Huang Dalong Patrick, Chen Janell, Dang Qianyu, Tsong Yi
a Office of Biostatistics, Office of Translational Sciences, CDER, FDA.
J Biopharm Stat. 2019;29(2):378-384. doi: 10.1080/10543406.2018.1535498. Epub 2018 Oct 22.
A concurrent positive control should be included in a thorough QTc clinical trial to validate the study according to ICH E14 guidance. Some pharmaceutical companies have started to use "hybrid TQT" study to meet ICH E14 regulatory requirements since the release of ICH E14 Q&A (R3). The "hybrid TQT" study includes the same treatment arms (therapeutic and/or supratherapeutic dose of investigational drug, placebo, and positive control) with sample size less than traditional TQT studies, but use concentration-QTc (C-QTc) analysis as primary analysis and assay sensitivity analysis. To better understand the statistical characteristics of assay sensitivity with a commonly used positive control - Moxifloxacin - in "hybrid TQT" studies, we examined the original and subsampled moxifloxacin and placebo data from more than a hundred of TQT studies submitted to FDA. The assay sensitivity results are quite consistent between classical E14 analysis and C-QTc analysis using the original datasets. Performance of assay sensitivity in "hybrid TQT" studies using subsampled data depends on number of moxifloxacin subjects, study design (crossover design and parallel design), and C-QTc model. The results presented here can aid the design of future "hybrid TQT" studies.
根据国际人用药品注册技术协调会（ICH）E14指南，在全面的QTc临床试验中应纳入一个同步阳性对照以验证研究。自ICH E14问答（R3）发布以来，一些制药公司已开始采用“混合TQT”研究来满足ICH E14的监管要求。“混合TQT”研究包括相同的治疗组（试验药物的治疗剂量和/或超治疗剂量、安慰剂和阳性对照），样本量小于传统TQT研究，但使用浓度-QTc（C-QTc）分析作为主要分析和分析灵敏度分析。为了更好地了解在“混合TQT”研究中使用常用阳性对照——莫西沙星时分析灵敏度的统计特征，我们检查了提交给美国食品药品监督管理局（FDA）的一百多项TQT研究中的原始和二次抽样的莫西沙星及安慰剂数据。使用原始数据集时，经典E14分析和C-QTc分析之间的分析灵敏度结果相当一致。在使用二次抽样数据的“混合TQT”研究中，分析灵敏度的表现取决于莫西沙星受试者数量、研究设计（交叉设计和平行设计）以及C-QTc模型。此处给出的结果有助于未来“混合TQT”研究的设计。
