Presentation (CTI)

OBJECTIVES: External control arms (ECAs) are increasingly used to generate comparative evidence when randomized controlled trials are infeasible, unethical, or insufficient to address specific regulatory and health technology assessment (HTA) requirements. This analysis aimed to characterize regulatory and HTA expectations for ECAs, summarize patterns of acceptance and rejection across therapeutic areas, and assess the potential role of ECA-supported and hybrid designs in asthma.
METHODS: A structured methodological synthesis was conducted using regulatory guidance, HTA frameworks, published acceptance analyses, and case studies. Evidence from major agencies (FDA, EMA, NICE, CADTH, PMDA, MHRA, and EUnetHTA) was reviewed to identify common acceptability criteria. Key elements assessed included selection of external data sources (historical trials, registries, electronic health records, and claims databases), alignment of eligibility criteria, endpoint consistency, and approaches to confounding adjustment. Reported analytical methods included propensity score matching, inverse probability weighting, covariate adjustment, sensitivity analyses, and Bayesian dynamic borrowing. Evidence across development stages, including ECA-augmented RCTs and externally controlled open-label extension studies, was also examined.
RESULTS: ECAs were accepted when supported by clear clinical rationale, well-defined external cohorts, baseline comparability, and pre-specified analytical approaches. Acceptance was most frequent in oncology and rare diseases, where RCT feasibility is limited and endpoints are well validated. In oncology, external controls were used in a subset of approvals and accepted in most cases; rejections were primarily linked to population heterogeneity, analytical limitations, or incomplete outcome capture. HTA submissions incorporating ECAs often received positive recommendations when anchored to prior trials or robust real-world data. In asthma, ECAs are not positioned as primary Phase III evidence; however, opportunities exist in hybrid designs, rare phenotypes, and analyses of extension studies to inform long-term effectiveness.
CONCLUSIONS: ECAs are considered a complementary evidence approach when supported by methodological rigor and clinical plausibility. In asthma, targeted applications may address long-term evidence gaps while maintaining evidentiary standards.