Use of composite outcomes to assess risk-benefit in clinical trials

Before a novel treatment can be deemed a clinical success, an assessment of its risk-benefit profile must be made. One of the inherent challenges for this assessment comes from the multiplicity that arises from comparing treatment groups across multiple outcomes. Composite outcomes that summarize a patient's clinical status, or severity, across a prioritized list of safety and efficacy outcomes have become increasing popular. In this article, we review these approaches and illustrate through examples some of the challenges and complexities of a composite derived from prioritized outcomes, such as the win ratio. These challenges include the difficult tension between the analytical validity that comes from choosing a pre-specified outcome and an evaluation that is responsive to unexpected safety events that arise during the course of a trial. Other challenges include a sensitivity of the resulting test statistic to the underlying censoring distribution and other nuisance parameters. Approaches that resolve some of the difficulties of the analytical challenges associated with prioritized outcomes are then discussed. Ultimately, a composite outcome of net clinical benefit is another decision tool, but one to be used alongside more traditional analyses of efficacy and safety, and with the broader perspective that investigators, the data safety monitoring board, and regulators bring to an evaluation of risk-benefit.