Presentation (CTI)

OBJECTIVES: Health economic evaluations of orphan drugs face unique challenges due to limited clinical evidence and methodological uncertainties. Small patient populations often preclude large-scale randomized controlled trials, leading to reliance on single-arm studies or indirect comparisons. Additionally, disease heterogeneity, limited natural history data, and challenges in measuring health-related quality of life (QoL) contribute to uncertainty in model inputs, especially in utility estimation and extrapolation of long-term outcomes. These factors complicate the application of standard health economic frameworks.
METHODS: We reviewed all efficiency opinions published by the French Health Technology Assessment (CEESP) between 2019 and 2024, focusing on rare disease submissions only. Non-validation was defined as the presence of a Major Reserve or Major Overall Uncertainty. We analyzed key methodological concerns leading to non-validation, notably according to therapeutic areas.
RESULTS: Among 142 CEESP assessments published between 2019-2024, 29 (20.4%) concerned rare diseases. The proportion of rare disease evaluations increased from 16% in 2020 to 40% in 2024. Hematology (12/29, 63.2%) and neurology (4/29, 21.1%) were the most represented therapeutic areas. Of the 29 rare disease submissions, 19 (65.5%) were not validated, substantially higher than the overall non-validation rate (42.3%). The main methodological concerns involved indirect comparison methods (6/19, 31.6%) followed by QoL estimation (5/19, 26.3%). For indirect comparisons, common issues were insufficient documentation (4/6, 66.7%), lack of covariate adjustment (3/6, 50%), and population heterogeneity (3/6, 50%). Regarding QoL, the primary concern was the use of heterogeneous data sources without relevant rational (3/5, 60%). Additional issues included insufficient documentation, reliance on vignette-based studies and failure to use clinical trial data.
CONCLUSIONS: The high non-validation rate highlights persistent methodological quality issues, inherent to rare disease context. Greater flexibility in comparator selection and utility measurement, along with clearer guidance on indirect comparisons, may improve the acceptability and relevance of CEESP evaluations in this context.