Biometric Research Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Clin Trials. 2010 Dec;7(6):626-33. doi: 10.1177/1740774510382801. Epub 2010 Sep 6.
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.
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.
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.
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.
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.
Nondifferential measurement error due to variability in estimating time-to-event outcomes will typically not be a major concern in randomized clinical trials.
在结局中存在测量误差会使随机临床试验的解释复杂化。美国食品和药物管理局肿瘤药物咨询委员会投票反对推荐贝伐单抗用于转移性乳腺癌的初始治疗；他们主要关注的问题之一是在评估无进展生存期（随机临床试验 E2100 的主要结局）时存在大量非差异性测量误差。
研究在事件时间结局中存在非差异性测量误差对随机临床试验比例风险分析结论的影响。
进行模拟研究，以展示测量误差对临床试验中估计治疗效果（风险比）的影响。在一些模拟中，近似了 E2100 数据中的测量误差结构；在其他模拟中，考虑了更大或更小的测量误差。
使用测量误差和与 E2100 相似的风险比，估计风险比的偏差非常小。即使存在更大的非差异性测量误差，当风险比处于临床试验中常见的范围内时，偏差仍然很小。对估计治疗效果的变异性几乎没有影响。
由于删失问题，对已完成试验的测量误差结构进行回顾性评估很困难。虽然我们的模拟涵盖了一系列合理的测量误差值，但理论上，试验可能存在比我们考虑的更大的测量误差。仅简要考虑了差异性测量误差。
由于估计事件时间结局的变异性而导致的非差异性测量误差通常不会成为随机临床试验中的主要关注点。
