ECG Evaluation as Part of the Clinical Pharmacology Strategy in the Development of New Drugs: A Review of Current Practices and Opportunities Based on Five Case Studies.

Abstract

The International Conference on Harmonization (ICH) E14 document was revised in 2015 to allow concentration-corrected QT interval (C-QTc) analysis to be applied to data from early clinical pharmacology studies to exclude a small drug-induced effect on QTc. Provided sufficiently high concentrations of the drug are obtained in the first-in-human (FIH) study, this approach can be used to obviate the need for a designated thorough QT (TQT) study. The E14 revision has resulted in a steady reduction in the number of TQT studies and an increased use of FIH studies to evaluate electrocardiogram (ECG) effects of drugs in development. In this review, five examples from different sponsors are shared in which C-QTc analysis was performed on data from FIH studies. Case1 illustrates a clearly negative C-QTc evaluation, despite observations of QTc prolongation at high concentrations in nonclinical studies. In case2 C-QTc analysis of FIH data was performed prior to full pharmacokinetic characterization in patients, and the role of nonclinical assays in an integrated risk assessment is discussed. Case3 illustrates a positive clinical C-QTc relationship, despite negative nonclinical assays. Case4 demonstrates a strategy for characterizing the C-QTc relationship for a nonracemic therapy and formulation optimization, and case5 highlights an approach to perform a preliminary C-QTc analysis early in development and postpone the definitive analysis until proof of efficacy is demonstrated. The strategy of collecting and storing ECG data from FIH studies to enable an informed decision on whether and when to apply C-QTc analysis to obviate the need for a TQT study is described.