Design, simulate, refine: simulation-guided clinical trials for accelerated drug development

Modern clinical trials are embracing innovative strategies including adaptive designs, biomarker-guided enrolment, master protocols and real-time decision-making. These approaches may accelerate discovery and improve outcomes, yet they also introduce additional complexity in study conduct and understanding of the design. Simulation-guided design can be a powerful tool for identifying the optimal design to address research questions and for understanding and communicating how the design functions in practice. Simulations can evaluate the operating characteristics of complex trials, including control of type I error and false discovery rate, power for sample size determination, and probabilities of adaptive decisions at interim analyses. Examining individual simulated trials alongside these summaries provides insight into how the design will perform in practice, allowing potential risks to be anticipated and the design refined. Here, we outline how trial simulation can empower clinical development teams, statisticians, data monitoring committees, regulators, sponsors, funders and patient advocates by improving cross-functional communication, enhancing understanding and providing objective justification for design choices. We also provide best-practice recommendations to ensure that simulation studies are valid, transparent, thorough, efficient and comparable - helping to create trial designs that are scientifically rigorous, ethically sound, operationally practical and ultimately capable of bringing safe and effective therapies to patients as efficiently as possible.