Häckl Sebastian, Koch Armin, Lasch Florian
Hannover Medical School, Institute of Biostatistics, Hannover, Niedersachsen, Germany.
European Medicines Agency, Amsterdam, Noord-Holland, The Netherlands.
Pharm Stat. 2023 Nov-Dec;22(6):1046-1061. doi: 10.1002/pst.2328. Epub 2023 Jul 30.
Pre-specification of the primary analysis model is a pre-requisite to control the family-wise type-I-error rate (T1E) at the intended level in confirmatory clinical trials. However, mixed models for repeated measures (MMRM) have been shown to be poorly specified in study protocols. The magnitude of a resulting T1E rate inflation is still unknown. This investigation aims to quantify the magnitude of the T1E rate inflation depending on the type and number of unspecified model items as well as different trial characteristics. We simulated a randomized, double-blind, parallel group, phase III clinical trial under the assumption that there is no treatment effect at any time point. The simulated data was analysed using different clusters, each including several MMRMs that are compatible with the imprecise pre-specification of the MMRM. T1E rates for each cluster were estimated. A significant T1E rate inflation could be shown for ambiguous model specifications with a maximum T1E rate of 7.6% [7.1%; 8.1%]. The results show that the magnitude of the T1E rate inflation depends on the type and number of unspecified model items as well as the sample size and allocation ratio. The imprecise specification of nuisance parameters may not lead to a significant T1E rate inflation. However, the results of this simulation study rather underestimate the true T1E rate inflation. In conclusion, imprecise MMRM specifications may lead to a substantial inflation of the T1E rate and can damage the ability to generate confirmatory evidence in pivotal clinical trials.
在确证性临床试验中，预先设定主要分析模型是将家族性I型错误率（T1E）控制在预期水平的前提条件。然而，重复测量混合模型（MMRM）在研究方案中的设定往往不够精确。由此导致的T1E率膨胀程度仍不明确。本研究旨在根据未明确的模型项目类型和数量以及不同的试验特征，量化T1E率膨胀的程度。我们模拟了一项随机、双盲、平行组III期临床试验，假设在任何时间点都不存在治疗效果。使用不同的聚类对模拟数据进行分析，每个聚类包含几个与MMRM不精确预先设定兼容的MMRM。估计每个聚类的T1E率。对于不明确的模型设定，可显示出显著的T1E率膨胀，最大T1E率为7.6%[7.1%；8.1%]。结果表明，T1E率膨胀的程度取决于未明确的模型项目类型和数量以及样本量和分配比例。干扰参数的不精确设定可能不会导致显著的T1E率膨胀。然而，本模拟研究的结果相当低估了真实的T1E率膨胀。总之，MMRM设定不精确可能导致T1E率大幅膨胀，并可能损害在关键临床试验中产生确证性证据的能力。
