Targeted survival improvements in clinical trials: Are you an absolutist or relativist?

The design of a clinical trial is a complex business that requires careful consideration of several factors, with one of the most crucial being the assessment of the targeted improvement in the primary outcome measure, which is also one of the principal determinants of sample size. The article by Castonguay et al in the current issue of Cancer reviews the accuracy with which the median progression-free survival (PFS) and overall survival (OS) in the control arm have been estimated in studies of epithelial ovarian cancer over the past 10 years, and in doing so they have highlighted that the design process is even more challenging than was perhaps believed. Their primary observation is that the median OS in the control arm was underestimated by >25% in 80% of the trials they examined (12 of 15 trials); by way of contrast, the median PFS or time to disease progression (TTP) was underestimated by 25% in 20% of the trials studied (4 of 20 trials). In those studies in which significant underestimation occurred, the authors noted the detrimental impact on the power to detect absolute differences in these endpoints. Conventionally, the overall sample size for a clinical trial with a time-to-event endpoint depends on: