PS37: Design, Simulate, Refine: Simulation-Guided Clinical Trial Design in the Age of ICH E20

Modern clinical trials increasingly rely on adaptive designs, innovative statistical methodologies, and complex operational features to answer nuanced research questions more efficiently and ethically. While these approaches offer substantial advantages over traditional fixed designs, they also introduce layers of complexity that can hinder understanding, communication, and confidence among key stakeholders. In practice, many development teams struggle to balance methodological sophistication with interpretability, feasibility, and regulatory acceptability. Reflecting these challenges, recent regulatory guidance has elevated simulation from a supportive tool to a central component of trial design and evaluation, with both the FDA's Adaptive Designs and Complex Innovative Trial Design guidances and the draft ICH E20 guideline explicitly emphasizing simulation as a primary means of evaluating operating characteristics, understanding design behavior, and justifying adaptive features. By treating simulations as virtual "test flights" of a planned study, trial designers can explore how design choices behave under uncertainty, quantify operating characteristics beyond simple power calculations, and iteratively refine designs before enrolling the first patient. Simulations allow investigators to examine both individual trial trajectories and aggregate operating characteristics across many plausible scenarios, making complex decision rules tangible and facilitating shared understanding across clinical, statistical, operational, and regulatory perspectives. Importantly, well-designed simulation programs have played a critical role in enabling constructive regulatory interactions and supporting the approval of innovative trial designs and, ultimately, effective therapies. However, practical guidance on how to properly conduct simulation studies in real development programs remains limited. This 75-minute parallel session features two speakers and one discussant, each with extensive experience in simulation-guided trial design from complementary perspectives. The session begins with two presentations describing real-world experiences in designing complex clinical trials using simulations, with emphasis on iterative development, anticipated risks, and cross-functional communication. These examples illustrate both how simulations were set up, and how their results were used, to shape design decisions, engage regulators, and support successful development outcomes. The discussant will synthesize key themes, place them in the broader methodological and regulatory context, and reflect on the evolving role of simulations in drug development under ICH E20. The session concludes with a 15-minute Q&A, inviting questions and perspectives from the audience on challenges, opportunities, and future directions for simulation-guided clinical trial design.