Real-World Evidence in FDA Approvals for Labeling Expansion of Small Molecules and Biologics

Real-world evidence (RWE) can support the evaluation of safety and efficacy for medical products, but its extent of use in labeling expansion submissions remains unclear. This study aimed to characterize the RWE used in labeling expansion or likely used, as identified through literature search, for drugs and biologics.

We identified RWE used in FDA-approved labeling expansion for drug and biologic supplemental applications from January 2022 to May 2024 (Drugs@FDA), using FDA prescribing information and review documents. We also searched ClinicalTrials.gov and PubMed to identify RWE not included in the FDA approval letter and labeling but could have been incorporated into submissions by sponsors. Characteristics of the RWE were extracted and summarized.

Among 218 labeling expansions granted, RWE was found in FDA documents for 3 approvals and elsewhere for 52 approvals. The proportion of approvals with RWE was 23.3%, 27.7%, and 23.7% in 2022, 2023, and 2024, respectively. RWE was most commonly found in submissions for oncology (43.6%), infection (9.1%), and dermatology (7.3%). Greater use of RWE was identified in submissions for drugs (69.1%) and to expand indications (78.2%). RWE came from 88 studies, with 48.9% addressing both safety and efficacy. Most of the RWE studies were retrospective (65.9%), employed a cohort study design (87.5%), and used electronic health records (EHR) data (75.0%).

We observed limited RWE use in granted labeling expansion, and the reason is unclear due to incomplete FDA documentation of supplemental approvals-RWE may not have been submitted, may have been submitted but determined by FDA to be of limited use, may have contributed substantively to the supplemental approval, or some combination of these across submissions. Improving accessibility and transparency in RWE's acceptability within review documents can enhance our understanding of the extent and quality of RWE used for labeling expansion.