Validation of an ICH E14/S7B Q&A best practice compliant hERG assay

SPS 2023 -- The new ICH E14/S7B Q&A guideline introduces the concept of "double negative" (negative hERG and negative in vivo QTc) nonclinical data, which can be used along with negative Phase I clinical QTc data to substitute for a clinical thorough QT study in specific cases (Q&As 5.1 and 6.1). The nonclinical data are to be generated using "best practice" designs in order to increase data quality and ensure consistency and harmonisation across the industry. For the hERG assay, best practice recommendations affect recording temperature, voltage protocol, stimulation frequency and recording/data quality. The hERG assay is considered negative if the safety margin of the drug is greater than safety margins determined under a similar best practice design for reference drugs with known clinical torsadogenic liability (Moxifloxacin, Ondansetron and Dofetilide). The objective of this work was to validate an ICH E14/S7B Q&A compliant hERG assay with the three recommended reference drugs. Experiments were performed at 35-37°C using the recommended pipette solution, external buffer and hERG voltage protocol. Cell health parameters (holding current and input resistance) were monitored and reported for each cell tested.

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