Detecting Rare Adverse Events in Postmarketing Studies: Sample Size Considerations

Identifying causal relationships between drugs and rare but serious/irreversible adverse events is an increasingly important issue in postmarketing studies. The observational cohort study is among the most rigorous and appropriate class of designs when it is unfeasible to conduct prospective, randomized clinical trials. A new class of hybrid designs is described in this article; this class uses external data such as established databases or pre-NDA (New Drug Application) data. These designs are intended to achieve the ideal of detecting associations between the drug and rare adverse events and have a moderate sample size requirement to reach safety decisions more quickly. A new sample size formula based on the Poisson distribution is developed for a design in which the incidence of adverse events for subjects treated with the compound is compared to an external control cohort not receiving the compound under study. The results provide direct evidence for a reduction in sample size with the incorporation of external controls.