(A42) Case studies of FDA recently approved product applications using real-world evidence - What are the attributes of studies that support effectiveness determinations?
Associate Director for RWE at Office of Surveillance and Epidemiology, CDER US Food and Drug Administration Silver Spring, United States
Background: The 21st Century Cures Act mandates that FDA evaluates the potential use of real-world evidence (RWE) to support regulatory decision making.
Objectives: The goal of this study is to examine a convenience sample of recently approved product applications between 2020 and 2021 and summarize distinctive attributes of the RWE that support a determination of effectiveness.
Methods: We report on five NDA/BLA submissions (Erbitux, Fabrazyme, Nulibry, Voxzogo, Prograf) and describe attributes of the studies that used real-world data (RWD) serving as an adequate and well-controlled clinical investigation, confirmatory evidence, or post-marketing requirement in support of approval.
Results: Studies using different RWD sources and methods have been submitted in support of efficacy claims for various pharmaceutical products. Certain patterns of the attributes of these study emerged across the therapeutic areas. First, these studies used RWD that are fit-for-purpose. For example, the approval of tacrolimus was based on relevant and reliable data from a national transplant registry of all US organ transplant recipients since 1999. Second, the studies employed objective, primary study endpoints (e.g., body height in the vosoritide study) and appropriate comparators (e.g., bi-weekly vs. weekly use in the cetuximab study), with standardized data measurement and collection. Third, external control arms were selected using similar patient inclusion and exclusion criteria to those in single-arm trials to allow for causal inference, often employing propensity score or other methods to reduce baseline differences. Fourth, when the natural history of the disease predicted a uniformly poor outcome and the observed treatment effect size was relatively large, it was less likely that confounding or bias explained the observed treatment effect. Fifth, consistent results from various types of evidence (e.g., PK/PD or biomarker data) and/or from multiple sensitivity analyses provided additional assurance about the study findings. Lastly, detailed study protocols with clear justifications for the selection of data source(s) and study design, together with descriptions of study conduct and relevant clinical and regulatory contexts, allowed the FDA to evaluate the RWE thoroughly in a timely manner for regulatory decision making.
Conclusions: Data reliability and relevance, as well as appropriate study design, play crucial roles in determining the acceptability of RWE for efficacy determinations. Despite the limitation of using a convenience sample which may not represent all RWE-related approvals, this analysis shows that carefully designed and analyzed RWE studies can be a component of an FDA-approval decision.