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Originally aired on April 24, 2014.
An informational webinar, discussing the CiPA initiative and improved strategies with the MICE approach. The CEO of ChanTest, Arthur "Buzz" Brown, and one of the authors of the recent CiPA paper, Philip Sager, will be presenting their findings in this field.
CV Safety Assessments During Drug Development- the Need for a New Paradigm
The current approach, outlined in ICH S7B and E14, to cardiac arrhythmia risk is focused on preclinical and clinical assessments: 1) the effect of new chemical entities on the hERG encoded IKr current and QTc prolongation in animals and 2) measuring QTc prolongation at supratherapeutic exposures in humans, typically during Phase 2 of development. While this approach has largely eliminated the unanticipated presence of new torsadogenic drugs entering the market, it has become clear that there are important limitations to this methodology. Block of hERG alone is often insufficient in predicting delayed repolarization and hERG-related prolongation of repolarization does not necessarily translate into human torsade de pointes risk. Increases in the QTc interval are highly sensitive but not very specific for the prediction of ventricular proarrhythmia risk. The use of the hERG repolarizing ionic current assay (in early nonclinical development) and QTc interval prolongation (in later nonclinical and clinical development) as gatekeepers for the continued development of a new chemical entity has likely led to the inappropriate discontinuation of development programs for drugs with potentially high public health benefits. The talk will focus on these key issues and a potential new approach to drug-induced arrhythmia development.
Making sense of the CiPA
initiative: a paradigm shift in cardiac safety
This presentation also discusses the present nonclinical (S7B) and clinical (E14) assays for cardiac risk assessment of non-cardiac drugs and how regulators arrived at them. The initial concern was with Torsade de Pointes, a potentially lethal ventricular arrhythmia. TdP occurred infrequently but it was always associated with delayed repolarization and QTc prolongation. The rarity of TdP shifted emphasis to the detection of delayed repolarization. The shortcomings of this approach have become obvious and the CiPA initiative is meant to re-direct emphasis towards predicting the likelihood of TdP.
Philip Sager, MD, FACC, FAHA, FHRS
Chair, Scientific Programs Committee
Arthur M. "Buzz" Brown, MD, PhD
Founder, President, CEO
Ernie Bush, PhD
Cambridge Healthtech Associates