Quasi-experimental methods for pharmacoepidemiology: difference-in-differences and synthetic control methods with case studies for vaccine evaluation

Difference-in-differences and synthetic control methods have become common study designs for evaluating the effects of policy changes, including health policies. They also have potential for providing real-world effectiveness and safety evidence in pharmacoepidemiology. To effectively add to the toolkit of the field, however, designs—including both their benefits and drawbacks—must be well understood. Quasi-experimental designs provide an opportunity to estimate the average treatment effect on the treated without requiring the measurement of all possible confounding factors, and to assess population-level effects. This requires, however, other key assumptions, including the parallel trends or stable weighting assumptions, a lack of other concurrent events that could alter time trends, and an absence of contamination between exposed and unexposed units. The targeted estimands are also highly specific to the settings of the study, and combining across units or time periods can be challenging. Case studies are presented for three vaccine evaluation studies, showcasing some of these challenges and opportunities in a specific field of pharmacoepidemiology. These methods provide feasible and valuable sources of evidence in various pharmacoepidemiologic settings and can be improved through research to identify and weigh the advantages and disadvantages in those settings.