OBJECTIVES: To develop insights and lessons learned for economic modeling for ultra orphan drugs based on review of NICE’s Highly Specialized Technology (HST) assessment reports.

METHODS: A systematic review of all NICE HST HTAs was conducted. Case studies were designed to develop insights and lessons from NICE’s committee review of company submission, updates and final ERG accepted model. For each case study, we analyzed the requested changes from NICE, missed or not captured benefits and recommendations for inputs for efficacy, utility scores, transition probabilities, cost/resource use, stopping rules and application of QALY weights.

RESULTS: During 2015-2022, NICE conducted 20 HST assessments for ultra orphan products. Overall, in these assessments there were 29 instances of NICE mentioning benefits which were not captured in the company submission, suggesting opportunity to learn from previous assessments and improve future submissions. Case studies highlight lessons related to change in comparators (e.g. Givosiran), allowing proxy collection of utility scores from clinical experts (e.g. Cerliponase alfa; which could potentially addresses the disability paradox issue for severe rare diseases), allowing caregiver and sibling disutility in nearly all submissions (e.g. Cerliponase alfa, Setmelanotide, Atidarsagene, Burosumab, Elosulfase alfa), stopping rules (e.g. Inotersen, Volanesorsen, Patisiran), use of transition probabilities from trial versus natural history study (e.g. for Cerliponase alfa NICE preferred trial based probabilities), capturing mortality from trial, real-world or general population (e.g for Voretigene neparvovec) and treatment effect waning assumptions (eg. Burosumab, Odevixibat). In some assessments, the cost-effectiveness ratio improved after NICE’s preferred assumptions were applied (e.g. Setmelanotide).

CONCLUSIONS: Previous HST submissions provide valuable insights and lessons for future ultra orphan economic modeling. In many instances NICE mentioned benefits that were not captured by the sponsor and also allowed or suggested methods to address lack of evidence in a rare disease setting.