Randomized controlled trials (RCTs) encounter feasibility gaps when addressing rare genetic disorders and molecularly defined patient subgroups. The U.S. Food and Drug Administration has increasingly integrated real-world evidence (RWE) into the regulatory lifecycle. The objective of this article is to analyze the regulatory evolution following the 21st Century Cures Act and evaluate landmark drug approvals and expansions where real-world data (RWD) provided the primary or supplementary evidentiary foundation. A structured search of electronic databases, including PubMed, Embase, and Web of Science, was performed to identify relevant peer-reviewed articles. The tumor-agnostic approval of pembrolizumab demonstrated how RWE can establish clinical utility across multiple cancer types sharing specific biomarkers. For rare diseases like N-acetylglutamate synthase deficiency (carglumic acid), RWE provided essential external comparators where RCTs were impossible. In cystic fibrosis (ivacaftor), the U.S. Cystic Fibrosis Foundation Patient Registry facilitated indication expansions to ultra-rare genetic variants through longitudinal real-world outcomes. RWE proved vital for post-market surveillance in populations typically excluded from trials. While technical challenges in data interoperability and ethical concerns regarding genomic privacy remain, RWE offers a dynamic model that accelerates access to targeted therapies. The integration of high-fidelity RWD ensures that the safety and efficacy of precision medicines are validated within the complex global clinical practice.
Nagel et al. (Sat,) studied this question.