Real-World Data as External Controls: Practical Experience from Notable Marketing Applications of New Therapies

Introduction Real-world data (RWD) can contextualize findings from single-arm trials when randomized comparative trials are unethical or unfeasible. Findings from single-arm trials alone are difficult to interpret and a comparison, when feasible and meaningful, to patient-level information from RWD facilitates the evaluation. As such, there have been several recent regulatory applications including RWD or other external data to support the product’s efficacy and safety. This paper summarizes some lessons learned from such contextualization from 20 notable new drug or biologic licensing applications in oncology and rare diseases. Methods This review focuses on 20 notable new drug or biologic licensing applications that included patient-level RWD or other external data for contextualization of trial results. Publicly available regulatory documents including clinical and statistical reviews, advisory committee briefing materials and minutes, and approved product labeling were retrieved for each application. The authors conducted independent assessments of these documents focusing on the regulatory evaluation, in each case. Three examples are presented in detail to illustrate the salient issues and themes identified across applications. Results Regulatory decisions were strongly influenced by the quality and usability of the RWD. Comparability of cohort attributes such as endpoints, populations, follow-up, index and censoring criteria, as well as data completeness and accuracy of key variables appeared to be essential to ensure the quality and relevance of the RWD. Given adequate sample size of the clinical trials or external control, the use of appropriate analytic methods to properly account for confounding, such as regression or matching, and pre-specification of these methods while blinded to patient outcomes seemed good strategies to address baseline differences. Discussion Contextualizing single-arm trials with patient-level RWD appears to be an advance in regulatory science; however, challenges remain. Statisticians and epidemiologists have long focused on analytical methods for comparative effectiveness but hurdles in use of RWD have often occurred upstream of the analyses. More specifically, we noted hurdles in evaluating data quality, justifying cohort selection or initiation of follow-up, and demonstrating comparability of cohorts and endpoints.