Experimental designs for small randomised clinical trials: an algorithm for choice

Catherine Cornu, Behrouz Kassai, Roland Fisch, Catherine Chiron, Corinne Alberti, Renzo Guerrini, Anna Rosati, Gerard Pons, Harm Tiddens, Sylvie Chabaud, Daan Caudri, Clément Ballot, Polina Kurbatova, Anne-Charlotte Castellan, Agathe Bajard, Patrice Nony, and the CRESim & Epi-CRESim Project Groups

Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple.