Assessing Non-Consent Bias with Parallel Randomized and Nonrandomized Clinical Trials

Abstract 

In some randomized clinical trials, a large proportion of patients eligible for randomization may withhold consent to be randomized. When the subjects in the randomized trial differ from the eligible population with respect to characteristics that are associated with the magnitude of the treatment effect, there may be non-consent bias, i.e., the treatment effect for those in the randomized trial may not reflect the treatment effect for the eligible population. In response to this problem, some investigators have conducted, in addition to the randomized trial, a separate nonrandomized but otherwise identical trial consisting of those patients who are eligible for randomization, but instead choose their own treatment.

Observed baseline covariate data can be used to adjust for differences between the randomized population and the eligible population when estimating the treatment effect for the eligible population. After adjusting, different outcomes for the randomized versus nonrandomized treated groups and/or the randomized versus nonrandomized control groups reflect the presence of hidden non-consent bias resulting from differences between the trial population and the eligible population with respect to unobserved covariates. A sensitivity analysis can display how hidden non-consent bias can account for an imbalance in the treatment groups with respect to an unobserved covariate. A parallel randomized and nonrandomized trial which compares adenoidectomy versus medical treatment for children with recurrent otitis media [Paradise et al. Efficacy of adenoidectomy for recurrent otitis media in children previously treated with tympanostomy-tube placement. J Am Med Assoc 1990; 263: 2066–2073] is used as an illustration.

Keywords:  Clinical trials, observational studies, generalizability, covariance adjustment, bias, treatment effect, consent for randomization, sensitivity analysis