Multi-laboratory comparisons of manual patch clamp hERG data generated using standardized protocols and following ICH...

Area of Science:

• Cardiovascular Pharmacology
• Drug Safety and Toxicology
• Electrophysiology

Background:

• Acute block of hERG channels is a primary cause of drug-induced QT_C prolongation and Torsade de Pointes.
• Recent regulatory updates permit the use of negative nonclinical hERG data for QT_C risk assessment.
• Interpreting hERG assay results necessitates understanding data reproducibility and variability across laboratories.

Purpose of the Study:

• To assess the impact of laboratory-to-laboratory variability on hERG assay results.
• To quantify the inherent data variability in manual patch clamp hERG assays.
• To establish acceptable thresholds for comparing hERG drug block potency data.

Main Methods:

• A multi-laboratory study involving five laboratories using a standardized manual patch clamp protocol.
• Testing of 28 drugs with a focus on hERG channel block potency.
• Statistical analysis, including descriptive statistics and meta-analysis, to determine data distribution and variability.

Main Results:

• Systematic differences in drug block potency were observed from one laboratory for initial drug sets.
• Retesting confirmed assay reproducibility within laboratories, with one exception showing significant deviation (7.6X).
• The estimated natural hERG data variability (inter-laboratory) was approximately 5X.

Conclusions:

• hERG block potency values within a 5X range should be considered consistent due to inherent assay variability.
• Systematic laboratory-specific differences can occur but may resolve over time or with protocol adherence.
• Laboratory-specific safety margins may be necessary to account for observed data variability in regulatory submissions.