Snehal Kothari

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

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.

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

AIM To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODS Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTS Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (ΔQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml(-1) (range 1.1-2.8) vs. 1.4 μg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTc I relationship was steeper in women (30 ms per μg ml(-1) vs. 23 ms per μg ml(-1) in men; P = 0.0135). CONCLUSIONS The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.

Intra- and interreader variability in QT interval measurement by tangent and threshold methods in a central electrocardiogram laboratory

BACKGROUND The QT interval can be measured by tangent (QT(Tan)) and threshold (QT(Thr)) methods; the better method is the one with lower reader variability. METHODS QT(Tan) and QT(Thr) were measured twice in 100 digital electrocardiograms (ECGs) by 8 experienced readers in a central laboratory. For QT(Thr), the end of the T wave was the point where the T wave reached the isoelectric baseline; for QT(Tan), it was the point where a line from the peak of the T wave through the steepest part of the descending limb intercepted the isoelectric baseline. RESULTS The average absolute intrareader variability ranged from 3.4 to 6.9 milliseconds for QT(Tan) and from 3.5 to 5.2 milliseconds for QT(Thr). By analysis of variance, intrareader SD of QT(Tan) was 7.0 and 7.5 milliseconds for QT(Thr); interreader SD was 13.1 milliseconds for QT(Tan) and 11.9 milliseconds for QT(Thr). QT(Tan) was shorter than QT(Thr) in 96 of the 100 ECGs, it exceeded QT(Thr) in 4 ECGs, which had prominent U waves. CONCLUSIONS For trained readers in a central ECG laboratory using sophisticated on-screen tools for QT measurement in high-quality digital ECGs, between- and within-reader variability are comparable for QT(Tan) and QT(Thr). However, QT(Tan) is consistently shorter than QT(Thr) by up to 10 milliseconds.

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers

INTRODUCTION We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study. METHODS QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment. RESULTS All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method. CONCLUSION The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies.

Early repolarization and short QT interval in healthy subjects.

BACKGROUND An early repolarization (ER) pattern is common in ECGs from patients with ventricular fibrillation (VF). These patients with ER have shorter QT intervals. Morphological variants of the ER pattern also have been associated with idiopathic VF, but their prevalence in healthy subjects is unclear. OBJECTIVE The purpose of this study was to study the prevalence of ER and its morphological variants, and its association with the QTc interval in healthy subjects. METHODS Digital ECGs from 1886 healthy subjects from Phase I clinical trials were analyzed by a central ECG laboratory. RESULTS ER, defined as J-point elevation ≥0.1 mV in ≥2 contiguous leads, was present in 514 subjects (27.3%), of whom 505 (98.2%) were males. The prevalence of ER declined progressively with increasing age. ER pattern was seen in lateral leads (I, aVL, V(4)-V(6)) in 26.1%, in inferior (II, III, aVF) or inferolateral leads in 8%, and was global in 1.9%. The terminal portion of the QRS complex was notched in 43.1% and slurred in 56.9%. Notching was common in inferior/lateral leads, and slurring was common in anterior leads. A non-ascending ST segment was seen in 71% of ECGs with a notched pattern but in only 12.3% of ECGs with a slurred pattern. The ER group had slower heart rates (9.3 ± 13.3 bpm [mean difference ± SD], P <.001) and shorter QTc intervals (QTcB = 20.2 ± 25.6 ms, QTcF = 11.0 ± 21.9 ms; P <.001). Four subjects in each group had a short QT interval (QTcF <350 ms). CONCLUSION ER and all of its variants are common in healthy young males with slower heart rates and slightly shorter QTc intervals. A short QT interval (QTcF <350 ms) is rare.

