Cardiac Safety Research Consortium Conference Current challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative Jonathan P. Piccini, MD, MHS, a David J. Whellan, MD, MHS, b Brian R. Berridge, DVM, PhD, c John K. Finkle, MD, d Syril D. Pettit, MEM, e Norman Stockbridge, MD, PhD, f Jean-Pierre Valentin, PhD, g Hugo M. Vargas, PhD, h and Mitchell W. Krucoff, MD a , for the CSRC/HESI Writing Group Durham and Research Triangle Park, NC; Philadelphia and Collegeville, PA; Washington, DC; Silver Springs, MD; Cheshire, United Kingdom; and Thousand Oaks, CA In October 2008, in a public forum organized by the Cardiac Safety Research Consortium and the Health and Environmental Sciences Institute, leaders from government, the pharmaceutical industry, and academia convened in Bethesda, MD, to discuss current challenges in evaluation of short- and long-term cardiovascular safety during drug development. The current paradigm for premarket evaluation of cardiac safety begins with preclinical animal modeling and progresses to clinical biomarker or biosignature assays. Preclinical evaluations have clear limitations but provide an important opportunity to identify safety hazards before administration of potential new drugs to human subjects. Discussants highlighted the need to identify, develop, and validate serum and electrocardiogram biomarkers indicative of early drug-induced myocardial toxicity and proarrhythmia. Specifically, experts identified a need to build consensus regarding the use and interpretation of troponin assays in preclinical evaluation of myocardial toxicity. With respect to proarrhythmia, the panel emphasized a need for better qualitative and quantitative biomarkers for arrhythmogenicity, including more streamlined human thorough QT study designs and a universal definition of the end of the T wave. Toward many of these ends, large shared data repositories and a more seamless integration of preclinical and clinical testing could facilitate the development of novel approaches to both cardiac safety biosignatures. In addition, more thorough and efficient early clinical studies could enable better estimates of cardiovascular risk and better inform phase II and phase III trial design. Participants also emphasized the importance of establishing formal guidelines for data standards and transparency in postmarketing surveillance. Priority pursuit of these consensus-based directions should facilitate both safer drugs and accelerated access to new drugs, as concomitant public health benefits. (Am Heart J 2009;158:317-26.) Because of the potentially catastrophic nature of unanticipated “off-target” drug-related cardiovascular complications, cardiac safety is of paramount importance in contemporary drug development. In the US, cardiac safety is the leading cause for the drug discontinuation at all phases of development, including drug discovery, preclinical evaluation, clinical evaluation, and postmarket surveillance (Table I). 1,2 For both cardiac and noncardiac pharmaceuticals, cardiac safety concerns arise from a variety of drug-tissue interactions, including direct myo- cyte toxicity, QT and non–QT proarrhythmic changes, and other effects on vascular tone and injury (Table II). Efficient and sensitive evaluation of cardiac safety in the research and development of new molecular entities begins with preclinical in vitro and in vivo modeling and carries through all phases of human testing and post- market use. In an era marked by increased public scrutiny, escalating industry costs, and limited resources at regulatory agencies, the need for efficient, yet safe drug development is more important than ever. 8 The US Food and Drug Administration's (FDA) Critical Path Initiative emerged with the general recognition that both (1) the rising costs of drug development and (2) the decline in the number of new drugs approved in the United States are significant problems that threaten the public health. Cardiac safety evaluations of off-target drug effects in particular are generally expensive, time consuming, and contribute to the From the a Duke Clinical Research Institute & Duke University Medical Center, Durham, NC, b Department of Medicine, Jefferson Medical College, Philadelphia, PA, c GlaxoSmithKline, Research Triangle Park, NC, d GlaxoSmithKline, Collegeville, PA, e ILSI Health and Environmental Sciences Institute, Washington, DC, f Division of Cardiovascular and Renal Products, CDER, FDA, Silver Spring, MD, g AstraZeneca, Cheshire, United Kingdom, and h Amgen, Inc., Thousand Oaks, CA. Submitted June 4, 2009; accepted June 4, 2009. Reprint requests: Mitchell W. Krucoff, MD, FACC, FCCP, eECG Core Laboratory, Duke Clinical Research Institute, 508 Fulton Street, Durham, NC 27705. E-mail: kruco001@mc.duke.edu 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2009.06.007 Progress in Cardiology