The National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
The National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia; Janssen-Cilag Pty. Limited, Australia.
Contemp Clin Trials. 2021 Nov;110:106544. doi: 10.1016/j.cct.2021.106544. Epub 2021 Aug 26.
Clinical trialists may regard an observed imbalance on a prognostic covariate as sufficiently troubling to warrant action.
To elucidate the issues associated with selecting, and switching between, an unadjusted versus an adjusted analysis in response to an observed covariate imbalance.
Simulation study performed under the null hypothesis of no treatment effect using data from a large secondary prevention trial of statin therapy. The operating characteristics of three reaction strategies to baseline imbalances observed post-hoc were assessed.
Unadjusted analyses produced valid p-values irrespective of chance imbalance on a prognostic covariate. Switching to an adjusted analysis introduced no bias when the decision was made without knowledge of the direction of the imbalance. When the decision was based on the direction of the imbalance, the risk of incorrectly declaring the experimental treatment superior was inflated (by up to 48% in the scenarios investigated).
Overreaction to baseline imbalances observed post-hoc is unwarranted and we support adherence to the ICH guideline recommendations on the use of covariates. A legitimate case for switching to an adjusted analysis prior to finalisation of the statistical analysis plan (SAP) could nevertheless be potentially made provided that the direction of an observed covariate imbalance is unknown. Investigators should avoid reviewing the distribution of baseline characteristics across randomised groups in an unblinded fashion, for open-label and blinded studies alike, prior to finalisation of the SAP.
ICH guidelines on adjustment for covariates in RCT analyses appropriately advise against overreaction to baseline imbalances observed post-hoc. CONSORT reporting guidelines nevertheless place an emphasis on comparability of baseline characteristics across randomised groups. We demonstrate through a series of simulation studies why the ICH guidance is sound, but that a switch to an adjusted analysis in reaction to an observed prognostic covariate imbalance could legitimately be made provided that, when reaching the decision, treatment allocation is masked, and the direction of the imbalance is unknown. Trialists should therefore consider preserving the masking of actual treatment assignment when assessing the distribution of baseline characteristics across randomised groups.
临床研究者可能会认为观察到的预后协变量不平衡足以引起关注并采取行动。
阐明在观察到协变量不平衡时，选择和切换未调整分析与调整分析之间的相关问题。
在他汀类药物二级预防试验数据的基础上，在无治疗效果的假设下进行模拟研究。评估了三种对事后观察到的基线不平衡的反应策略的操作特征。
无论预后协变量是否存在偶然不平衡，未调整分析均产生有效 p 值。当决策是在不了解不平衡方向的情况下做出时，切换到调整分析不会引入偏差。当决策基于不平衡方向时，错误地宣布实验治疗效果更好的风险会增加（在所研究的情况下最多增加 48%）。
过度反应事后观察到的基线不平衡是没有道理的，我们支持遵守 ICH 关于使用协变量的指南建议。在最终确定统计分析计划（SAP）之前，有可能出于正当理由切换到调整分析，但前提是未知观察到的协变量不平衡的方向。对于开放性和盲法研究，调查人员都应避免在最终确定 SAP 之前以非盲法方式审查随机分组之间的基线特征分布。
ICH 指南中关于 RCT 分析中协变量调整的建议适当反对过度反应事后观察到的基线不平衡。尽管 CONSORT 报告指南强调了随机分组之间基线特征的可比性。我们通过一系列模拟研究证明了为什么 ICH 指导是合理的，但如果在观察到预后协变量不平衡时切换到调整分析，只要在做出决策时，治疗分配是盲法的，并且不平衡的方向是未知的，那么这种做法是合理的。因此，在评估随机分组之间的基线特征分布时，试验者应考虑保留实际治疗分配的盲法。
