Can Bias Evaluation Provide Protection Against False‐Negative Results in QT Studies Without a Positive Control Using Exposure‐Response Analysis?. (7th July 2016)

• Record Type: Journal Article
• Authors: Ferber, Georg; Zhou, Meijian; Dota, Corina; Garnett, Christine; Keirns, James; Malik, Marek; Stockbridge, Norman; Darpo, Borje
• Is Part Of: Journal of clinical pharmacology. Volume 57:Number 1(2017)
• Page Start: 85
• Page End: 95
• Publication Date: 2016-07-07
• Subjects: QT -- exposure response analysis -- early phase -- first‐in‐human -- positive control -- bias; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.779
• Languages: English
• ISSNs: 0091-2700

Abstract

Abstract: The revised ICH E14 document allows the use of exposure‐response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant levels is achieved, a positive control is not required. In cases when 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 electrocardiogram 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 electrocardiogram algorithm (COMPAS). The slope estimate of the Bland‐Altman plot was used as a bias metric. With the deterministic bias methods, negative bias, measured between electrocardiogram laboratory values and COMPAS, had to be larger than approximately −20 milliseconds over a QTcF range of 100 milliseconds 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 ≤5% with bias severity < –10 milliseconds for all 5 drugs when plasma levels exceeded those of interest. Severe and therefore detectable bias has to be introduced into reported QTc values to cause false‐negative predictions with exposure‐response analysis.