will be collected, linked and reused across the lifetime of the pathway, including where information is drawn from clinical records, registries or other real-world data sources. A similar balance should be maintained between legitimate commercial confidentiality and the need for patients and the public to understand the purposes for which data are used, the organisations able to access them, and the safeguards governing onward use. Any data-sharing arrangements should remain proportionate, secure and consistent with patient expectations.

Question 8. Proposals for managing market exclusivity have not been addressed in the framework document. How should market exclusivity be managed to balance the potential benefits of incentivising investment with the risk of creating unintended barriers to future innovation?

Answer: No response – outside the HRA’s remit.

Question 9. Should decisions regarding market exclusivity and reimbursement be made on the basis of a combination of pre-determined transparent criteria rather than fixed prematurely within the framework?

Answer: No response – outside the HRA’s remit (reimbursement is a matter for NICE; market exclusivity for the MHRA and policymakers).

Question 10. The scope of the framework includes authorised medicines that are being repurposed (being used to treat a different condition). Do you agree that the framework is suitable for these cases?

Answer: Tend to agree

The suitability of the framework for licensing repurposed medicines is principally a matter for the MHRA. We note only that research to support repurposing is subject to the same research-ethics review and transparency expectations as other studies, and the framework should apply those consistently.

Question 11. Below we have listed six elements of the proposed framework. To what extent do you agree with each of these as an important element?; We are interested to hear of your further thoughts on them.

• an adaptive regulatory pathway for very small populations – Important. Supported in principle; the associated studies must remain ethically reviewable and proportionate for the populations involved
• defined entry criteria (rarity, severity, unmet need, biological plausibility) – Important. Sensible in principle; the criteria intersect with ethical risk/benefit assessment and with inclusion considerations (see the equality comment below)
• early regulatory engagement and designation – Very important. This mirrors the rationale of the HRA and MHRA's combined review; early, co-ordinated engagement supports better study design and faster, high-quality set-up
• use of prior knowledge, platform data and adaptive evidence generation – Very important, provided confidential patient information safeguards are respected where data is used without consent, there is clear accountability for decisions about data access, linkage and reuse, and identifiable information is used only where necessary. Patients should receive meaningful information about how their data will support research, care and post-market surveillance over time. The approaches must also remain deliverable within proportionate ethics review
• ongoing safety monitoring with periodic review – Very important. Effective only if data is genuinely registered, reported and revisited; this depends on the transparency arrangements set out under Question 7
• potential to progress to full marketing authorisation over time – Important. Principally an MHRA licensing matter; any progression should rest on an accumulating, transparently reported evidence base

Question 12. Do you have questions or observations about any aspects of the framework including those we have not specifically asked about?

Under section 111 of the Care Act 2014 the HRA has a duty to promote the co-ordination and standardisation of research regulation and to keep it proportionate. The new pathway will interface with research ethics review, combined review, HRA Approval and the clinical trials regulations, and should be designed to integrate with these rather than sit alongside them. The HRA’s current transformation work, including the new “Plan and manage health and care research” digital service, and joint work with the MHRA on combined review efficiency under the UK Clinical Research Delivery programme, offers a route to that integration. We would welcome working bilaterally with the MHRA on the operational detail, including to clarify how proportionate and consistent assurance should operate for the use of data from registries, linked clinical information and other real-world data, without unnecessary duplication at different stages of the pathway, consistent with our statutory duty to co-operate, and especially ahead of any subsequent legislative consultation.

Section 3 – Impact of the framework

Question 13. In your view, will the flexibility and adaptability of the proposed pathway provide sufficient encouragement to developers of treatments for rare diseases to bring them within a regulated pathway?

Answer: Neither agree nor disagree.

Whether the pathway provides sufficient encouragement to developers is principally a question about developer incentives, on which the HRA does not hold a view. We note only that uptake will also depend on the research-approval and transparency journey being coherent and predictable, and we are committed to supporting that through combined review and our wider transformation work.

Question 14. In your view, will the pathway achieve its aim of supporting innovation while safeguarding patients and maintaining confidence in regulatory decision-making?

Answer: Tend to agree.

We hope that the pathway will support innovation while safeguarding patients and maintaining confidence in regulatory decision-making. The aim will be met provided the framework retains proportionate and robust ethics review, applies research transparency requirements consistently, embeds meaningful public involvement, and integrates with existing research regulation.

Question 15. In your view could this framework reduce barriers to patient access, including time and cost, and in turn help reduce overall treatment costs?

Answer: Neither agree nor disagree.

The HRA can speak to the research-approval element of access timelines, where UK performance is strong – clinical trials of medicines are currently approved well within target. A coherent, well-integrated pathway should help reduce time-related barriers to access. Whether the framework reduces overall treatment costs is a matter of pricing and reimbursement outside the HRA’s remit, on which we offer no view.

Equality impact and satisfaction

Equality impact. Do you think the proposals risk impacting people differently, or could impact adversely on any of the protected characteristics covered by the Public Sector Equality Duty set out in section 149 of the Equality Act 2010 or by section 75 of the Northern Ireland Act 1998?

Answer: Yes