Correcting for cross-over bias in randomized controlled clinical trials

Abstract

Ideally, therapeutic interventions are evaluated through randomized clinical trials. These trials are commonly analysed with an intent-to-treat (ITT) approach, whereby patients are analyzed in their assigned treatment group regardless of actual treatment received. If an interim analysis of such trials demonstrates compelling evidence of a difference in benefit, ethical considerations often dictate that the trial be unblinded and participants be provided access to the more efficacious agent. Because interim analysis may not address longer-term outcomes of interest, important clinical questions such as overall survival benefit'the ultimate test of efficacy to many'may remain unanswered. The ensuing crossover disturbs randomization and may lead to biased longer-term analysis, compromising the utility of clinical data. In this thesis, I discuss the biases associated with ITT analysis and, alternatively, censoring of follow-up data after selective crossover. Moreover, discussed also is how