Overview of Regulatory Guidelines Related to Methods and Models for Small Populations

This paper provides an overview of approaches and related guidelines from the EMA, FDA, and ICH that are relevant for obtaining clinical evidence for small populations to support regulatory decision making. The approaches are grouped into three categories: (1) maximizing the attainable sample size, (2) adapting the trial design to deal with a small sample size, and (3) including external information, while also examining the role of modeling. Guidelines for clinical trials, guidelines specifically for small populations, as well as guidelines that include the use of modeling to support clinical evidence were included in the review. A recurring theme throughout the guidelines is the critical importance of the clinical context, affecting both the evidentiary standard and which approaches and models are acceptable. Two key gaps were identified: (1) guidance on Bayesian approaches is limited, and (2) there is no clear guidance on how to synthesize evidence across different modalities, such as trial results and Real-World Data, from both a practical and regulatory perspective.