Challenges in Phase 4 post-licensure safety studies using real world data in the United States: Hepatitis B vaccine example

•Post-licensure vaccine safety studies can identify adverse events that were not detected in pre-licensure trials.•Study design in real-world settings involves many pragmatic and scientific decisions.•We discuss these considerations in design of a post-licensure hepatitis B vaccine safety study.•This example can inform design of other post-licensure vaccine safety studies. Post-licensure vaccine safety studies are essential to identify adverse events that may not have been detected in pre-licensure clinical trials and to address questions that arose during the pre-licensure phase. These studies are increasingly conducted using real-world data collected as part of routine health care delivery. However, design of post-licensure vaccine safety studies involves many pragmatic and scientific decisions, which must be made while balancing diverse stakeholder opinions. Challenges include selecting exposure and comparison groups, deciding on the most appropriate outcome, determining sample size and length of follow-up time, and other analytic considerations. As an example of this process and to inform other post-licensure vaccine safety studies in real-world settings, we discuss our experience with design of an FDA-required Phase 4 post-licensure safety study of a hepatitis B vaccine in a large integrated health care organization in the United States.