Fooled by Randomness. The Misleading Effect of Treatment Crossover in Randomized Trials of Therapies with Marginal Treatment Benefit

Abstract

Crossover can bias clinical outcomes of randomized clinical trials by increasing the risk of both type I (false positive) and type II (false negative) errors. To show how crossover can increase type I error, we provide computer simulation and review herein illustrative examples (iniparib, olaratumab) of recently reported RCTs that demonstrated false-positive treatment efficacy signals due to crossover. The ethical issues associated with crossover are also discussed.

Keywords:

• Crossover
• bias
• randomized clinical trials

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.