OBJECTIVES: The number of gene therapies (GTs) is expected to increase in the coming years. Evaluating these therapies poses unique challenges. We reviewed the methods of clinical studies for GTs appraised by the Haute Autorité de Santé (HAS) between 2018 and 2024 and the HAS' judgments on these methods.

METHODS: Data were sourced from the NaviHTA database, which contains structured information extracted from HTA reports through systematic approaches with human and machine-driven quality controls. This included data on clinical studies and appraisal outcomes for GTs, including CAR-T cells, appraised by the HAS up to June 2024.

RESULTS: HTA reports for 13 GTs and CAR-T cells were identified. All products were approved for reimbursement, but 5 out of 13 had restricted indications, such that 18 assessments were issued. Six out of 18 assessments concluded that there was no clinical added value (ASMR V). These were mostly based on non-comparative early-phase studies with open-label designs and no external control (5/6). Indirect treatment comparisons were submitted but not taken into consideration due to methodological limitations in 5 of these 6 cases. Other critiques included non-clinically relevant primary endpoint, lack of multiplicity adjustment, small sample sizes, and non-generalizability of results. Drugs awarded ASMR II/III were supported by randomized controlled trials or phase I/II studies with pre-planned historical cohort comparisons or supplemented by French real-world evidence. Exceptions included tisagenlecleucel and axicabtagene ciloleucel, which received ASMR III without any comparative clinical evidence. Uncertainty around long-term safety and efficacy due to short follow-up was noted in all assessments, leading to recommendations for coverage with evidence development.

CONCLUSIONS: The HAS tended to acknowledge a clinical added value for GTs based on lower quality of evidence than for other therapies, particularly for the first launched products. This advantage granted to GTs may not persist in the future.