Correcting for non-compliance in randomized non-inferiority trials with active and placebo control using structural models

The three-arm clinical trial design, which includes a test treatment, an active reference, and placebo control, is the gold standard for the assessment of non-inferiority. In the presence of non-compliance, one common concern is that an intent-to-treat (ITT) analysis (which is the standard approach to non-inferiority trials), tends to increase the chances of erroneously concluding non-inferiority, suggesting that the per-protocol (PP) analysis may be preferable for non-inferiority trials despite its inherent bias. The objective of this paper was to develop statistical methodology for dealing with non-compliance in three-arm non-inferiority trials for censored, time-to-event data. Changes in treatment were here considered the only form of non-compliance. An approach using a three-arm rank preserving structural failure time model and G-estimation analysis is here presented. Using simulations, the impact of non-compliance on non-inferiority trials was investigated in detail using ITT, PP analyses, and the present proposed method. Results indicate that the proposed method shows good characteristics, and that neither ITT nor PP analyses can always guarantee the validity of the non-inferiority conclusion. A Statistical Analysis System program for the implementation of the proposed test procedure is available from the authors upon request.