Real-World Evidence Utilization in Clinical Development Reflected by US Product Labeling: Statistical Review

The US Food and Drug Administration (FDA) has shown scientific discretion in interpreting the substantial evidence requirement for the approval of new drugs with its considerations on the use of single controlled or uncontrolled trials (Federal Food, Drug, and Cosmetic Act § 505(d), 21 USC 355(d), 1962). With the passage of the 21st Centuries Cures Act (21st Century Cures-patients. House, Energy and Commerce Committee, Washington, DC, 2019 available at: https://energycommerce.house.gov/sites/republicans.energycommerce.house.gov/files/analysis/21stCenturyCures/20140516PatientsWhitePaper.pdf ), the FDA is mandated to expand the role of real-world evidence (RWE) in support of drug approval. This mandate further broadens the scope of scientific discretion to include data collected outside clinical trials. We summarize the agency's past acceptance of real-world data (RWD) sources for supporting drug approval in new indications which have been reflected in US labels. In our summary, we focus on the type of RWD and statistical methodologies presented in these labels. Furthermore, two labels were selected for in-depth assessment of the RWE presented in these labels. Through these examples, we demonstrate the issues that can be raised in data collection that could affect interpretation. In addition, a brief discussion of statistical methods that can be used to incorporate RWE to clinical development is presented.