Presentation (CTI)

OBJECTIVES: External control arms (ECAs) offer a promising solution for rare disease clinical trials where recruitment is slow, randomization often infeasible, and delaying treatment ethically questionable. While regulators and health technology assessment bodies have expressed willingness to accept ECAs when real-world data (RWD) and evidence meet quality standards, significant implementation barriers persist. This research examines the practical challenges of developing acceptable ECAs in rare diseases, with particular emphasis on incorporating patient-reported outcomes (PROs) and establishing fit-for-purpose data infrastructure.
METHODS: Using published examples of ECAs developed in rare conditions, we conducted a structured review of trial publications, regulatory and HTA assessments, and methodological guidance to characterise how ECAs have been designed and evaluated in practice. We extracted information on disease, data sources, eligibility, endpoints, covariates, and analytic approaches, with a focus on how clinical heterogeneity, small sample sizes, and non-standardized endpoints were addressed. To examine patient-centricity, we catalogued how PROs were defined and collected across trial and non-trial settings and evaluated the ECAs captured PROs.
RESULTS: Traditional RWD sources (eg, retrospective chart reviews) rarely included PRO instruments aligned with those used in corresponding trials, and often lacked standardized timing or complete follow-up, limiting their suitability for ECA construction in rare diseases. Across published cases, ECAs that were viewed more favorably by decision-makers relied on purpose-built/enhanced datasets created through partnerships between sponsors, patient advocacy organizations, and specialized data platforms, enabling consistent endpoint definitions, clinical phenotyping, and structured PRO collection. Hybrid designs that combined retrospective RWD with prospectively collected PROs and key clinical variables demonstrated greater potential to mitigate data quality and comparability concerns while maintaining feasibility in small, heterogeneous rare disease populations.
CONCLUSIONS: Moving from case-by-case regulatory negotiations to standardized, scalable ECA frameworks requires earlier implementation of value-based PRO measurement standards to ensure that patient voice is represented.