Abstract
Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around t max are missed.
Highlights
A designed thorough QT/QTc (TQT) study has been identified by the E14 guideline of the International Conference on Harmonization as a crucial element for clinical assessment of potential cardiac risks of any drug [1]
The rate of false negatives is below 5% for all studies and all sample sizes considered (Figure 1(a)), and studies based on the simulated inactive drug are correctly classified as negative in more than 95% of the case for sample sizes of N ≥ 9
If the method has a substantial risk for a false positive result with respect to QTc prolongation, it becomes unattractive for the sponsor, since, as a minimum, an additional TQT study has to be performed in such a case
Summary
A designed thorough QT/QTc (TQT) study has been identified by the E14 guideline of the International Conference on Harmonization as a crucial element for clinical assessment of potential cardiac risks of any drug [1]. The study is solely designed to demonstrate if a drug-induced effect on the heart rate corrected QT interval beyond an upper bound of 10 ms—“the threshold of regulatory concern” [1] can be excluded. This needs to be demonstrated by showing that for each time point the 2-sided 90% confidence interval for the difference of the mean effect and that under time matched placebo are completely below this threshold. Moxifloxacin is commonly used in this role and the use of this antibacterial fluoroquinolone outside its indication has contributed to a search for alternatives to conventional TQT studies [4]
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