When a disease affects only hundreds or thousands of patients worldwide, conducting a traditional placebo-controlled trial can be ethically and practically impossible. Understanding when regulators will accept alternative evidence structures — and when they won't — has become one of the most consequential questions in advanced therapy development, directly shaping which patients gain access to potentially curative treatments.
This review, analyzing FDA-approved gene and cell therapies from 2019 to 2025, dissects the architecture of successful external control applications. Rather than randomizing patients to a placebo arm, sponsors in accepted cases relied on natural history cohorts — rigorously documented disease trajectories drawn from registries and prior clinical records. The analysis highlights two landmark cases: onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy, where untreated disease progression is both rapid and near-universal, and elivaldogene autotemcel (Skysona) for cerebral adrenoleukodystrophy, a uniformly devastating pediatric condition. Both approvals hinged on disease characteristics that made withholding treatment ethically untenable, paired with endpoints measurable against well-documented historical benchmarks. The review also examines failed applications, pinpointing gaps in data quality, patient matching methodology, and endpoint selection as recurring failure modes.
This work arrives as the FDA's Rare Disease Evidence Principles program formalizes a degree of regulatory flexibility that had previously been case-by-case and opaque. That shift matters because external controls remain deeply contested — propensity matching and historical cohort comparisons cannot eliminate unmeasured confounding, and patient populations, standard-of-care practices, and diagnostic criteria drift over time in ways that can bias apparent treatment effects. The review's editorial contribution is essentially a framework for sponsors: external controls succeed when disease natural history is stereotyped and well-characterized, when endpoints are clinically unambiguous, and when the alternative — randomization — is genuinely untenable. For the broader rare disease field, this represents incremental but practically significant regulatory science, not a paradigm shift.