Novel clinical trial design and analytic methods to tackle challenges in therapeutic development in rare diseases.

While only a fraction of the worldwide population may have a particular rare disorder, millions of people worldwide are affected across the over 6,000 rare disorders and do not have a safe and effective approved therapy to help them live or manage complications from the disorder. Challenges to clinical development of new therapies in rare disorders include difficulty in powering and recruiting into a study in small and often heterogenous population, scarcity of natural history data informing critical design elements such as endpoint selection and study duration, and ethical and recruitment challenges in randomizing patients to a placebo arm. In this review, we describe some existing and novel strategies to tackle these challenges, by efficient utilization of available resources. We discuss the role of natural history studies and endpoint selection as they remain critical features that apply across designs and disorders. We also review some novel clinical trial designs including incorporating external control and/or longitudinal measures, master protocol designs, and adaptive designs. Additionally, we review some analytic strategies that are often associated with these designs, such as the use of causal inference methods, and Bayesian methods. We hope this review will raise awareness of these novel approaches and encourage their use in studies of rare diseases. 2022 Annals of Translational Medicine. All rights reserved.