OBJECTIVES: To understand the role of Real-World Evidence (RWE) for reimbursement and market access of Ultra Orphan Drugs.

METHODS: A systematic review of all NICE HST HTAs was conducted. Based on the type of real-world evidence (RWE) a database was developed for each ultra orphan drug assessment. Case studies were designed to understand the role, importance and context of RWE. Insights and Lessons were developed to help future reimbursement and market access of ultra orphan drugs.

RESULTS: During 2015-2022, NICE conducted 20 HST assessments for ultra orphan products. In 18 of 20 (90%) of the reports NICE cited, considered, requested or recommended use of RWE. Overall, there were 86 instances of mention of RWE, with 30 for survey(s), 29 for natural history study, 25 for registry, 6 for observational study and 6 for retrospective chart review. Five products with most use of RWE were Asfotase alfa, Eculizumab, Selumetinib, Burosumab and Metreleptin. For Asfotase alfa, NICE acknowledged that RWE demonstrated urgent need for new treatments. For Selumetinib, an independent natural history study was leveraged for unmet need and external control. For Eculizumab, 5 registries were used to understand patient characteristics and prognosis with standard care. For Burosumab, RWE was used for assessing long-term effectiveness. For Metreleptin, natural history study was used for conducting indirect comparison and to estimate transition probabilities.

CONCLUSIONS: Review of ultra orphan drug assessments shows importance of RWE to demonstrate unmet need, assess burden of disease, conduct indirect comparisons and estimate inputs for cost-effectiveness modeling. Case studies provide examples of successful use of RWE for HTA submission.