Winners, losers, and controls

Abstract

Innumerable explanations have been put forth for the failures that have occurred in translating promising preclinical and early-phase treatments in ischemic and hemorrhagic stroke. In their work over the last decade, neurologists Mandava and Kent have promulgated their own unique theory.1,2 In essence, they posit that phase 3 trials that failed were destined to fail because they were based on false-positive phase 2 trials. They believe that false-positive results arise because of (1) the difficulty in achieving randomization balance in baseline factors that influence outcome; (2) the noise generated by errors in subjective outcome measures; and (3) the complex, nonlinear relationships between baseline factors and outcomes that often violate assumptions required for typical statistical methods intended to correct for imbalances and noise. They assert that these factors together have contributed to misleading early-phase results that ultimately led to failed late-phase trials.