OBJECTIVES: With 6 chimeric antigen receptor-T cell therapies (CAR-Ts) approved in Europe in onco-haematology indications since 2018, health technology assessment bodies (HTABs) must deal with uncertainties associated with these innovative treatments. This study identified key lessons from HTABs assessment of CAR-Ts in France, Germany, and the United Kingdom.

METHODS: A review of available CAR-Ts HTA reports (cut-off, May 2023) from the HTA websites was conducted.

RESULTS: Thirty-two HTA reports for 6 CAR-Ts in B-cell malignancies were identified. Most recommendations were positive (94%) with (81%) or without (13%) restrictions. 75% of positive decisions included managed entry agreements (MEA), while 3% MEA and restriction of indication, and 3% restriction of indication only. Nearly all CAR-Ts pivotal trials (12/14 trials) were small phase 1/2-2 (median 111 patients), single-arm using objective response rate as the primary endpoint with a short median follow-up at the initial HTA appraisal (median 15.1 months). Long-term follow-up and/or clinical registries were key conditions to allow for time-limited access under further re-assessment. The major challenges to unrestricted positive recommendations were comparative effectiveness assessments based on indirect comparisons with historical cohort or other CAR-Ts, the cross-over design and short follow-up of randomized controlled trials (RCT) (2/14). CAR-T safety signals were scrutinized for all assessed products. The ability of autologous CAR-Ts to replicate trial results in practice due to complexity of production, time lag before administration, and impact of bridging therapy, were key additional concerns raised by HTABs.

CONCLUSIONS: CAR-Ts have successfully reached the onco-haematology European market in the last 5 years, despite clinical uncertainty, through restrictions of indication, time-limited and outcome-based re-assessment decisions. With increasing experience and competition in the new-generation CAR-Ts (new target, allogenic CAR-Ts, indication expansion), HTABs may strengthen their requirements. The upcoming revision of EU pharmaceutical legislation and new EU HTA framework should be tracked for potential implications on future CAR-Ts.