Cardiovascular system assessment best practices: a Safety Pharmacology Society meeting

Abstract

A group of selected Safety Pharmacology (SP) experts (∼ 50) were convened at the Cambridge Amgen Research Center for a brain-storming reflection on avenues to pursue in order to promote inter-laboratory harmonization in the conduct of regulatory non-clinical cardiovascular SP investigations. Following a few plenary lectures, the participants, divided into three groups, discussed how to optimize the outcome of cardiovascular assays and how best to capture a pro-arrhythmic potential of clinical candidates in dog and non-human primate studies. The first presentation analyzed impending SP challenges and, in particular, the necessity to detect drug-induced minor, cardio-hemodynamic and electrocardiographic changes that, if sustained over time, can cause premature morbidity and lethality events. Then, the importance of optimized experimental design and data analysis approaches to capture cardiovascular liability signals was examined. Finally, four cardiovascular case studies on strategies to enhance human predictability of non-clinical findings were illustrated. The reflection groups analyzed the best available means for optimizing precision, power, design, execution of, and data exploitation from, SP assays. The proceedings of this meeting will constitute the first official SP Society guidance on best practices for reducing cardiovascular attrition during drug development. Nonetheless, my personal view is that the chief, most powerful and cost-effective approach to establish pharmacological safety of potential clinical candidates is to apply, from the earliest research stages, mechanism-driven Exploratory SP assay paradigms with elevated human translation power. In this scenario, Regulatory SP will have the role to confirm and validate safety evidences obtained by Exploratory SP by conducting guideline recommended assays under best experimental practices.

Keywords::

• assay design
• best practices
• cardiovascular system
• data summarization and analysis
• power analysis
• pro-arrhythmia assessment
• safety pharmacology

Acknowledgements

The author thanks H Holzgrefe and R Towart for thoroughly and patiently reviewing and improving the text. Thanks are also extended to P Atterson, P Champeroux, D Gallagher, J-M Guillon, B Guth, D Leishman, PE Puddu, F Rossi and P Zitoun for their suggestions to improve this report.

The Author assumes full responsibility for the entire content of the report and, in particular, for any portion that may not accurately reflect the presented material.