Statistical approaches to evaluate the positive control drug using the hERG assay

The assessment of human ether-a-go-go-related gene (hERG) safety assay is essential for estimating the risk that a drug will cause delayed repolarization and QT interval prolongation prior to human administration. Quantitative assessment of hERG safety assay similarity presents significant challenges due to the absence of consensus methodology and substantial inter-laboratory variability in hERG assay performance. We developed a statistical framework to conduct quantitative assessment of hERG safety assay similarity for drug products between sponsor's laboratories and laboratories that follow the ICH E14 S7b Q&A Best Practice recommended protocol. Our approach employs fixed margin equivalence testing methodology. Using real-world and/or simulated data, we demonstrate that the proposed equivalence testing methods successfully identify similar hERG assays between laboratories for 28 Comprehensive In Vitro Proarrhythmia Assay (CiPA) drugs. The testing results align with the domain experts' assessments, validating the framework's utility for regulatory decision-making.