PS46: Advanced Designs and Analytical Approaches for Rare Disease Trials

With over 7,000 rare diseases affecting more than 30 million people in the United States, the urgency for new treatments is palpable. The field of drug development is rapidly responding to this need, as evidenced in 2025 when 26 of the FDA's 46 novel drug approvals (57%) were designated for treating these rare conditions. However, rare disease drug development commonly faces challenges, including small patient populations, heterogeneous clinical manifestations, slowly progressive disease courses, limited knowledge of disease natural history, and a paucity of early-phase trials. These challenges necessitate strategic selection of clinical trial designs and statistical analysis approaches, and the Food and Drug Administration (FDA) actively encourages flexible and innovative trial designs, alongside advanced statistical methods for rare diseases, to address small patient populations and disease complexity through initiatives such as the Accelerating Rare Disease Cures (ARC) program and the rare disease innovation hub. This parallel session will feature three speakers and will focus on advanced clinical trial designs and analytical methods in the rare disease setting. The first two speakers, from the FDA, will present their research on advanced trial designs, bringing both regulatory and practical perspectives to rare disease drug development. The first speaker will discuss adaptive designs with adaptations beyond sample size, which may be particularly useful when increasing sample size is infeasible and rare disease information is limited. The second speaker will focus on the utility and key considerations of crossover designs with real case studies, which have become increasingly popular and are often favored by trial sponsors in rare disease drug development in recent years. Finally, the third speaker, from academia, will discuss novel covariate adjustment methods, which provide a practical, unifying framework for incorporating external controls, leveraging novel statistical and machine learning techniques, and implementing innovative trial designs to facilitate rare disease treatment development. Collectively, the session will focus on how advanced and innovative statistical methods can practically facilitate real-world rare disease drug development, helping to bridge the gap between advanced statistical methodologies and practical implementation in a regulatory setting.