Annual Meeting of the Japanese Society of Toxicology

Drug-induced QT interval prolongation and Torsades de Pointes (TdP) remain serious public health issues in bringing safe new pharmaceuticals to the market place. To help address this issue, the ILSI Health and Environmental Sciences Institute (HESI), a consortium including representatives from pharmaceutical companies, regulatory agencies and opinion leaders from the scientific and medical research communities conducted a multi-year program to evaluate the predictivity of data submitted to the U.S. Food and Drug Administration (FDA). The project involved evaluation of data extracted from thorough clinical QT studies and non-clinical studies (i.e., in vitro hERG assay, action potential duration in isolated cardiac tissue, and in vivo QTc studies) submitted to the FDA to support marketing approval of new pharmaceuticals (150 drugs in the database). The data were evaluated for concordance between non-clinical repolarization assays and clinical measures of QT interval prolongation and established the sensitivity, specificity and predictivity of non-clinical assays towards clinical outcome. This introductory presentation will describe the program structure, participants, and objectives.

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Drug-induced QT interval prolongation and Torsades de Pointes remain serious public health issues when new pharmaceuticals are brought to the market place. Under the auspices of ILSI Health and Environmental Sciences Institute (HESI), a consortium involving representatives from pharmaceutical companies and regulatory agencies has been initiated. One objective is to assess the predictivity of non-clinical repolarization assays in relation to clinical measures of QT interval prolongation, i.e., establish a quantitative risk assessment for individual compounds. To this end, the consortium conducted a retrospective analysis of non-clinical and clinical data housed in the U.S. Food and Drug Administration database. This presentation will provide a final analysis of the predictivity of data from Thorough clinical QT (TQT) studies and nonclinical studies submitted to support marketing approval of >150 new pharmaceuticals. Nonclinical studies analyzed include in vitro ion channel assays for effects on hERG current, action potential duration (ADP) in isolated cardiac tissue, and in vivo ECG studies (QTc). Normalized concentration response data is compiled for each assay and compared across studies to determine the predictivity of nonclinical to clinical data. This analysis will be shared along with estimation of sensitivity and specificity of these assays at various nonclinical to clinical exposure multiples. The results suggest that a robust non-clinical risk assessment provides reasonable predictivity when the clinical QT signal is of sufficient magnitude (>10ms).

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