Why, when and how to adjust for multiplicity in clinical trials: a perspective on regulatory activities

The need for multiplicity adjustments in clinical trial is a very controversial issue. The aim of this paper is to provide general recommendations that can help determine whether multiplicity adjustment is necessary. A brief overview of the most commonly encountered multiplicity adjustment methods and of the multiplicity issues that often arise in clinical trial settings (multiple endpoints, subgroups, multiple doses or treatments and interim monitoring) is given. To provide an insight into the Italian context, protocols which have been evaluated by the Ethical Committee of the Policlinico of Padova from January 2009 to May 2010 are reviewed and discussed. The literature suggests that there is no one single method for multiplicity adjustment that is preferred in all instances. Regardless of which approach is used, however, the selected procedure must be specified in the clinical trial protocol and the statistical plan before undertaking any analyses of the data. Multiplicity adjustments are related to the need of the clinical research to fully exploit the information from clinical trials and their usage should be motivated by the effective benefits of exploiting such information at the maximum extent.