Koji Oba

Background The net benefit is an effect measure for any type of endpoint, including the time-to-event outcome, and can provide intuitive and clinically meaningful interpretation. It is defined as the probability of a randomly selected subject from the experimental arm surviving by at least a clinically relevant time longer than a randomly selected subject from the control arm. In oncology clinical trials, an intercurrent event such as treatment switching is common, which potentially causes informative censoring; nevertheless, conventional methods for the net benefit are not able to deal with it. In this study, we proposed a new estimator using the inverse probability of censoring weighting (IPCW) method and illustrated an oncology clinical trial with treatment switching (the SHIVA study) to apply the proposed method under the estimand framework. Methods The net benefit can be estimated using the survival functions of each treatment group. The proposed estimator was based on the survival functions estimated by the inverse probability of the censoring weighting method that can handle covariate-dependent censoring. The simulation study was undertaken to evaluate the operating characteristics of the proposed estimator under several scenarios; we varied the shapes of the survival curves, treatment effect, covariates effect on censoring, proportion of the censoring, threshold of the net benefit, and sample size. We also applied conventional methods (the scoring rules by Péron or Gehan) and the proposed method to the SHIVA study. Results Our simulation study showed that the proposed estimator provided less biased results under the covariate-dependent censoring than existing estimators. When applying the proposed method to the SHIVA study, we were able to estimate the net benefit by incorporating the information of the covariates with different estimand strategies to address the intercurrent event of the treatment switching. However, the estimates of the proposed method and those of the aforementioned conventional methods were similar under the hypothetical strategy. Conclusions We proposed a new estimator of the net benefit that can include covariates to account for the possibly informative censoring. We also provided an illustrative analysis of the proposed method for the oncology clinical trial with treatment switching using the estimand framework. Our proposed new estimator is suitable for handling the intercurrent events that can potentially cause covariate-dependent censoring.