A New Source of Heterogeneity in Comparative and Translational Clinical Trials: The “Border-Time” Bias

SIMPLE SUMMARY: Target-oriented drugs are profoundly changing the anti-cancer treatments. Progression-free survival is a primary or co-primary endpoint in the large part of comparative and translational clinical trials about target-oriented anti-cancer agents. In this context, the time before treatment start and the reassessment of disease (“border-time” bias) are an underestimated source of heterogeneity with unpredictable and uncontrollable impact on final evaluation of progression-free survival. ABSTRACT: The use of target-oriented drugs is profoundly changing the anti-cancer treatments. This new and expanding therapeutic context relies on the translation of biomarkers expression (laboratory testing) into clinical practice (treatment). Progression-free survival is a primary or co-primary endpoint in the large part of comparative clinical trials about biologic anti-cancer agents. Here, we describe the “border time” bias represented by specific time points and intervals that are an underestimated source of methodologic heterogeneity and can contribute to wrong evaluation of time-to-outcome. These issues are concentrated at the beginning (head: pre-screening and screening activities) and at the end (tail: modalities of disease reassessment) of the anti-cancer treatment and can represent a time-related bias. Reporting, and ideally shortening, the time spent in pre-screening and screening activities with synthetic and innovative methodological tools as well as more harmonized rules about timing of disease reassessment can contribute to reduce, or even prevent, this bias in clinical studies.