Clinical ECG Assessment

Abstract

With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE's effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA's Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined.

Concentration–Response Modeling of ECG Data From Early‐Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk — Experience From the Development Program of Lemborexant

“…ECGs were extracted and measured by a central ECG laboratory (iCardiac Technologies, Rochester, New York) using the high‐precision QT technique, as previously described . This technique was chosen, as it has been demonstrated that it results in substantially lower variability of change‐from‐baseline QTc (∆QTc) and therefore improves the power to exclude small QT effects . The QT interval was heart rate–corrected using Fridericia's formula (QTcF = QT/RR 1/3 ), and a subject‐specific correction using all QT/RR pairs from the full 24‐hour baseline recording was applied as follows: based on the QT/RR pairs from each individual subject, the QTcI correction factor was derived from linear regression modeling: log(QT) = log(a) + b × log(RR).…”

Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

“…The maximum, baseline-adjusted and vehicle-adjusted (ΔΔ)QTc (ms) was used as the primary response endpoint for human TQT studies and maximum, baseline-adjusted (Δ)QTc (ms) for in vivo QTc studies (Anonymous, 2005a;Darpo, 2010;Stockbridge et al, 2012;Darpo, 2015). A positive response in the in vivo QTc assay was defined by the sponsor's claim of a significant drug-related effect.…”

Effect of Futibatinib on Cardiac Repolarization: Results of a Randomized, Controlled, Double‐Blind, QT/QTc, Phase 1 Study in Healthy Subjects

“…Moreover, there were no clinically significant effects of futibatinib on heart rate, other ECG parameters, or ECG morphology, and a concentration‐dependent effect on QTcF prolongation between the 2 doses of futibatinib was not apparent. Overall, the study met the criteria for a negative thorough QT/QTc study per ICH guidance 11–14 …”

“…To characterize the clinical effects of futibatinib on cardiac repolarization and to assess its proarrhythmic potential, we conducted a randomized, controlled, double‐blind, thorough QT/QTc, phase 1 study in healthy subjects following established guidelines 11–14 . The primary objective of this study was to assess the impact of the therapeutic and supratherapeutic futibatinib doses of 20 and 80 mg, respectively, on the QT interval corrected for heart rate with the Fridericia formula (QTcF) compared with placebo.…”