Impact of informative censoring on the Kaplan-Meier estimate of progression-free survival in phase II clinical trials.

Informative censoring in a progression-free survival (PFS) analysis arises when patients are censored for initiation of an effective anticancer treatment before the protocol-defined progression, and these patients are at a different risk for treatment failure than those who continue on therapy. This may cause bias in the estimated PFS when using the Kaplan-Meier method for analysis. Although there are several articles that discuss this issue from a theoretical perspective or in randomized phase III studies, there are little data to demonstrate the magnitude of the bias on the estimated quantities from a phase II trial. This article describes the issues by using two oncology phase II trials as examples, evaluates the impact of the bias using simulations, and provides recommendations. The two trials were selected because they demonstrate two different reasons for censoring. Simulations show that the magnitude of the bias depends primarily on the proportion of patients who are informatively censored and secondarily on the hazard ratio between the group of patients who remain on study and the group of patients who are informatively censored. Recommendations include using an alternative end point, which includes inadequate response and initial signs of clinical progression as treatment failure, and a competing risk analysis for studies in which competing events preclude or modify the probability of observing the primary event of interest. If informative censoring cannot be avoided, then all patients should be observed until progression, and sensitivity analyses should be used as appropriate.