The National Institute for Health and Care Excellence (NICE) has recently updated the routing criteria for itsHighly Specialised Technologies (HST) appraisal process. These amendments, approved on 19 March 2025, will be implemented from 1 April 2025, with the goal of enhancing consistency, predictability, and transparency in the evaluation of ultra-rare disease treatments.
The HST programme plays a crucial role in assessing the clinical and economic viability of interventions targeting ultra-rare, debilitating conditions. These diseases often pose significant challenges in evidence generation due to limited patient populations, making traditional randomised controlled trials (RCTs) difficult to conduct. By facilitating access to novel therapies, the HST programme aims to bridge this gap while ensuring equity in the allocation of NHS resources.
Ultra-rare conditions are stringently defined by a prevalence threshold of ≤1 in 50,000 individuals in England. Given the scarcity of affected patients, the programme prioritises treatments with high disease-modifying potential, particularly those that can alter disease trajectory or substantially improve survival and quality of life. Over the past five years, NICE has endorsed 19 new treatments for ultra-rare diseases.
Professor Jonathan Benger, Chief Medical Officer at NICE, stated: “Our aim throughout this initiative was not to change the number of medicines routed through the HST programme, but to clearly define the circumstances when it is appropriate to do so and improve the efficiency of the routing process.”
To qualify for HST appraisal, a therapy must satisfy all four core criteria, which are now more stringently defined:
- Ultra-Rarity and Disease Burden: The condition must have a point prevalence of ≤1 in 50,000 individuals in England (approximately 1,100 patients nationwide). Additionally, it must be a chronic, life-threatening or severely debilitating disorder with a significant burden on patients and caregivers.
- Restricted Patient Population: The therapy must be indicated for no more than 300 individuals in England within its licensed indication. Furthermore, across all potential indications, the total eligible population must not exceed 500 patients. Importantly, this excludes therapies targeting small subgroups within broader disease populations.
- Clinical Need and Absence of Viable Alternatives: The intervention must address an area of high unmet clinical need, offering substantial improvements over existing treatments or addressing conditions where no effective therapeutic alternatives exist. The magnitude of benefit should be demonstrable via robust clinical endpoints, such as survival gains, reduction in morbidity or clinically meaningful improvements in validated patient-reported outcome measures (PROMs).
- Mechanism of Action and Innovative Potential: The therapy must introduce a novel mechanism of action rather than being a repurposed drug or an extension of an existing indication. The innovation should also provide long-term benefits beyond symptomatic management, potentially modifying the disease course or offering curative potential.
The revised framework aims to balance scientific rigor with pragmatic flexibility. NICE acknowledges that ultra-rare disease therapies often rely on surrogate endpoints, single-arm studies or real-world evidence (RWE) due to small patient numbers. Consequently, the revised criteria place greater emphasis on:
- Longitudinal Data and Registry Evidence: Inclusion of patient registries, real-world datasets and natural history studies to contextualise treatment benefits.
- Comparative Effectiveness Modelling: Use of Bayesian frameworks, indirect treatment comparisons (ITCs) and economic models tailored for small sample sizes.
- Incremental Cost-Effectiveness Ratios (ICERs): Consideration of extended cost-effectiveness thresholds (£100,000–£300,000 per QALY in exceptional cases) given the limited economies of scale in ultra-rare disease treatment development.
By refining the HST criteria, NICE aims to ensure that the appraisal process remains aligned with scientific advancements while maintaining fiscal responsibility. The revised framework encourages Early Stakeholder Engagement that includes collaboration with patient advocacy groups, regulatory bodies and industry stakeholders to streamline evidence submission, as well as Adaptive Licensing Pathways that integrates with regulatory initiatives such as the Innovative Licensing and Access Pathway (ILAP) to accelerate access and lastly, Investment in Orphan Drug Research: Incentivisation of R&D efforts targeting diseases with high unmet medical need.
For an in-depth examination of the updated criteria and their broader implications, refer to NICE’s official announcement here.