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Abstract
The standard intent-to-treat (ITT) approach can lead to erroneous conclusions about treatment efficacy in noninferiority trials with noncompliance. Per-protocol and as-treated analyses are also known to result in biased comparisons of treatment effects. Alternative statistical methods are therefore needed to better address the effects of noncompliance in noninferiority trials. In this paper, we consider the use of the instrumental variables (IV) estimator in a noninferiority trial with a binary outcome and evaluate the performance of this approach in comparison to other conventional analytic methods. Unlike the ITT, per-protocol, and as-treated approaches, the IV method provides an unbiased estimate of the average causal effect of treatment among the subgroup of compliers and maintains the nominal type I error rate, but does increase the sample size requirements of the study as the expected proportion of noncompliers increases. Further development of the IV estimator for more general patterns of noncompliance would be useful and would encourage broader application of this method in noninferiority trials.