All Times EDT
Keywords: Personalized medicine, Pragmatic Trial, Multiple Testing Procedure, Sample size, SMART trial, Strategy Comparison
Patient management is dynamic, a sequence of decisions with therapeutic adjustments made over time. Adjustments are personalized, tailored to individuals as new information becomes available. Strategies allowing for such adjustments are infrequently studied.
Two major treatment decisions occur during the treatment of serious bacterial infections: empiric and definitive therapies. Empiric therapy selection is based on immediately available and often limited information upon recognition of the clinical syndrome. Definitive therapy is selected once organism identification and antibiotic susceptibility testing (AST) results are known, frequently 48-72 hours later. COMparing Personalized Antibiotic StrategieS (COMPASS) is a trial design that compares strategies consistent with clinical practice, decision-rules that guide empiric and definitive therapy decisions. Sequential multiple assignment randomized (SMART) COMPASS allows evaluation when there are multiple definitive therapy options. SMART COMPASS is pragmatic, mirroring clinical treatment decision-making, and addresses the most relevant issue for treating patients: identification of the strategy that optimizes ultimate patient outcomes.
Several statistical challenges arise with SMART COMPASS trials including how to: estimate effects and standard errors, control trial-wise error, and calculate sample size and power. Weighting of patients is required to obtain appropriate estimates of effects and associated standard errors. Multiple testing methods must be applied to control error rates as sequential randomization implies at least three strategies. Estimates of the proportions of patients that will be re-randomized at the definitive treatment stage are required for sample size calculations.
Multiple testing procedures for identification of the best strategy are evaluated and guidance on procedure selection is provided. Approaches for the calculation of the sample size are discussed.