  The analysis of adverse events (AEs) is a key component in the assessment of
a drug's safety profile. Inappropriate analysis methods may result in
misleading conclusions about a therapy's safety and consequently its
benefit-risk ratio. The statistical analysis of AEs is complicated by the fact
that the follow-up times can vary between the patients included in a clinical
trial. This paper takes as its focus the analysis of AE data in the presence of
varying follow-up times within the benefit assessment of therapeutic
interventions. Instead of approaching this issue directly and solely from an
analysis point of view, we first discuss what should be estimated in the
context of safety data, leading to the concept of estimands. Although the
current discussion on estimands is mainly related to efficacy evaluation, the
concept is applicable to safety endpoints as well. Within the framework of
estimands, we present statistical methods for analysing AEs with the focus
being on the time to the occurrence of the first AE of a specific type. We give
recommendations which estimators should be used for the estimands described.
Furthermore, we state practical implications of the analysis of AEs in clinical
trials and give an overview of examples across different indications. We also
provide a review of current practices of health technology assessment (HTA)
agencies with respect to the evaluation of safety data. Finally, we describe
problems with meta-analyses of AE data and sketch possible solutions.
