Eurofins Discovery as part of CiPA initiative to form future industry regulatory guidelines

Haiyang (David) Wei, Drug Discovery Partnerships Director, Eurofins Discovery, DavidWei@eurofins.com

The withdrawal of FDA approved drugs from the market beginning in the late 1990s due to Torsade de Pointes (TdP) in patients shocked the global regulators and the pharmaceutical industry and led to the issuing of ICH S7B and E14 guidelines in May 2005. For the past decade, in vitro hERG channel assays and in vivo QT measurements have been conducted as surrogates for proarrhythmic risk propensity according to these guidelines. This paradigm, although effective, suffered from lack of specificity and led to unnecessary compound attrition during drug development. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a new cardiac safety testing paradigm sponsored by the Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and Food and Drug Administration (FDA) intended to address this limitation with improved prediction of a drug’s proarrhythimic liability.

This new CiPA paradigm includes a panel of in vitro assays that integrates effects of the test compounds on several cardiac ion channels for safety margin calculations and in silico modelling, which relies on automated patch clamp platforms (APC) to efficiently provide reliable and reproducible estimates of the potency of a drug block of multiple currents that modulate repolarisation and affect proarrhythmic risk. Eurofins Discovery is a member and key contributor of the CiPA initiative and has recently published a research article on Scientific Reports jointly with 17 major pharmaceutical companies, CROs, instrument providers, and academic labs, presenting results from a pilot study to determine variability of APC data from multiple sites. This multi-platform/multi-site study provides the largest comparison of results and provide estimates of the variability associated with IC50 values characterising the blocking potency of 12 blinded drugs on four prominent human cardiac currents using suggested experimental protocols across five automated patch platforms and 17 sites.

This study will guide the industry on the development of best practices using APC technologies for early screening to avoid cardiac safety liabilities and subsequent characterisation of the risk of delayed repolarisation and proarrhythmia to guide clinical studies and regulatory submissions of CiPA initiative.

For information, visit: www.eurofinsdiscoveryservices.com