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Abstract

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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Measurement error in the timing of events: effect on survival analyses in randomized clinical trials

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