A major challenge faced by the pharmaceutical industry in the development of new noncardiovascular drugs is evaluating the
potential risk for life-threatening ventricular arrhythmias—in particular, Torsade de Pointes (TdP). In the past two decades,
several noncardiovascular drugs, after a long and expensive approval process, were found to induce TdP, resulting in their
withdrawal from the market and profound negative financial consequences to sponsors.
A potentially "torsadogenic" drug may initially appear safe when administered to large numbers of patients in a trial if patients
at risk, by chance or by design, are excluded from the study population. The proarrhythmic risk may only become manifest after
approval, when administered to individuals who have a latent genetic risk or an acquired predisposition due to underlying
heart disease, electrolyte abnormalities or concurrent medications adversely affecting the drug's metabolism. On the other
hand, a potentially useful and safe drug may be inappropriately withdrawn during early drug testing because of the erroneous
impression that the ECG data indicates a potential proarrhythmic risk.
The many issues concerning drug safety are extremely complex, and the costs of evaluating new drugs are staggering (over $800
million per drug). This article will consider current methodologies for evaluating the risk of new noncardiovascular drugs
for TdP and other life-threatening arrhythmias. Limitations in current guidelines will be considered, and recommendations
for further study will be reviewed.
TdP under the microscopeTorsade de Pointes is an unusual but eye-catching and life-threatening polymorphic ventricular tachycardia that has its origin
in patients with the hereditary or acquired long QT syndrome (LQTS).1 The onset of TdP is often precipitated by one or more premature ventricular complexes occurring during the prolonged repolarization
phase of the preceding beat. Typically, the arrhythmia is short lived, but it can unexpectedly degenerate into ventricular
fibrillation leading to syncope and sudden death.
Figure 1. Onset of Torsade de Pointes in patient with LQTS.
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The characteristic QRS morphology during TdP involves recurring cycles of gradually changing QRS direction around the ECG
baseline (see Figure 1). While the mechanism of the arrhythmia is not well understood, it is clear that abnormal dispersion
of ventricular repolarization plays an important role in its initiation. Currently, the electrocardiogram is the basic tool
for assessing TdP risk, and a prolonged QT interval is almost a necessary prerequisite for making the diagnosis.
The prevalence of TdP in the general population is exceedingly rare, somewhere between 1/100,000 and 1/1,000,000. Because
it is so uncommon, yet potentially life threatening, the FDA and other regulatory agencies in Europe and Japan have struggled
to develop appropriate guidelines for analyzing the ECG data obtained during the evaluation of new drugs. The most recent
consensus guidelines were approved by the International Committee on Harmonization (ICH) and published in 2005.2
The European Union, Japan, and the United States have adopted these guidelines (ICH E-14), which rely almost entirely on one
ECG parameter, the QT interval, and its correction for changes in heart rate. Other reliable and reproducible ECG markers
of abnormal repolarization and TdP are also being investigated, but a more definitive marker for abnormal repolarization has
yet to be defined.
Based on the ICH E-14 guidelines, Morganroth discussed the "thorough ECG trial," also known as the "thorough QT/QTc trial"
(TQT), for assessing the TdP risk of new drugs undergoing early Phase II testing.3 The TQT is designed to detect small but important drug-induced changes in QT intervals that would identify a drug as potentially
dangerous and preclude it from further large and expensive Phase III trials.
