A ‘double-negative’ integrated nonclinical risk assessment includes: (1) hERG assays following best practices (S7B Q&A 2.1 [5]) showing low risk for parent and major human metabolites (S7B Q&A 1.1 [5]), demonstrated by hERG safety margins higher than a threshold defined based on the safety margins computed under the same experimental protocol for a series of drugs known to cause TdP; and (2) no evidence of QTc prolongation in an in vivo assay conducted according to ICH S7B at exposures covering high clinical exposures of parent and major human metabolites (S7B Q&A 3 [5]). The gene discussed is KCNH2; the disease is torsades de pointes.