(P-451) Creating High Quality External Control Arms from RWD in Support of Regulatory Decision Making

Background: Generating evidence and bringing novel medical advances to patients is challenging, particularly for well-defined medical indications where there is clear unmet medical need, significant morbidity/mortality, or meaningful rarity. In these situations, consideration for a single-arm clinical trial with a comparator external control arm may be warranted.

Use of real-world data (RWD) sources for this purpose requires not only rigorous assessment and understanding of the data but also application of strong medical informatics and data science approaches to increase confidence that the data is of sufficient quality to meet regulatory requirements. This is particularly important to ensure the control cohort is similar to the treatment cohort and that the data reliably represents the study endpoints.

Objectives: To present essential study design aspects and challenges to assessing and leveraging real-world data to create a high-quality external control arm for comparison to a clinical trial treatment arm in support of regulatory decision making.

Methods: Recent FDA approvals that included RWD-based external control arm evidence and current trials in planning with intent to submit evidence from a RWD-based external control arm to the FDA, including those conducted/in planning by authors, were reviewed to determine distinct RWD and study design requirements that are uniquely different from traditional clinical trial studies or real-world evidence (RWE) studies conducted alone. These requirements were evaluated within the context of published regulatory documents that reference relevant RWD and external control arm concepts. We further grouped requirements that naturally fit within a common topic, identified the function best aligned to accomplish each grouping of requirements, and placed each grouping into a proposed study workflow.

Results: Several groupings of requirements related to the potential use of RWD in establishing a cohort of patients appropriate to serve as a comparator cohort to a clinical trial treatment cohort (aka external/synthetic control arm) were identified, defined, grouped and placed within the context of a study workflow. In addition, a multi-functional team approach, representing both the RWE and randomized clinical trial (RCT) functions, was identified and determined to be essential to the successful completion of this novel study approach.

Conclusions: This grouping of RWD-focused requirements aligned with a multi-functional team approach provides a framework for sponsors, RWD providers, and regulators to effectively engage in external control arm studies.