Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

Abstract

Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a 'thorough QT/QTc' (TQT) study to detect drug-induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK-PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug-induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug-induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult.

Effect of Therapeutic and Supratherapeutic Doses of Vonoprazan on the QT/QTc Interval in a Phase I Randomized Study in Healthy Subjects

“…Placebo‐control and positive‐control (moxifloxacin) groups were included to meet ICH E14 requirements and to demonstrate assay sensitivity 6. A dose of 40 mg was selected as the therapeutic dose for this study because in a previous phase II study,10 40 mg was the maximum dose used and doses ≥20 mg were expected to be used for different indications.…”

“…Cardiac safety studies have been an integral part of the development of investigational drugs, identifying drugs with potential cardiovascular liability as well as providing opportunities for safer drug administration regimens 6. QT prolongation is associated with cardiac arrhythmias, and may lead to torsades de pointes , which can be fatal 7.…”

Comparison of the spatial QRS-T angle derived from digital ECGs recorded using conventional electrode placement with that derived from Mason-Likar electrode position

“…QT prolongation due to delayed repolarization due to inherited or acquired conditions is the most well-known example of this. 1 Similarly, transmural repolarization heterogeneity resulting in morphological variants of early repolarization has recently been identified as a risk factor for malignant ventricular arrhythmias. 2 Other repolarization abnormalities linked to life-threatening ventricular arrhythmias include microvolt T wave alternans or presence of a wide, notched T wave.…”

Congenital short QT syndrome: Landmarks of the newest arrhythmogenic cardiac channelopathy

“…Rate-dependence of the QT interval was recognized 93 years ago by Henry Cuthbert Bazett [20], calculating the heart rate--corrected QT interval QT B. This nonlinear formula, obtained from data in only 39 young men, is not Andrés Ricardo Pérez-Riera et al, Landmarks of the newest arrhythmogenic cardiac channelopathy accurate and overcorrects at high heart rates and undercorrects at low heart rates [21]. Additionally, in congenital SQTS the QT interval is not affected by the heart rate [20]; in other words, in this channelopathy a discrete QT interval reduction is observed with increases in heart rate.…”