On Analysis of Low Incidence Adverse Events in Clinical Trials

In drug or vaccine development, some adverse events (AEs) of interest may occur infrequently. Because of their clinical importance, those AEs may be studied in a clinical trial with large sample size, long-term follow-up, or in meta-analysis of combined data from multiple trials. The conventional summary and analysis methods based on frequency of first occurrence and comparing the proportion difference between treatment groups may not be the best approach because (1) the drug exposure information is not considered in the frequency summary and analysis and (2) any recurrence of an event in the long-term follow-up is not accounted for. When recurrence events are considered, issues on the analysis such as intra-subject correlation among the recurrence events, over-dispersion, and zero inflation may need to be considered. In this paper, we review several approaches for summary and analysis of safety data in these settings. Considerations are given on the assumptions of the risk function, adjustment for differential follow-up, and handling of over-dispersion and excessive zero for low incidence events. Applications to drug and vaccine clinical trials will be used for demonstration.