Presentation (CTI)

OBJECTIVES: Single-arm trial designs are employed to investigate novel therapies where conducting a randomized control trial is not feasible. External control arms (ECA) constructed from real-world data (RWD) have been used by multiple sponsors to contextualize the benefits and risks of a therapy. This review examines Canadian regulatory and health technology assessment (HTA) evaluations of ECAs and highlights best practice considerations for future development.
METHODS: Regulatory filings to Health Canada (HC) supported by ECAs and subsequent reimbursement recommendations from Canada’s Drug Agency (CDA-AMC) and Institut national d’excellence en santé et services sociaux (INESSS) between 2015 to 2025 were identified. Review comments were summarized and interpreted for best practice considerations.
RESULTS: Nineteen filings employing ECAs were identified across HC, CDA-AMC (n=15) and INESSS (n = 14). Most ECAs applied to rare disease and hematology-oncology indications, using observational cohort or natural history cohort studies as controls, often with propensity score matching to address differences in baseline characteristics. Where further details were available, HC noted challenges of comparability of the ECA to the target patient population, and robustness of data collection. CDA-AMC and INESSS critiqued limited generalizability to Canadian clinical practice, inadequate confounding adjustment, and lack of representation to Canadian standard-of-care. We interpreted that ECAs had a moderate effect on HTA submission outcomes. When developing future ECAs, strong methodological rigor in study design, appropriate statistical analysis, and alignment with Canadian clinical populations and practices are important considerations.
CONCLUSIONS: ECAs developed from RWD are a strategic methodological approach to enhance the relevance of evidence from single-arm trials, when designed with appropriate rigor and context.