External controls for rare disease drug development: Lessons for emerging and advanced therapeutic modalities.

External controls, particularly natural history studies, play an increasingly important role in rare disease therapeutic development where traditional randomized trials are often infeasible. This review examines regulatory acceptance patterns for gene and cell therapies approved between 2019 and 2025, analyzing successful cases like onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy and elivaldogene autotemcel (Skysona) for cerebral adrenoleukodystrophy alongside unsuccessful applications. Key success factors include systematic data collection, clinically meaningful endpoints, appropriate patient matching, and disease characteristics that preclude randomization. Recent FDA initiatives, including the Rare Disease Evidence Principles program, signal growing regulatory flexibility, although acceptance remains context-dependent and requires robust data quality standards.