Estimation of expectedness: predictive accuracy of standard therapy outcomes in randomized phase 3 studies in...

The anticipated clinical outcome of the standard/control arm is an important parameter in the design of randomized phase 3 (RP3) trials to properly calculate sample size, power, and study duration. Changing patterns of care or variation in the study population enrolled may lead to a deviation from the initially anticipated outcome. The authors hypothesized that recent changes in patterns of care in epithelial ovarian cancer (EOC) have led to challenges in correctly estimating the outcome of control groups.

A systematic review of the literature was conducted for RP3 trials of EOC published between January 2000 and December 2010. The expected outcome of the control arm as well as the actual outcome achieved by this cohort was collected and a ratio (actual-over-expected ratio) was calculated. The estimation of outcome was deemed accurate if the outcome of the control arm was between 0.75 to 1.25 times the anticipated outcome.

A total of 35 trials were eligible for analysis. Fifteen trials had survival as the primary endpoint whereas 20 had a progression-based primary endpoint. In total, 12 of 15 trials with a survival-based endpoint significantly underestimated the outcome of the control arm, whereas only 4 of 20 trials with a progression-based endpoint did. Studies with a survival endpoint underestimated outcome more frequently than those with a progression endpoint (P<.001).

Survival of the control arm has frequently been underestimated in recent EOC RP3 trials. This underestimation means that the initial statistical assumptions of these trials may have been inaccurate. Underestimating the outcome of the control arm may result in trials being underpowered to demonstrate the absolute benefit they were designed to show.