Dr. Nicholas J. Schork (UCSD)

Title: Single Subject or ‘N-OF-1’ Crossover-Based Clinical Trials: Design, Power and Applications

Abstract: “N-of-1,” or single subject, clinical trials are designed to test if an intervention developed for a particular individual is better than an alternative intervention based on the objective and empirical evaluation of the efficacy and side effects profiles of the interventions when administered to that individual. The design of such trials is typically rooted in a simple crossover design with multiple intervention response evaluation periods. The effect of serial correlation between measurements, the number of evaluation periods, the use of washout periods, heteroscedasticity (i.e., unequal variances among responses to the interventions) and carry-over phenomena on the power of such studies is crucially important for putting the yield and feasibility of N-of-1 trial designs into context. We evaluated the effect of these phenomena on the power of different designs for N-of-1 trials using standard likelihood-based theory assuming an autoregressive, lag 1, i.e., AR(1), serial correlation structure between the observations. We show that both the influence of serial correlation and heteroscedasticity on power can be substantial but can be mitigated to some degree through the use of multiple evaluation periods and that the detection of carry-over effects is heavily influenced by design considerations as well. We also suggest that developments in biomarker assays, imaging technologies and wireless health devices can motivate and facilitate N-of-1 trials.