Design of clinical trials with failure-time endpoints and interim analyses: an update after fifteen years

Time to event is the clinically definitive endpoint in Phase III trials of new treatments of cancer, cardiovascular and many other diseases. Because these trials involve relatively long follow-up, their protocols usually incorporate periodic interim analyses of the data by a Data and Safety Monitoring Board/Committee. This paper gives a review of the major developments in the design of these trials in the 21st century, spurred by the need for better clinical trial designs to cope with the remarkable advances in cancer biology, genomics and imaging that can help predict patients’ sensitivity or resistance to certain treatments. In addition to this overview and discussion of related issues and challenges, we also introduce a new approach to address some of these issues.

Keywords: Adaptive design, Calendar time, Early stopping, Multiple endpoints, Nonproportional hazards, Survival analysis