Challenges and Possible Strategies to Address Them in Rare Disease Drug Development: A Statistical Perspective

Developing drugs for rare diseases presents unique challenges from a statistical perspective. These challenges may include slowly progressive diseases with unmet medical needs, poorly understood natural history, small population size, diversified phenotypes and genotypes within a disorder, and lack of appropriate surrogate endpoints to measure clinical benefits. The Real‐World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section has assembled a research team to assess the landscape including challenges and possible strategies to address these challenges and the role of real‐world data (RWD) and RWE in rare disease drug development. This paper first reviews the current regulations by regulatory agencies worldwide and then discusses in more detail the challenges from a statistical perspective in the design, conduct, and analysis of rare disease clinical trials. After outlining an overall development pathway for rare disease drugs, corresponding strategies to address the challenges are presented. Other considerations are also discussed for generating relevant evidence for regulatory decision‐making on drugs for rare diseases. The accompanying paper discusses how RWD and RWE can be used to improve the efficiency of rare disease drug development.