Methodological approaches to the use of real-world data(RWD) for medical products to treat breast cancer: An FDA oncology center of excellence evaluation of RWD submissions

Abstract Background: Aligning with 21st Century Cures legislation, FDA is exploring various methodologies to advance appropriate uses of Real-World Data (RWD) to generate Real-World Evidence (RWE). Inclusion of RWD to support regulatory decision making has increased in oncology, and this review specifically focused on characterizing RWD submissions for the treatment of breast cancer (BC). Methods: A systematic search was conducted using internal FDA databases to identify RWD submissions from 2010 to 2020. Search terms included real world evidence, real world data, cancer registry, administrative claims, external control arm, and other terms relevant to RWD/RWE. Relevant regulatory submissions were reviewed, pre-defined common data elements were extracted, and the subset applicable to breast cancer was evaluated. Results: Of 142 regulatory submissions that included RWD, 6 specifically evaluated BC indications and 3 were for solid tumor indications with potential applicability to BC, corresponding to 4 new molecular entities. Regulatory objectives included support for labeling changes including efficacy (expanded indications), safety , and dose or administration modifications. The most commonly used design was a retrospective observational study with structured electronic health records (EHRs) or medical claims data, supplemented by unstructured data from medical records or chart review for missing data elements. Four of the 6 BC submissions were significantly limited by a high degree of data missingness and confounding, with some studies including key covariates that were missing in >50% of the structured data. RWD was used to provide contextual evidence for label expansion for populations not included or adequately represented in the registration trial. Of note, for the application expanding the label to include treatment of male BC, the regulatory decision was primarily based on clinical trial data. The primary rwEndpoints submitted were overall survival (rwOS), progression free survival (rwPFS), response rate (rwORR) and time to next treatment (TTNT). Safety outcomes were investigated in all but 1 of the studies, most commonly as a secondary RWD endpoint. Conclusion: In our review of regulatory submissions relevant to breast cancer therapies, RWD has largely been used to contextualize and complement prospective clinical trial data. Evaluating that selected RWD is fit for purpose to address the regulatory objective(s) and all analytical plans are prespecified allows for robust data characterization, and appropriate evaluation. Data relevance (availability of key variables) along with reliability assessment which includes evaluating data for completeness, consistency, and trends over time are necessary for the rigorous evaluation of RWE in drug development. Data missingness is a key issue in RWD, especially when structured data are not available and specific variables are unlikely to be captured in a reliable way in the unstructured data or further validation is not feasible. To optimize RWD as evidence for specific patient populations, attention to the proportion of patients excluded is necessary to avoid concerns regarding the generalizability of the data. Careful selection of rwEndpoints must be aligned with the study design and objective, include data such as prior, concomitant and subsequent anti-cancer treatments, and the ability for outcome validation to be methodologically appropriate. When contemplating a regulatory submission using RWD, early consultation with the appropriate FDA review division can provide additional feedback on the appropriate use of RWD or pragmatic designs. Citation Format: Melanie E Royce, Jennifer J. Lee, Christy L. Osgood, Laleh Amiri-Kordestani, Julia A. Beaver, Paul G. Kluetz, Donna R. Rivera. Methodological approaches to the use of real-world data(RWD) for medical products to treat breast cancer: An FDA oncology center of excellence evaluation of RWD submissions [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-19-02.