The QTc Prolongation Test Frequently Fails to Provide Clarity Cardiac safety represents a critical concern for drugs in development, yet currently required cardiac safety assessment falls short of providing definitive answers. A new drug’s potential to prolong the heart’s ventricular repolarization process – the brief period between heart beats that has been associated with a rare cardiac arrhythmia known as torsades de pointes (TdP), which can lead to sudden cardiac death.

Current FDA-required arrhythmia safety testing, mandated for all new drugs in development, consists of measuring for possible drug-induced prolongation of a segment called the “QT interval” on electrocardiograms (ECGs) collected from clinical trial subjects. These trials cannot detect a new drug’s propensity to cause TdP directly because this type of arrhythmia occurs rarely – at a rate of less than one per hundred thousand drug exposures. The majority of Thorough QT (TQT) studies conducted today rely exclusively on measuring the QT interval from brief ECG recordings, and because the QT interval changes with heart rate, a mathematical correction factor is applied to produce a so-called QTc (QT-corrected) measure. This surrogate marker has been widely criticized for producing a high rate of over-and under-estimated QT prolongation measurements because it does not properly account for the effects of hysteresis (a non-linear lag in the adaptation of the QT interval in relationship to the heart rate), and autonomic nervous system balance, as well as spatial heterogeneity changes that affect the morphology of the T-wave. (Download Cardiac Safety Evaluation Whitepaper). The over- and under-estimation of QT prolongation frequently leads to adverse labeling, unnecessary termination of a new drug development program or, more alarmingly, to marketed products with higher than expected risk of adverse cardiac events.

Improved Cardiac Safety Assessment from Advanced ECG/Holter-Based Biomarker Analysis iCardiac provides drug developers with a set of tools for more accurate analysis of the effects of drugs on cardiac repolarization. Our solutions span from pre-clinical to phase III clinical trials. Our accurate, quantitative analysis greatly reduces false positives and false negatives and dramatically decreases the number of subjects required for a TQT cardiac safety study.

Dynamic QTbtb method addresses the dynamicity of the QT-RR relationship, enabling the quantification of QT interval changes under varying conditions of heart rate and autonomic tone not possible with the use of standard QT correction formulae.

Thorough QT Plus method identifies the periods of Holter recordings most suitable for measurement of the QT interval based on the index of stability of repolarization process and quality of the ECG recording.

Beyond QT Morphology method provides sophisticated vector-cardiographic analysis of 12-lead ECG data using quantitative markers of T-Wave morphology. These markers offer additional insight into arrhythmia liability (or lack thereof) and improve the precision of QT measurements. They enable researchers to better identify benign QT prolongation as well as compounds with small QT prolongation properties that may be torsadogenic.

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