TABLE 3-1 Strengths and Weaknesses of the QTc Interval as a Safety Biomarker

Area

Strengths

Weaknesses

Biology

  • Knowledge of molecular mechanisms and ion channels

  • Cellular models

  • In vivo models

  • Weak links between experimental models and clinical events

Clinical experience and relevance

  • Genetic syndromes (LQT), documented clinical events

  • Rare clinical events, multifactorial etiologies, unpredictability

  • Insufficient data available to close gap between signal and rare events

Measurable biomarker

  • Old technology, universally available

  • Low-frequency and low-amplitude signal, resulting in difficult measurement and poor signal-to-noise ratio

  • Numerous methods of measurement

  • Measured in static condition

Multisector involvement

  • Interest from academia, clinical medicine, industry (technology, diagnostics, pharma), regulatory agencies

  • Lack of harmonization among stakeholders

  • Lack of infrastructure for a coordinated collaborative effort (now addressed by Cardiac Safety Research Consortium)

QT (LQT) syndrome; and a wide array of stakeholders are interested in advancing the understanding and use of this biomarker.

Despite these strengths, however, QTc also has several weaknesses as a biomarker for safety. First, there is no consensus on the optimal method of acquiring, measuring, and analyzing the QTc interval. This is due in part to the nature of the signal, which has low frequency and low amplitude, has a poor signal-to-noise ratio, is intrinsically variable, and is affected by a number of important confounding factors. Second, the link between the experimental models of QTc and the occurrence of rare and unpredictable clinical events is weak, in part because insufficient data have been collected to close this gap. Specifically, clinical epidemiology data have not been collected that would define the probability of an episode of the ventricular tachycardia known as torsade de pointes based on the QTc interval.

It should be noted that, while many biomarkers are used to understand a wide range of cardiovascular conditions—such as hyperlipidemia, inflammation, and ischemia—the scope of the discussion in this session of the workshop was limited to biomarkers of electrophysiologic toxicity, in particular, those related to QT interval prolongation.



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