Observation of Time-Dependent Adverse Events and the Influence of Drop-Out Thereon in Long-Term Safety Studies—Simulation Study Under the Current Practice of Post-marketing Safety Evaluation in Japan

Abstract

Safety assessment of a new drug should be continuously carried out in the premarketing phase as well as in the postmarketing phase. Considering the actual conditions and problems of postmarketing safety studies in Japan, i.e., the lack of attention to the extent of patients’ exposure to the drug (duration and the number of patients), we simulated the number of adverse events to be observed after specified intervals of exposure. This was done by applying different sets of hazard functions for a Weibull distribution under the circumstances that a certain number of patients has dropped out, focusing on rare and delayed adverse events associated with chronically used drugs. By using the result of these simulations, we point out potential problems of underestimating adverse event rates in situations where the hazard rate of the event escalates over time. Patients drop-out from the study also deteriorates the ability to observe such time-dependent adverse events. The simulation can also serve as a useful tool to examine the necessary sample size and the duration of exposure in order to observe and characterize potentially expected adverse events. It is important to take the two key factors into consideration: the change of hazard function over time and the effect of drop-out in designing, analyzing, and evaluating safety studies for new drugs.

Key Words:

• Delayed adverse events
• Long-term safety study
• Simulation of adverse event patterns
• Drop-out
• Weibull model

Acknowledgments

The authors express their gratitude to Dr. Robert T. O’Neill for his advice and encouragement. We also thank the editor and two referees for their valuable comments. The views and opinions expressed in this paper are not those of the Ministry of Health, Labour and Welfare.