Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective

Abstract

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.

Figure 1

Fully integrated proarrhythmia risk assessment: leveraging exploratory safety data, ICH S7B core and phase I QT assays for a new and balanced approach. The schematic outlines the overall process and data streams that can be used to integrate the ICH S7B & E14 documents. The nonclinical core assays (hERG/in vivo QT; black box) and early‐stage screening assays (gray dash box) are primary inputs for a WoE‐based proarrhythmia risk assessment (see section “Linking ICH S7B and ICH E14: Acknowledging the Predictive Value of the Core Assays”). New drug candidates identified as low risk (“double‐negative”) based on nonclinical WoE (blue boxes) would bypass a TQT study and benefit from basic safety ECG monitoring during clinical development. Examples of low‐risk drugs include mAbs and small molecules with large hERG and in vivo QTc margins. Some promising new drug candidates may have proarrhythmic signals (“Preliminary High Risk”) that require more nonclinical and/or clinical assessment (“Mitigation Options”). This additional safety data would augment the WoE and confirm agents as having either low or high proarrhythmia risk, i.e., inform the degree of phase III ECG collection. The ICH S7B‐E14 Stage 1 and 2 Q&As process will address key nonclinical and clinical assay elements to improve current practices, and enable this new approach to develop a fully integrated proarrhythmia risk assessment for future drug candidates. APD, action potential duration; C‐QT, concentration‐QT modelling; CaV1.2, cardiac calcium channel; CIPA, Comprehensive in vitro Proarrhythmia Assay; CV, cardiovascular; ECG, electrocardiogram; hERG, human Ether‐à‐go‐go‐Related Gene; ICH, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use; IKr, rapid component of the delayed rectifier potassium current; mAbs, monoclonal antibodies; NaV1.5, cardiac sodium channel; QTc, corrected QT interval; TQT, thorough QT; WoE, weight of evidence.

Figure 2

ICH S7B core assay outcomes and the probability of clinical proarrhythmia risk. The figure shows the posttest probability of a QT prolongation liability (left) or TdP liability (right) after the ICH S7B core assays (x‐axis) have been conducted. After the hERG test there are two possible outcomes, and following the in vivo QT evaluation there are four possible outcomes. The prior probabilities (20% for QTc and 10% for TdP) are described in the Supplementary Material (Supplement S1). A higher prior probability for QTc is expected given that not all QTc‐prolonging drugs are associated with TdP. The probability of QT prolongation in man following a nonclinical double‐negative is 3.8% (solid + dash green lines). The probability of a TdP liability following a nonclinical double‐negative is 0.1% (solid + dash green lines). It is anticipated that improvements in nonclinical study conduct or quality will reduce the probability even further (for the double negative cases). hERG, human Ether‐à‐go‐go‐Related Gene; ICH, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use; QTc, corrected QT interval; TdP, torsades de pointes.