Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability...

Area of Science:

• Pharmacology
• Drug Safety
• Clinical Pharmacology

Background:

• Assessing drug-induced corrected QT interval (QTc) prolongation, a marker for torsades de pointes arrhythmia, is critical in drug development.
• Current International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and ICH E14 guidances utilize specific nonclinical and clinical assays.
• These assays have successfully reduced QTc-prolonging drugs in trials and market withdrawals.

Purpose of the Study:

• To evaluate the underappreciated value of nonclinical "double-negative" findings (low risk for hERG block and in vivo QTc prolongation) in clinical QTc prolongation risk assessment.
• To advocate for a more integrated approach combining nonclinical and clinical data for a flexible QTc monitoring strategy.
• To streamline drug development by potentially reducing the need for extensive clinical QTc studies.

Main Methods:

• Review of existing ICH S7B (nonclinical) and ICH E14 (clinical) guidances and their application.
• Analysis of the influence of nonclinical delayed repolarization evaluations on clinical QTc assessment strategies.
• Exploration of the utility of "double-negative" nonclinical findings in specific clinical scenarios.

Main Results:

• Nonclinical evaluations of delayed repolarization minimally influence current clinical QTc assessment strategies.
• "Double-negative" nonclinical findings are valuable, especially when clinical evaluations are limited.
• Integrating nonclinical and clinical data can enhance the assessment of proarrhythmic risk.

Conclusions:

• A fully integrated nonclinical/clinical risk assessment strategy is proposed for QTc monitoring.
• Implementing this integrated approach for compounds with "double-negative" nonclinical findings can relieve the burden of unnecessary clinical QTc studies.
• This strategy aims to streamline drug development while maintaining patient safety.