OBJECTIVES: Rare diseases are often characterized by the challenges they pose for health technology assessments (HTA), especially the lack of understanding of natural history, heterogeneous treatment patterns, small sample sizes, and ambiguity on long-term outcomes and benefits. Against the backdrop of the Ireland government’s upcoming rare disease plan, our objective was to understand the evidence-related challenges faced by manufacturers in the National Centre for Pharmacoeconomics (NCPE) submissions and its implications on reimbursement decisions.

METHODS: We have reviewed published NCPE technical summary documents between 2020 to 2023 from the NCPE website. Identified HTAs were categorized as “orphan” based on the Orphanet classification of group disorders and the European Union definition. Outcomes on review group comments, NCPE recommendation status, health services executive (HSE) decisions, and clinical effectiveness methods were extracted for further statistical analysis. Appraisals with “Assessment Process Complete” status were only included.

RESULTS: Fifty-two “orphan” HTAs have been identified in which only 5 drugs had negative NCPE recommendations while the other 47 were recommended conditionally, implying that HSE sanctioned reimbursement following confidential price negotiations. Correlation analysis showed a negative association of -0.27 between HSE and NCPE decision outcomes. Randomized controlled trials (RCTs) were the most popular approach for showing clinical effectiveness (40/47) rather than single-arm trials (7/47). Further, real-world data was used by manufacturers in 7 out of 52 submissions to improve generalizability, sample size issues, and immature data out of which 3 were conditionally approved by NCPE.

CONCLUSIONS: Our findings suggest that the HSE had traded off between unmet needs and innovation against sub-optimal evidence generation by manufacturers, contrary to the NCPE HTA standards. The upcoming national rare disease plan should try to address these aspects more holistically especially regarding the concerns about lack of publicly available HTA grade evidence, lack of patient involvement, generalizability to the Irish population, and long-term benefits.