Presentation (CTI)

OBJECTIVES: Gene therapies can be transformative for people with rare genetic conditions, but evidence is constrained by small populations and limited long-term or comparative data, creating challenges meeting HTA evidentiary standards. We reviewed European HTAs to identify divergence in interpretation of clinical evidence and implications for access in the Joint Clinical Assessment (JCA) era.
METHODS: Four gene therapies launched within the past five years (valoctocogene roxaparvovec, etranacogene dezaparvovec, atidarsagene autotemcel, onasemnogene abeparvovec) were selected based on availability of documentation across French (HAS), German (G-BA), Swedish (TLV/FINOSE) and Irish (BeNeLuxA) HTA bodies.
RESULTS: Submitted evidence for each therapy was derived from single-arm trials. While primary endpoints were accepted as clinically relevant by HTA bodies, the absence of comparators limited causal inference, and outcomes were considered descriptive. Similarly, PROs were rarely considered in decision‑making due to the lack of comparative data and the high risk of bias associated with single‑arm, open‑label studies. Durability of effect was a consistent area of uncertainty, with short follow-up reducing confidence in long-term benefit. Supportive surrogate endpoints were considered biologically plausible, but insufficient alone to demonstrate clinical benefit or reduce uncertainty in efficacy. Indirect treatment comparisons were generally rejected by G-BA, making comparative efficacy the primary driver of uncertainty. In France, single-arm evidence was accepted but considered insufficient to establish comparative benefit. Swedish and Irish appraisals factored uncertainty in single-arm evidence within cost-effectiveness assessments, where durability assumptions represented key model drivers and central determinants of pricing and access decisions.
CONCLUSIONS: Despite similar evidence limitations, differences in local HTA methods led to variation in the sources of uncertainty driving decision making. Harmonised clinical evaluation under JCA is unlikely to eliminate these differences. Evidence generation planning for gene therapies should identify where uncertainty can feasibly be reduced, and where strong contextual justification or post-approval evidence generation is required, to support broad European access.