The impact of drug-related QT prolongation on FDA regulatory decisions

Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

“…In vivo studies, typically performed in dogs or rodents, assess major functional changes in the cardiovascular system (heart rate, blood pressure, electrocardiogram) while in vitro screens focus on the drug's potential to elongate the QT interval using cell-based hERG assays or isolated tissues to examine changes in action potential (ICH S7B, 2005;ICH S7A, 2000). While these approaches have been mostly successful in reducing the percentage of proarrhythmic drug submissions to the FDA in the last few years (from 60% in 2005 to 10% in 2012 (Park et al, 2013)), limitations do exist. For example, animal models may not accurately reflect the human response to drug given the differences in receptor subtypes and signaling pathways between species (Khan et al, 2013).…”

Principles of Safety Pharmacology

“…Among these initiatives, the project of the HESI Cardiovascular Safety Subcommittee represented an analysis of the largest database among the different consortia, a survey of 150 molecules studied in the clinic for QT prolongation (Koerner et al 2013). This initiative is comparing the concordance between preclinical cardiac repolarization assays and the results from the "TQT" study; data were collected from INDs and NDAs submitted to the FDA between the periods of July 2012. Due to the proprietary nature of these datasets, the FDA populated the spreadsheets with the data and carried out a quality control and statistical analysis based on a methodology that was devised by the subcommittee in advance of the collection of data.…”

“…This initiative is comparing the concordance between preclinical cardiac repolarization assays and the results from the "TQT" study; data were collected from INDs and NDAs submitted to the FDA between the periods of July 2012. Due to the proprietary nature of these datasets, the FDA populated the spreadsheets with the data and carried out a quality control and statistical analysis based on a methodology that was devised by the subcommittee in advance of the collection of data. The summary results of this analysis of 150 compounds has been presented at conferences and is due for publication in 2015 (Koerner et al 2013).…”

Clinical ECG Assessment

“…Objectively verified proarrhythmias are however very rarely observed in development programs of normal size or even in programs up to 20,000 patients, with a few notable exceptions with more potent QT-prolonging drugs (Caprelsa US NDA 022405 2011;Darpo 2007). Even in the absence of demonstrated proarrhythmic events, drugs with a more pronounced QTc effect, i.e., above 20 ms, are generally regarded as proarrhythmic by regulators and come with warnings and precautions in the label (Park et al 2013). …”