OBJECTIVES: For rare diseases, Real-World Evidence (RWE) is a useful resource to collect data. The objective of this analysis was to understand the value and role of RWE for treatments for ultra-rare diseases assessed by NICE under the Highly Specialized Technology (HST) program.

METHODS: A systematic review of all 2016-2022 NICE HST HTAs was conducted using NOVEL-HTA database. HST Reports were reviewed for all types of RWE (e.g. registry, observational, chart review, claims database). For selected reports, we analyzed the context for RWE, NICE’s determination and any concerns.

RESULTS: In 17 (~90%) out of the 19 HST reports NICE requested, considered, or accepted use of RWE for ultra-rare diseases. In these reports, there were a total of 115 different references of RWE, vast majority of which were for registry (42%) and natural history study (36%), followed by observational study (9%) and retrospective chart reviews (5%). In 11 reports, the context of RWE was for long-term effectiveness. In 8 reports, RWE was cited for health utilities scores and for conducting indirect comparisons. In 4 reports, RWE was used for determining standard of care and transition probabilities for cost-effectiveness modeling. In 2 reports, there were concerns regarding collection of quality of life from registries. Five products had relatively high references of RWE- Eculizumab (16 times), Asfotase alfa (11), Selumetinib (10), Metreleptin (8) and Burosumab (8). For 3 products NICE recommended use of RWE to assess adverse events (Voretigene neparvovec, Metreleptin, Odevixibat). In 2 assessments, NICE acknowledged that there was an urgent need for new treatments (Asfotase alfa) and high burden of the disease (Eculizumab).

CONCLUSIONS: To our knowledge this is the first report describing use of RWE for ultra-rare disease HTA submissions. This analysis provides valuable lessons and insights for manufacturers to leverage RWE for HTA submission.