PS03: Innovative Approaches to Address Challenges in Externally Controlled Trial Designs

Traditional randomized clinical trials (RCTs) are increasingly impractical for clinical development programs targeting rare diseases or highly selected patient populations with significant unmet medical needs. Ethical concerns and operational challenges often make such trials infeasible. Externally controlled trial (ECT) designs have emerged as an innovative solution to address these issues, offering an alternative approach that uses historical clinical trial or real-world data to create a comparator. Although this methodology may have regulatory acceptance depending on the therapeutic context, the adoption of ECT designs brings significant risks and limitations, including biases, confounding, and practical implementation challenges. While advanced statistical methods have been developed to mitigate these methodological challenges, their adoption remains limited. To address this critical gap, the American Statistical Association (ASA) Biopharmaceutical Section (BIOP) Real-World Evidence (RWE) Scientific Working Group (SWG) has conducted a comprehensive assessment. This includes a review of relevant regulatory guidance, analysis of historical case studies involving ECT designs, and an evaluation of both methodological and practical challenges. Session Content and Objectives: This session will provide a deep dive into ECT designs, focusing on: • Successful and unsuccessful regulatory cases to highlight lessons learned. • Sources of bias, confounding factors, and design options to minimize these issues. • Statistical methods to address biases and ensure rigorous trial results. • Regulatory perspectives on the importance of mitigating bias and ensuring credibility in ECT designs. • Practical challenges in implementing ECT designs and strategies to overcome them. The session will feature three expert speakers and one discussant from industry, academia, and regulatory agencies, providing a comprehensive, multifaceted perspective. Participants will gain practical insights into the development and implementation of ECT designs, along with methodological advancements and regulatory considerations. The list of speakers and their talk titles is provided below: • Ran Duan (Vertex): Uncovering the challenges of utilizing RWE in regulatory decision making: barriers, mitigations, and future directions. • Herb Pang (Genentech): Design considerations for externally controlled trials in regulatory decision making • Mark van der Laan (UC Berkeley): The causal roadmap and adaptive TMLE for ECT-hybrid designs. • Hana Lee (FDA): discussant Relevance and Novelty: ECT designs are a timely and highly relevant topic as they address urgent challenges in clinical development for rare diseases and small, hard-to-enroll populations. While the concept of external controls has been discussed at prior conferences, this session will deliver fresh and actionable insights by showcasing recent methodological developments, lessons from historical cases, and forward-looking strategies to enhance their utility. The inclusion of a multidisciplinary panel ensures a balanced and comprehensive discussion. This session stands out by emphasizing not only the practical implementation of ECT designs but also the interplay between statistical rigor, regulatory frameworks, and real-world applicability. Participants will leave equipped with actionable knowledge in implementation of ECT designs and navigatation of inherent challenges.