Delta Inflation, Optimism Bias, and Uncertainty in Clinical Trials.

The phenomenon of delta inflation, in which design treatment effects tend to exceed observed treatment effects, has been documented in several therapeutic areas. Delta inflation has often been attributed to investigators' optimism bias, or an unwarranted belief in the efficacy of new treatments. In contrast, we argue that delta inflation may be a natural consequence of clinical equipoise, that is, genuine uncertainty about the relative benefits of treatments before a trial is initiated. We review alternative methodologies that can offer more direct evidence about investigators' beliefs, including Bayesian priors and forecasting analysis. The available evidence for optimism bias appears to be mixed, and can be assessed only where uncertainty is expressed explicitly at the trial design stage.