Presentation (CTI)

OBJECTIVES: The inclusion of orphan medicines in the EU HTAR from 2028 introduces significant methodological challenges to robust evidence generation in rare diseases (RD), which are characterised by small, heterogeneous populations, fragmented data sources, and variation in clinical practice. While HTAR guidance aims to harmonise assessment requirements across Member States (MS), evidence challenges associated with RD remain. This study assessed how current health technology assessment (HTA) guidance reflects RD challenges and explored how these were addressed in the first EU Joint Clinical Assessment (JCA) report.
METHODS: A targeted review was conducted; guidance documents from the EU HTAR and seven key MS, and peer-reviewed methodological literature published since 2023 were screened. Screening and extraction were performed by one reviewer, with 10% validated by a second. The published EU JCA report for tovorafenib was reviewed as a case study.
RESULTS: Based on the thirty-three guidance documents reviewed, there is no comprehensive or harmonised HTA guidance at either the EU or national level that adequately addresses the challenges of assessing orphan medicines. Guidance lacks clear recommendations on minimum evidence requirements and approaches, including the need for adaptive systematic search strategies to capture sparse data landscapes and expanding evidence bases beyond narrowly defined populations. Together with heterogenous outcome definitions, these impact the feasibility and choice of comparative effectiveness analysis methods. The first EU JCA report acknowledged RD evidence challenges and highlighted the substantial remaining uncertainty.
CONCLUSIONS: While EU-level harmonisation may improve assessment consistency, it remains unclear how current methodological expectations affect the evidence burden for sponsors developing orphan medicines. Limited guidance and flexibility may limit a sponsor’s ability to meet HTAR evidence requirements. The impact of differing assessment frameworks across MS also remains uncertain. Clear guidance is essential to ensure that assessments of orphan medicines are feasible, scientifically appropriate, and lead to access to innovative treatments.