A comparison of the results of intent-to-treat, per-protocol, and g-estimation in the presence of non-random treatment changes in a time-to-event non-inferiority trial.

While intent-to-treat (ITT) analysis is widely accepted for superiority trials, there remains debate about its role in non-inferiority trials. It has often been said that ITT analysis tends to be anti-conservative in demonstrating non-inferiority, suggesting that per-protocol (PP) analysis may be preferable for non-inferiority trials, despite the inherent bias of such analyses. We propose using randomization-based g-estimation analyses that more effectively preserve the integrity of randomization than do the more widely used PP analyses. Simulation studies were conducted to investigate the impacts of different types of treatment changes on the conservatism or anti-conservatism of analyses using the ITT, PP, and g-estimation methods in a time-to-event outcome. The ITT results were anti-conservative for all simulations. Anti-conservativeness increased with the percentage of treatment change and was more pronounced for outcome-dependent treatment changes. PP analysis, in which treatment-switching cases were censored at the time of treatment change, maintained type I error near the nominal level for independent treatment changes, whereas for outcome-dependent cases, PP analysis was either conservative or anti-conservative depending on the mechanism underlying the percentage of treatment changes. G-estimation analysis maintained type I error near the nominal level even for outcome-dependent treatment changes, although information on unmeasured covariates is not used in the analysis. Thus, randomization-based g-estimation analyses should be used to supplement the more conventional ITT and PP analyses, especially for non-inferiority trials.