A meeting convened by Friends of Cancer Research focused on the methodology for using external control arms in cancer clinical trials.
At the April 7 meeting, titled “Application of External Control Arms in Oncology Drug Development,” leaders across government, academia, industry, and patient advocacy examined the evolving role of external control arms, or ECAs, in oncology drug development.
Participants discussed how ECAs can be integrated into clinical development programs by addressing specific use cases, operational barriers, and analytic methodologies.
The meeting highlighted preliminary findings and insights from the Friends ECA Pilot Project to establish best practices for generating rigorous, reliable evidence and examined policy priorities to align stakeholder expectations for the scalable, responsible use of ECAs in the future.
Friends offered a list of key takeaways from the meeting:
Data Feasibility: The ability to generate a credible ECA depends fundamentally on the quality, completeness, and relevance of the underlying data. Complete or nearly complete baseline information is essential to operationalize eligibility criteria and achieve balance with the target trial control arm. Data missingness remains a significant barrier to ECA implementation and distinguishing whether data are structurally missing or simply not collected is critical for assessing fitness for use.
Methodological Rigor: Approaches such as propensity score matching and weighting, alongside multiple imputation by chained equations (MICE), are important for addressing confounding and missing data. However, these techniques cannot compensate for the absence of key prognostic variables, underscoring the importance of robust data collection at the outset.
Evolution Toward Modern Evidence Generation: Evidence generation is shifting toward more integrated use of clinical trials and external data. ECAs are already providing value in settings such as rare cancers and diseases with limited or poor-prognosis SOC. Further progress will be supported by more prospective use of ECAs, including hybrid trial designs and improved integration of longitudinal data, digital health tools, and biomarker-driven approaches.
Regulatory Alignment and Prospective Planning: Effective use of ECAs requires early and iterative engagement with FDA. ECAs should be incorporated into trial design from the outset rather than applied retrospectively. While regulatory flexibility exists, evidentiary standards for demonstrating effectiveness remain unchanged. Future trial designs should better reflect real-world clinical practice to support more generalizable populations and enable the use of robust external comparators.