Externally Controlled Clinical Trials for Pediatric Rare Diseases: Current Practices and Guidance

Abstract

Objective: To describe the design and conduct of externally controlled trials in pediatric populations with genetic rare diseases (RD), including their alignment with regulatory and health technology assessment guidance.

Methods: We conducted a scoping review to identify and describe externally controlled trials in pediatric populations with genetic RDs, between 2014-2025. We also reviewed publicly available guidance on the conduct of externally controlled trials from leading regulatory and health technology assessment organizations and evaluated alignment of trials with this guidance.

Results: Among 67 articles reporting on externally controlled pediatric genetic RD trials, only eighteen applied an analytic method to address imbalances in baseline covariates between arms beyond age and baseline outcomes. Alignment with guidance was low due to poor comparability of outcome assessments, limited reporting of missingness, and under-utilization of sensitivity analyses.

Conclusion: Tailored guidance is needed to promote strategies that better mitigate against known sources of bias in externally controlled pediatric genetic RD trials.