Statistical approaches to classify investigational product using hERG safety assay

The hERG safety assay is crucial for assessing the risk of delayed repolarization and QT interval prolongation in investigational drugs, yet a lack of consensus exists on classifying drugs into appropriate risk categories based on assay results. We propose a two-stage statistical framework for quantitative assessment of hERG safety assay classification for investigational products adhering to ICH E14 S7b Q&A Best Practice protocols. Our framework employs a fixed margin equivalence testing approach to evaluate concurrent positive controls against the positive control reference in Stage 1, followed by a logistic regression model based on a T-score to classify the investigational product into two risk categories (QT effect ≥ 10 msec or < 10 msec) in Stage 2. Applied to real-world data, our method demonstrates the ability to classify investigational products with an AUROC of at least 0.9, using a pre-specified probability margin. Additionally, our approach addresses lab-to-lab variability in hERG safety assay assessment, providing a standardized, quantitative method for evaluating hERG assay results that could improve consistency in drug risk assessment across the pharmaceutical industry.