OBJECTIVES:

CAR-Ts are innovative therapies with high curative potential and economic impact. We evaluated whether ongoing clinical trials of CAR-Ts can generate the evidence expected by main European HTABs.

METHODS:

National HTA decisions in EU5 countries (France, Germany, Italy, Spain, UK) for tisagenlecleucel and axicabtagene ciloleucel were reviewed to assess appraisal outcome, evidence gaps, and future data needs. All ongoing clinical trials of any CAR-T monotherapy in hematological malignancies were identified from clinicaltrials.gov. Trial features including design, endpoints, and comparators, were extracted and benchmarked against evidence requirements articulated by HTABs in their appraisals.

RESULTS:

Reviewed HTA decisions (n=14) showed that EU5 HTABs have approved CAR-Ts with evidence from single-arm trials, and required outcome-based agreements and mandatory collection of additional data. Overall, availability of a comparator arm and survival endpoints in trials were key evidence requirements cited in these decisions. Of 38 CAR-T trials meeting inclusion criteria, 35 (92%) were phase 1/2 or phase 2 single-arm studies (n=3−500 participants); 3 (8%) were phase 3, head-to-head studies (n=220−381 participants). Overall response rate (ORR) was the most common primary endpoint (26 trials; 68%), followed by adverse events/toxicity (13 trials; 34%). Overall survival (OS) was measured in 25 (66%) trials and progression-free survival (PFS) in 26 (68%), mostly as secondary endpoints. Only phase 3 trials included a comparator arm and measured OS or PFS as a primary endpoint, thereby meeting both the stated evidence requirements of HTABs.

CONCLUSIONS:

Our assessment suggests that only a minority of ongoing clinical trials for CAR-Ts in hematological cancers are currently designed to generate comparative efficacy evidence matching existing EU5 HTAB expectations. Some ongoing single-arm phase 2 trials may support conditional reimbursement, however, with increasing number of CAR-Ts and appraisals, HTAB decisions may evolve to require more robust survival and comparative data before expanding patient access to these therapies.