Scientific Publications by FDA Staff

J Clin Pharmacol 2017 Jan;57(1):85-95

Can bias evaluation provide protection against false negative results in QT studies without a positive control using exposure response analysis?

Ferber G, Zhou M, Dota C, Garnett C, Keirns J, Malik M, Stockbridge N, Darpo B

The revised ICH E14 document allows the use of exposure-response analysis to exclude a small QT effect of a drug. If plasma levels exceeding clinically relevant are achieved, a positive control is not required. In cases where this cannot be achieved, there may be a need for metrics to protect against false negative results. The objectives of this study were to create bias in ECG laboratory QT interval measurements and define a metric that can be used to detect bias severe enough to cause false negative results using exposure-response analysis. Data from the IQ-CSRC study, which evaluated the QT effect of 5 QT prolonging drugs, were used. Negative bias using 3 deterministic and 2 random methods was introduced into the reported QTc values and compared with fully automated data from the underlying ECG algorithm (COMPAS). The slope estimate of the Bland-Altman plot was used as bias metric. With the deterministic bias methods, negative bias, measured between ECG laboratory values and COMPAS had to be larger than approximately -20 ms over a QTcF range of 100 ms to cause failures to predict the QT effect of ondansetron, quinine, dolasetron, moxifloxacin and dofetilide. With the random methods, the rate of false negatives was