EMA Guideline on clinical trials in small populations

This EMA guideline provides methodological recommendations for the design, conduct and analysis of clinical trials in conditions where the number of eligible participants is limited. It is particularly relevant for rare disease clinical trials, where conventional study designs may not be feasible because of small patient populations, disease heterogeneity and limited opportunities for recruitment. The guideline supports protocol development by describing approaches that optimise evidence generation while maintaining scientific validity and ensuring that methodological choices are prospectively justified.

The guidance discusses key aspects of protocol design, including study design, randomisation, control group selection, sample size justification, endpoint selection, statistical analysis, stratification, matching and methods to improve study efficiency. It also addresses the appropriate use of surrogate endpoints, patient registries, historical or external controls, case series and other complementary sources of evidence when randomised controlled trials are not feasible. Throughout the document, emphasis is placed on balancing methodological rigour with the practical constraints inherent to small populations and on ensuring that any deviations from conventional trial designs are scientifically justified.

Researchers developing rare disease clinical trial protocols can use this guideline to select appropriate methodological strategies, strengthen the rationale for their design choices, and develop feasible, robust and interpretable studies that align with EMA expectations. The guideline also highlights the value of early statistical expertise and regulatory scientific advice when planning innovative trial designs for small populations.