OBJECTIVES: For ultra-orphan products, cost-effectiveness analyses are critical to demonstrate value to payers and providers. The objective of this analysis was to systematically review uncaptured benefits reported in ultra-rare disease treatments assessed by NICE under the Highly Specialized Technology (HST) program.

METHODS: A systematic review of all 2016-2024 NICE HST HTAs was conducted. For each assessment, the uncaptured benefits were reviewed, summarized, and categorized. All uncaptured benefits were analyzed to develop lessons and insights for future rare disease treatments. Key opinion leaders were interviewed to further understand the implications of missed opportunities in cost-effectiveness analyses.

RESULTS: During 2016-2024, there were 28 Highly Specialized Technology (HST) assessments published by NICE. Overall, there were 138 mentions of uncaptured benefits for cost-effectiveness analyses in HST reports. There were 19 categories of uncaptured benefits, with the top 10 categories being: Quality of Life Improvements (19), Psychological and Social Benefits (19), Economic Benefits (18), Educational and Employment Opportunities (10), Healthcare Resource Utilization (12), Innovative Mechanism of Action (10), Long-term Health Benefits (12), Impact on Health Inequality (8), Social and Developmental Benefits (10), and Support for Carers (8). Some assessments highlighted missed benefits due to inadequate trial endpoints, lower infusion burden, fewer transplants, and broader impact on family and society. Nearly all assessments had significant uncaptured benefits, suggesting the need for the development of a more holistic disease conceptual framework to include all domains.

CONCLUSIONS: Several assessments had uncaptured benefits for cost-effectiveness analysis, indicating a need to learn from previous assessments and an opportunity to develop a more holistic burden of disease framework.