Methodology for Small Clinical Trials

¹ Institut Pasteur, Unité Epidémiologie Pathologies Emergentes, Paris, France
² Laboratoires Takeda, Puteaux, France
³ Afssaps, Saint-Denis, France
⁴ Hôpital Saint-Louis, Paris, France
⁵ Hôpital Necker, Paris, France

Abstract

Small clinical trials are trials in which the number of patients does not enable the objective of the study to be appropriately met with the usual methodological rules. This situation is common in the case of rare diseases, in paediatrics, in certain cancer pathologies or when the number of patients exposed to the treatment needs to be limited. The principal methodological problems are initially identified, and the classical methods (controlled, randomised, double-blind trial using parallel groups, crossover trial, factorial design, trial performed with several measures repeated over time, add-on design, randomised withdrawal design or early-escape design) and more uncommon methods (sequential approaches, meta-analyses, the "N of 1" method and other methods that facilitate decision making or modelling) are then discussed. Subsequently, recommendations are made to ensure that the results obtained are not a matter of chance, and to increase the level of proof.