Activity Number:
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238
- SPEED: Biopharmaceutical Applications: Trials, Biomarkers, and Enpoint Validation
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Type:
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Contributed
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Date/Time:
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Monday, July 30, 2018 : 2:00 PM to 3:50 PM
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Sponsor:
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Biopharmaceutical Section
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Abstract #329136
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Title:
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Pre-Specified Bias Evaluation of ECG Measurements for Assay Sensitivity Assessment
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Author(s):
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Xiaoli Hou* and Nancy Kim and Wei Gao and Leticia Arrington and Kajal Larson
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Companies:
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Merck and Merck and Merck and Merck and Merck
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Keywords:
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Concentration-response model;
ECG measurement;
Thorough QT (TQT);
QTc;
Positive control
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Abstract:
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During the recent development of a new molecular entity, the originally proposed clinically efficacious dose was increased to a higher dose to obtain potentially greater efficacy for this compound. Prior to this update, a dedicated thorough QT (TQT) trial had already demonstrated lack of QTc prolongation at a supratherapeutic dose achieving ~4 fold exposure to the original dose. Subsequently, a drug-drug interaction (DDI) study using the higher clinical dose was being planned, which was expected to provide a ~2-fold exposure margin to the higher proposed clinical dose and an opportunity to collect rich ECG data at higher exposures to augment the information across the program. Could an exposure-response analysis using the combination of the existing TQT data and the new QT data collected from this DDI study provide sufficient information to derisk QTc prolongation? Without a positive control for assay sensitivity, is it possible to increase confidence in the QT data collected from this DDI study? Will the regulatory agency accept this modeling approach without requiring a further dedicated TQT study? This talk will discuss these questions through a real life project.
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Authors who are presenting talks have a * after their name.