AERO: An AI Agent for Adaptive Eligibility Refinement and Optimization of Clinical Trial Criteria in Real-World Trial Emulation

Randomized controlled trials (RCTs) provide high internal validity but often rely on restrictive eligibility criteria that limit generalizability and complicate real-world trial emulation. We propose AERO (AI Agent for Adaptive Eligibility Refinement and Optimization), an agentic framework that systematically adapts clinical trial eligibility criteria for application to electronic health record data. AERO integrates external clinical knowledge sources and large language model-based reasoning to classify criteria as strict inclusion, safety exclusion, confounder, or operational artifact. We evaluated AERO by emulating the WARCEF trial using Mayo Clinic Platform data restricted to the pre-trial completion period. Emulation with optimized criteria yielded a hazard ratio of 1.561 (p = 0.0605), consistent with the original neutral trial finding (HR = 1.01, p = 0.91). An ablation analysis demonstrated that eligibility handling decisions materially influence observed treatment effects. These results highlight the importance of systematic, knowledge-informed eligibility refinement in real-world evidence generation.