Validation and qualification of an ex vivo human cardiac tissue-based assay for t

描述（由申请人提供）：药物引起的心脏毒性和不良事件仍然是行业和监管机构面临的主要挑战。目前，在药物发现和开发过程中，早期识别这些潜在缺陷的策略包括体外和体内试验的结合，然后在II期对人类受试者进行广泛的基于心电图的心脏复极研究。这些后一项研究被称为“全面QT”研究（TQT），因为它们特别关注QT间期的药物相关变化，QT间期是心脏复极和诱发心律失常的生物标志物。虽然这些策略无疑有助于早期识别潜在危险的促心律失常分子，但也越来越明显的是，这种方法现在已经超过8年了，可以进行重大改进。最近，制药行业的领导者和FDA的监管机构都表达了以下担忧：a)与当前方法相关的成本，特别是TQT研究；b) TQT研究的时间延长；c)由于使用与心律失常发生不完全相关的生物标志物（如QT间期延长）而导致的假阳性率；d)根据TQT研究的要求，将患者暴露于高剂量仍在开发中的药物所涉及的风险。基于这些担忧，FDA药物评估和研究中心心血管和肾脏产品部门的领导促进了一系列旨在征求开发和验证新实验模型的倡议，以评估新药的心脏安全性，特别是其致心律失常的潜力。正如监管机构明确表示的那样，目标是“

DESCRIPTION (provided by applicant): Drug-induced cardiac toxicity and adverse events remains a major challenge for both industry as well as regulators. The current strategies for early identification of these potential liabilities in the drug discovery and development process involves a combination of in vitro and in vivo assays, followed by an extensive ECG-based cardiac repolarization study which is conducted on human subjects during Phase II. These latter studies are known as "Thorough QT" studies (TQT) since they have specifically focused on drug-related changes in the QT interval, a biomarker for cardiac repolarization and the induction of pro-arrhythmic cardiac activity. While these strategies have undoubtedly contributed in the early identification of potentially dangerous pro-arrhythmic molecules, it is also becoming apparent that this approach, now over 8 years old, is amenable to significant improvements. Recently, both leaders in the pharmaceutical industry as well as regulators from the FDA, have expressed concerns related to: a) The costs associated with the current approach, in particular the TQT studies; b) The prolonged timelines involved in TQT studies; c) The false positive rate due to the utilization of biomarkers (like QT prolongation) that do not completely correlate with the occurrence of arrhythmias; d) The risks involved in exposing patients to high doses of drugs still in development, as required by the TQT studies. Based on these concerns, the leadership at the Division of Cardiovascular and Renal Products of the FDA Center for Drug Evaluation and Research has facilitated a number of initiatives aimed at soliciting the development and validation of novel experimental models for assessing cardiac safety of new drugs and, in particular, their pro-arrhythmic potential. As explicitly stated by the regulators, the goal is "to replace the TQT clinical studies with one or more pre-clinical assays, by July 2015" (Dr. Norman Stockbridge, CSRC-HESI-FDA Meeting, July 24, 2013, Silver Spring, MD). AnaBios has recently developed a novel human heart-based drug safety evaluation platform, which is currently undergoing formal Biomarker Qualification at the FDA. The technology relies upon the utilization of viable human donor hearts in the laboratory for conducting ex-vivo measurements of cardiac function. This approach will be utilized to test human cardiac responses to novel drug in a pre-clinical assay, providing the next best kin to a human clinical cardiac study, but avoidin the risks related to drug exposure in man, the high costs and extended timelines which come with the clinical studies. The present proposal focuses on the validation of this ex-vivo heart platform in order to demonstrate its feasibility, robustness and overall value in predicting human clinical responses.