The Impact of Cardiac Safety on the Regulatory Landscape: Recent Case Studies

Adverse cardiovascular events are one of the leading causes of drug withdrawal or restriction; drugs spanning multiple therapeutic areas have been implicated in these major adverse events, and recent years have witnessed a major focus on the cardiac safety of metabolic agents. Emerging therapies such as Orexigen/Takeda's Contrave, Abbott's Meridia, and GlaxoSmithKline's Avandia all have recently faced intense regulatory scrutiny over their cardiovascular safety profiles. Although drug development guidelines for obesity agents currently only stipulate one-year trials, agents with a cardiac safety signal are likely to face regulatory requirements similar to those of diabetes agents. Navigating the stringent regulatory requirements for cardiovascular safety is therefore becoming increasingly challenging and expensive for developers of new biopharmaceutical products.

Questions Answered

• Recent regulatory failures have demonstrated an increased emphasis on safety versus efficacy. Cardiac safety is an area of major focus, given that it is a leading cause of drug discontinuation and withdrawal in the major markets. How have regulatory cardiac safety requirements evolved? What dedicated cardiac safety tests must developers perform during drug development?
• The FDA is planning a general advisory committee meeting in early 2012 to specifically address cardiovascular assessments for obesity agents in development. What clues do the regulatory challenges faced by Orexigen/Takeda's Contrave and Arena/Eisai's Lorqess give to potential developers of obesity agents?
• Postmarketing initiatives will help to reduce the risk of cardiac adverse events. How have companies utilized REMS to address regulatory concerns? How have REMS been used to limit cardiovascular risk?

Scope

• Regulatory environment: The FDA and the International Conference on Harmonisation guidelines, preclinical and clinical cardiac safety assessments.
• Postmarketing surveillance: Risk Evaluation and Mitigation Strategies (REMS).
• Strategies to reduce the regulatory burden of demonstrating CV safety: Public-private partnerships, modeling of cardiovascular outcomes trials.
• Insight: Author Matthew Killeen, Ph.D., has published numerous journal articles on topics including sudden cardiac death and atrial fibrillation. He also has written a book on the role of cardiac safety in drug development, "Cardiac Drug Safety: A Bench to Bedside Approach." Dr. Killeen holds a doctorate in cardiac electrophysiology from Cambridge University. In addition to being a member of the Cardiac Safety Research Consortium, an initiative formed by the FDA and Duke University, he has spoken at FDA conferences on topics including drug safety and pharmaceutical development.

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