Presentation (CTI)

OBJECTIVES: Chimeric antigen receptor (CAR)-T cell therapies are often supported by single-arm trials (SATs), making patient-level external control arms (ECAs) an important source of comparative effectiveness evidence in health technology assessment (HTA). However, how HTA agencies evaluate and accept such evidence remains unclear. This study examined the acceptance of patient-level ECA evidence and methodological concerns raised during CAR-T appraisals across five HTA agencies in the United Kingdom (NICE), France (HAS), Germany (G-BA/IQWiG), Australia (MSAC), and Canada (CDA-AMC).
METHODS: HTA appraisal reports of approved CAR-T therapies as of December 2025 were reviewed. Initial appraisals based on SATs were included. Among these, appraisals addressing patient-level ECAs were further evaluated. Acceptance was classified as accepted, partially accepted, or rejected based on whether agencies used ECA evidence in comparative effectiveness or additional benefit assessments. Methodological concerns raised by agencies were extracted and categorized by type. All classifications were independently coded by two reviewers.
RESULTS: A total of 44 CAR-T HTA appraisals were identified, of which 29 (66%) addressed patient-level ECA evidence (NICE, n=3; HAS, n=8; G-BA/IQWiG, n=8; MSAC, n=4; CDA-AMC, n=6). Acceptance varied substantially across agencies, ranging from 100% for NICE (3/3) to 0% for HAS (0/8). G-BA/IQWiG accepted only one ECA (1/8), whereas MSAC and CDA-AMC showed mixed acceptance patterns. Even when all agencies evaluated the same ECA, acceptance varied. Methodological concerns were raised in most appraisals, reflecting uncertainty in ECA-based comparisons. The most common concerns were unmeasured confounding and selection bias, followed by transparency and reporting issues. However, the focus of methodological critiques differed across agencies.
CONCLUSIONS: Patient-level ECA evidence was commonly used in CAR-T HTA appraisals. Acceptance varied substantially across agencies, while methodological concerns regarding ECAs were frequently raised. As Joint Clinical Assessment (JCA) is implemented, greater clarity and alignment in evaluating ECA evidence may be needed.