Hutmacher Matthew M, Chapel Sunny, Agin Marilyn A, Fleishaker Joseph C, Lalonde Richard L
Pfizer Inc., Ann Arbor, Michigan, USA.
J Clin Pharmacol. 2008 Feb;48(2):215-24. doi: 10.1177/0091270007311921.
The International Conference on Harmonization (ICH) guidance for clinical evaluation of QT prolongation (E14) affected drug development by advocating that a thorough QT study (TQT) be conducted during development to assess the QT prolongation liability of a compound. The ICH E14 Statistics Group shortly thereafter recommended that a noninferiority intersection-union test (IUT) be used to exclude a clinically worrisome QT prolongation. Recent analyses have indicated that the IUT might be overly conservative with respect to excluding QT prolongation. This report assesses the IUT false positive rate for 4 recently conducted TQT trials using simple simulation experiments. Positive TQT study rates ranged from negligible to nearly 60% depending on study design, sample size, and patient status, despite no drug effect. Addition of clinically nonmeaningful QT prolongations (up to 5 milliseconds) increased the positive study rate to 80% for 1 particular study design. Ultimately, these results reveal significant limitations of the IUT with respect to excluding an effect and study interpretation for certain trial designs.
国际协调会议（ICH）关于QT间期延长临床评估的指导原则（E14）对药物研发产生了影响，该原则主张在研发过程中进行全面的QT研究（TQT），以评估化合物导致QT间期延长的可能性。此后不久，ICH E14统计小组建议使用非劣效性交叉并集检验（IUT）来排除临床上令人担忧的QT间期延长。最近的分析表明，在排除QT间期延长方面，IUT可能过于保守。本报告通过简单的模拟实验评估了4项近期进行的TQT试验的IUT假阳性率。尽管没有药物效应，但根据研究设计、样本量和患者状态，TQT研究阳性率从可忽略不计到近60%不等。对于1种特定的研究设计，添加临床上无意义的QT间期延长（长达5毫秒）可使阳性研究率提高到80%。最终，这些结果揭示了IUT在排除某些试验设计的效应和研究解读方面存在重大局限性。
