Non-clinical cardiovascular safety testing: Current status, gaps and emerging trends

Cardiovascular adverse drug reactions remain a leading cause of drug attrition. They may emerge during non-clinical or clinical development and often remain undetected until post-marketing, prompting increased regulatory focus. Historically, non-clinical cardiovascular safety testing has centered on assessing QT interval prolongation and torsades de pointes risk, primarily via inhibition of the delayed rectifier potassium current IKr. Such focus may overlook broader cardiovascular liabilities affecting other parameters of the cardiovascular system. This review explores the status and limitations of current non-clinical cardiovascular safety assessments, in particular the over-reliance on the core battery studies defined in ICH S7A and S7B and the insufficient use of mechanistic follow-up assessments. We highlight the gaps between the results of non-clinical cardiovascular safety testing and the emergence of cardiovascular adverse drug reactions in later clinical phases or real-world use. We conclude that to narrow the gaps, there is a need to advance non-clinical methods to detect and adequately measure adverse effects on cardiac rhythm, myocardial contraction, blood pressure, and thrombogenicity. The review further discusses emerging trends and challenges for improving translational relevance, including advanced in vitro and in vivo models, and proposes a re-evaluation of outdated regulatory frameworks to better address diverse cardiovascular risks. Emphasis is placed on functional and mechanistic endpoints over structural pathology, aligning non-clinical safety methodologies with clinical outcomes.