Recommendations for the design of small population clinical trials (Day et al, 2018)

This publication presents practical recommendations developed through the European Integrated Design and Analysis of Small Population Group Trials (IDEAL) project to support the design and analysis of clinical trials in small populations. It is particularly relevant for rare disease research, where limited patient numbers, clinical heterogeneity and uncertainty often require methodological approaches beyond those used in conventional randomised clinical trials. The recommendations complement existing regulatory guidance by translating methodological research into practical advice for investigators developing clinical trial protocols.

The publication supports protocol development by addressing key aspects of study design, including formulation of the research question, selection of appropriate trial designs, randomisation strategies, endpoint selection, statistical analysis planning, incorporation of external or prior information, and methods to improve efficiency when patient numbers are limited. It also discusses innovative approaches such as adaptive designs, Bayesian methods, modelling and simulation, and the use of patient registries or natural history data where appropriate. Throughout the recommendations, emphasis is placed on prospectively justifying methodological decisions, reducing uncertainty, and maximising the information obtained from every participant.

For researchers developing rare disease clinical trial protocols, this resource provides practical guidance for selecting robust methodological strategies that balance scientific rigour with feasibility. It also highlights the importance of multidisciplinary collaboration, early statistical input, patient involvement, and transparent reporting to strengthen the quality, efficiency and interpretability of clinical trials conducted in small populations.