Effect of Number of Replicate Electrocardiograms Recorded at Each Time Point in a Thorough QT Study on Sample Size and Study Cost

In a “thorough QT/QTc” (TQT) study, several replicate electrocardiograms (ECGs) are recorded at each time point to reduce within‐subject variability. This decreases the sample size but increases the cost of ECG analysis. To determine the most cost‐effective number of ECG replicates, the authors retrospectively analyzed data from the placebo and moxifloxacin arms of a TQT study with crossover design. Six replicate ECGs were recorded at 7 time points on day −1 (baseline day), day 1, and day 3 in 124 normal healthy volunteers who were randomized to receive moxifloxacin or placebo on day 1 and the other treatment on day 3. QT interval was corrected for heart rate by the Fridericia (QTcF) and individual subject‐specific (QTcI) formulas. Within‐subject and between‐subject standard deviations for QTcF obtained by repeated‐measures analysis of covariance were 9.5 and 13.3 milliseconds with 1 replicate; 7.8 and 12.7 milliseconds with 2 replicates; 7.3 and 12.3 milliseconds with 3 replicates; 6.9 and 12.2 milliseconds with 4 replicates; 6.8 and 11.9 milliseconds with 5 replicates; and 6.6 and 11.8 milliseconds with 6 replicates. Within‐ and between‐subject variance with QTcI also declined with increasing replicates. Sample size benefit based on these estimates was negligible beyond 4 replicates. The study cost was least with 3 or 4 replicates, depending on per‐ECG and per‐subject costs.

Z-score for benchmarking reader competence in a central ECG laboratory.

Background: ECGs from thorough QT studies must be read in a central laboratory by trained experts. Standards of expertise are not presently defined. We, therefore, studied the use of Z‐scores to define reader competence.

Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials.

Regulatory agencies encourage sponsors to submit 24‐hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early‐phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24‐hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug‐free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18‐65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs. Supraventricular arrhythmias such as supraventricular premature complexes were observed in 60.8% of healthy volunteers, supraventricular tachycardia in 2.2%, and atrial fibrillation in 0.1%. Ventricular arrhythmias included premature ventricular complexes (PVCs) in 43.4%, >200 PVCs per 24 hours in 3.3%, multifocal PVCs in 5.3%, nonsustained ventricular tachycardia in 0.7%, and accelerated idioventricular rhythm in 0.3%. Bradyarrhythmias included sinus pause >3 seconds in 0.3%, and second‐degree AV block in 2.4%. Complete heart block and torsades de pointes were not seen in any subject. Based on the observed incidence, we estimated the maximum number of healthy subjects in whom these arrhythmias may be seen as a matter of chance in studies with smaller sample sizes if the study drug has no arrhythmogenic effect. Our results and these estimates could help interpret whether cardiac arrhythmias observed in early‐phase studies are due to chance or possibly are a drug effect.

Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study

Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females). Placebo-subtracted change from baseline in QTc corrected by Fridericias method (ΔΔQTcF) at 1, 1.5, 2 and 4 hours after moxifloxacin was studied in all 12 leads. Unacceptably wide 90% confidence interval (CI) for ΔΔQTcF was seen in three leads; these leads also had maximum ECGs with flat T waves (60% in aVL, 45% in lead III and 42% in V1). After excluding ECGs with flat T waves, 90% lower CI of ΔΔQTcF was ≥ 5 ms in all leads except leads III, aVL and V1 in men. The 90% lower CI exceeded 5 ms in these leads in women despite wide 90% CIs because of greater mean ΔΔQTcF. Leads III, aVL and V1 should be avoided when measuring QT interval in thorough QT studies.

Recent developments in the science of proarrhythmic cardiac safety of new drugs

Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit-risk balance. The Comprehensive In vitro Proarrhythmia Assay paradigm is currently attracting considerable attention as a solution to this problem. While much evaluative work in this new paradigm will be conducted in the non-clinical domain, human electrocardiographic assessments will remain an important component of the overall investigational strategy, possibly being conducted in Phase I trials employing exposure-response modelling. This article reviews recent developments in proarrhythmic cardiac safety assessments of new drugs, their rationales, and current limitations.