Evaluation of the Case–Crossover (CCO) Study Design for Adverse Drug Event Detection

Introduction The case–crossover (CCO) design was originally intended to study exposures characterized as intermittent with acute effects. The performance of the CCO design is not well characterized under alternative exposure and outcome relationships. Objective The purpose of this study was to evaluate the ability of the CCO to identify simulated treatment effects under different drug exposures and outcomes relationships while varying the duration of the 1:1 matched risk and control windows. Methods The simulated data were obtained from the Observational Medical Dataset Simulator, version 2 (OSIM2). The area under the receiver operator characteristic curve (AUC) was calculated to compare CCO performance across outcome types, simulated relative risk (RR), and duration of risk and control windows. Results The AUC for acute outcomes was higher for shorter risk and control windows and improved with higher simulated RR. For example, the AUC for the simulated RR of 4 was 0.95 for a 30-day window length and 0.78 for a 360-day window length. The AUC for the accumulative outcomes increased with longer risk and control windows and stronger simulated RR. For example, the AUC for the simulated RR of 4 was 0.85 for a 360-day window length and 0.23 for a 30-day window length. Risk and control window lengths did not appear to sufficiently alter the AUC for insidious onset outcomes. Conclusions The CCO performed best for acute-onset outcomes, but may be useful for exploring adverse outcomes with accumulative effects. Careful consideration must be given to the hypothesized drug exposure and outcome distribution because specification of risk and control window duration affects CCO performance.