Can Bias Evaluation Provide Protection Against False-Negative Results in QT Studies Without a Positive Control Using Exposure-Response Analysis?
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.
Statistik Georg Ferber GmbH, Riehen, Switzerland.
Georg
G
Ferber
iCardiac Technologies, Inc, Rochester, NY, USA.
Meijian
M
Zhou
AstraZeneca R&D Mölndal, Mölndal, Sweden.
Corina
C
Dota
Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Christine
C
Garnett
Clinical Pharmacology & Exploratory Development, Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
James
J
Keirns
St Paul's Cardiac Electrophysiology, University of London, and Imperial College, London, UK.
Marek
M
Malik
Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Norman
N
Stockbridge
iCardiac Technologies, Inc, Rochester, NY, USA.|Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden.
Borje
B
Darpo
D054715:Cardiotoxins / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis* / Q000503:physiopathology
D054715:Cardiotoxins
QT; bias; early phase; exposure response analysis; first-in-human; positive control