Uncertainty in NICE HTA Assessments for Rare Disease: A Review of Methodological Recommendations and How They Are Applied

OBJECTIVES: Drugs for rare diseases (DRDs) can be lifesaving but are expensive to develop, with small patient populations making return on investment more difficult. Evidence generation for DRDs is challenging and traditional health technology assessment (HTA) methods often fail to fully capture their value. The UK has historically been a challenging market for DRD reimbursement due to the emphasis placed on cost effectiveness; however, in 2022 the National Institute for Health and Care Excellence (NICE) introduced updated methods guidance. This review examines NICE’s recommendations for DRDs under this new guidance and consolidates key insights for manufacturers.

METHODS: DRDs were defined as a pharmaceutical that treated a disease with prevalence of less than 1 in 2,000 in the UK. NICE single technology assessment (STA) HTA appraisals for DRDs conducted from 2022 to present were extracted and reviewed. Positive and negative recommendations for DRDs were compared to identify methodological reasons for why some products were recommended while others were not.

RESULTS: From 2022-2024, we identified 56 HTAs for DRDs, of which two were "Not Recommended", 20 were "Recommended", one was "Recommended (CDF)", 13 were "Optimized" and 20 were "Terminated Appraisal - non submission”. Key themes in DRD recommendations included lack of direct treatment comparisons, uncertainty around the clinical effectiveness, and uncertainty in cost-effectiveness estimates. The inclusion of evidence regarding unmet need and disease severity was referenced to mitigate uncertainty.

CONCLUSIONS: Although NICE has introduced the highly specialized technologies (HST) pathway for DRDs, most products do not meet criteria for HST and undergo standard STA processes. Results showed that most products received positive HTA recommendations despite limited evidence. Approaches to mitigate uncertainty, such as generating additional evidence via alternative methods, including structured expert elicitation and qualitative patient interviews, are crucial to ensure the added value of DRDs is well understood.