With more than 3.5 million people living with rare diseases in the UK, affecting 1 in 17 patients and carers alike, the MHRA has recently set a clear direction of travel for these conditions. In a new policy paper, the Agency commits to a bold framework designed to make it quicker and easier to test, manufacture, and approve rare therapies in the UK, with a draft “rulebook” due in spring 2026, and a refined, implementable model targeted for late 2026. Rather than what many in the space have seen as the standard “tweaks at the margins”, this new policy provides a true backbone for a faster, more flexible route from science to patient care.

What stands out is the MHRA’s focus on modernising evidence generation for conditions where traditional randomised controlled trials (RCTs) and regulatory evidence-generation requirements are often impractical for rare diseases, where large cohorts, use of disease-specific validated endpoints, and the ability to launch multiple trials are not feasible. While we all know of the challenges faced by those living with these conditions, from long diagnostic journeys to early mortality, what has to date been less prevalent are the landmark steps needed to materially change outcomes.

The new flexibility being proposed by the MHRA recognises what currently sits at only 5% of rare diseases having regulatory-approved therapies. Some of the key ways in which these frameworks may now be evolving are the use of adaptive trial designs reflective of smaller available cohorts, the use of real-world data (RWD) as acceptable comparators, utilising surrogate endpoints, enabling conditional or stepwise approvals, and ensuring mandatory long-term efficacy and safety monitoring over extended follow-up periods. Critically, these models emphasise the need for global-level collaboration that allows for the integration of multiple pools of otherwise scarce rare disease data to derive stronger and more reproducible evidence.

Of note, this paper has highlighted the potential acceptance of RWD and innovative technologies, such as artificial intelligence (AI) and machine learning (ML) models, to support new methods of evidence generation to drive decision-making. Alongside this is the proposed utilisation of real-world NHS and registry data in place of new control arms, accepting interim trial read-outs to unlock earlier access, exploring computer-generated “digital twins” as placebo comparators, and creating combined authorisations that bridge clinical trials, early access and rapid transition to full approval once efficacy is shown. This is critically an advanced patient-first framing that could compress current timelines without compromising on rigorous safety standards.

Equally important is who is at the table. The Rare Disease Consortium – spanning the MHRA, NICE, DHSC, NHS England, leading patient groups, academia and industry – is shaping the pathway, with consultation slated for early 2026. That breadth matters. Indeed, convergence across regulators, HTA, and the NHS is the difference between a promising policy and real uptake for families who have waited too long for noticeable change.

What this means for partners:

Firstly, evidence plans need to move earlier and run longer. With real-world comparators, natural history data and adaptive designs in scope, the quality of UK RWD – its completeness, linkage, and timeliness – becomes even more vital. Sponsors who can pre-specify real-world endpoints, build credible external control cohorts, and show longitudinal outcomes, including pre-initiation baselines, will be best placed to align with and utilise the new pathway.

Secondly, lifecycle-level thinking will be core to successfully navigating these new frameworks. The MHRA’s model points to conditional or stepwise approvals, with robust post-marketing surveillance. In practice, this will mean that planning for registries, patient follow-up, and ongoing safety/effectiveness reviews from day one is critical, ideally with designs that align regulatory and HTA evidence needs to smooth reimbursement and uptake.

Thirdly, and perhaps not news to many colleagues reading this, alignment is the strategy. With NICE and NHS England engaged via the Consortium, the strongest submissions will read across regulatory, HTA, and commissioning expectations. Sponsors should anticipate the dialogue, not react to it, and prepare national-level narratives that translate clinical value into system impact – early engagement with these bodies, as ever, a pivotal part of success.

How Sanius is supporting pathway evolution: 

Already, we are working with teams to operationalise this shift across a number of key domains:   

• External controls and natural history | We assemble UK-grade and protocol-ready external control cohorts and disease trajectories from linked, patient-level data, enabling partners to run smaller interventional arms without sacrificing rigour through pre-specified covariate sets, balance diagnostics and anchor-point calibration. We further establish baseline windows and sensitivity frameworks up-front, so that external controls land submission-ready.


• Interim readiness and rolling evidence | We stand up live evidence streams – pre-initiation baselines, on-treatment outcomes, and long-term follow-up – with full audit trails and versioning that ensure interim analyses are credible and decision-ready when regulators consider early access or combined authorisations. Rolling modules and audit-ready lineage reduce cycle time from interim reads to dossier updates.


• Post-marketing surveillance that doubles as HTA evidence | Sanius operates as a Living Registry++ across multiple data sources that work alongside national registries, enriching them with prospectively captured domains such as ePROs, to strengthen the evidence base. We design proportionate follow-up that minimises burden, maximises signal, and maps to outcomes HTA bodies care about, supporting managed access and sustained uptake.


• Patient voice and transparency | We embed patient-reported outcomes and lived-experience inputs into study and evidence plans, aligning with the MHRA’s emphasis on patient involvement throughout the framework’s development. From initial design and implementation, to continuous feedback that improves delivery and enhances future study delivery, our rare disease communities are core to our process. Ultimately, giving patients clearer visibility of innovation and their own health improves decision-making and helps people stay well at home and in their communities.

What to do next:
If you have a rare therapy in, or approaching, UK development:

1.      Pressure-test your evidence plan against the MHRA pathway | Where can RWD responsibly replace or augment control arms, and where are the interim decision points?

2.      Design surveillance early | Assume conditional steps and plan for proportionate, patient-centred follow-up that can satisfy both regulatory and HTA needs.

3.      Get nationally aligned | Shape a value story that anticipates HTA and NHS commissioning from the start, not after the fact.

Change is here. The UK intends to lead on rare therapies, and to do so with speed, safety, and system alignment. For those of you who want to turn that intent into improved and accelerated access for patients, we are ready to support across the pathway.

Contact us to learn more about our work or to partner with us at info@saniushealth.com.