BACKGROUND: Presence of measurement error in the outcome can complicate the interpretation of a randomized clinical trial. The Oncologic Drugs Advisory Committee of the US Food and Drug Administration voted against recommending approval of bevacizumab for the initial treatment of metastatic breast cancer; one of their major concerns was the presence of a large amount of nondifferential measurement error in the evaluation of progression-free survival, the primary outcome of the randomized clinical trial E2100. PURPOSE: To investigate the effects of nondifferential measurement error in time-to-event outcomes on the conclusions of a proportional hazards analysis of a randomized clinical trial. METHODS: Simulations were performed showing effects of measurement error on the estimated treatment effect (hazard ratio) in a clinical trial. In some simulations, the measurement error structure from E2100 data was approximated; for other simulations, larger or smaller measurement error was considered. RESULTS: The bias in estimating the hazard ratio was very small using measurement error and a hazard ratio similar to E2100. Even with a larger nondifferential measurement error, the bias remained small when the hazard ratio was in a range commonly seen in clinical trials. There was no or little effect on the variability of the estimated treatment effect. LIMITATIONS: Because of censoring issues, retrospective evaluation of the measurement error structure from a completed trial is difficult. Although our simulations cover a range of plausible measurement error values, in theory, a trial could have much larger measurement error than we considered. Differential measurement error is only briefly considered. CONCLUSIONS: Nondifferential measurement error due to variability in estimating time-to-event outcomes will typically not be a major concern in randomized clinical trials.
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Korn et al. (2010) studied this question.