OBJECTIVES: Single-arm trials (SATs) are commonly used to evaluate gene therapies given their novelty and targeting of life-threatening or rare diseases. The objective was to assess and compare the use of SATs, approach to generating comparative evidence, and recommendations by various health technology assessment (HTA) agencies for gene therapies.

METHODS: Axicabtagene ciloleucel (axi-cel)—the first Food and Drug Administration-approved chimeric antigen receptor T-cell therapy—was selected for review. Recent submissions to major HTA agencies for axi-cel in the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma were identified. Full-text screening of clinical evidence reports and reimbursement guidance was conducted by two independent investigators. Information on trial design, external comparator data, indirect treatment comparison methods, and HTA critiques/decisions was extracted.

RESULTS: Five English-based submissions for axi-cel were identified from the Canadian Agency for Drugs and Technologies in Health, National Institute for Health and Care Excellence, Scottish Medicines Consortium, Australian Medicare Services Advisory Committee, and Norwegian Medicines Agency in addition to an assessment by the Institute for Clinical and Economic Review. Consistently, the ZUMA-1 trial was the only submitted source for clinical efficacy of axi-cel, while salvage chemotherapy was selected as the comparator—sourced from a retrospective study (SCHOLAR-1)—across all the submissions/assessments. Comparative evidence was generated using different methods, including naïve comparison, covariate-adjusted regression analysis, propensity score analysis, and matching-adjusted indirect comparison. Despite varying level of criticisms on comparator data and comparison methods from HTA reviewers, positive recommendations were made by all agencies, which were mainly driven by patient unmet needs, quality of comparator evidence, and magnitude of relative clinical benefits demonstrated through the comparisons.

CONCLUSIONS: SAT-based submissions of axi-cel were well accepted for reimbursement across countries, with relative treatment effect being addressed through sensible external comparator evidence and comparison approaches.