Consortium Led Evaluation of Integrated Human-Relevant Approaches to Identify Drug Induced Cardiovascular Liabilities

标题：联合会领导的对识别药物的综合人类相关方法的评价 诱发心血管负债 FOA标题和编号：验证人类干细胞心肌细胞技术 药物性心脏毒性的预测性评估（不允许U 01临床试验），RFA- FD-19-002 项目拟开工日期：2019年9月30日 拟定结束日期：2022年9月30日 项目概要/摘要： 心血管药物诱导的毒性仍然是临床前和治疗中药物消耗的主要原因。 和药物开发的临床阶段（Laverty等人，2011年）。这很可能是由于 用于评估心脏毒性的传统临床前模型。此外，许多传统的 这些方法在药物开发的后期使用，导致昂贵的后期损耗。 在体外技术平台和人类干细胞衍生 心肌细胞（hSC-CM）提供了一个机会，以改善目前的临床前测试 通过在药物开发过程的早期使用机械相关的测定，一 像这样的范式转变将需要对测定平台、细胞和 与心脏毒性相关的潜在机制，以及收集专业知识， 进行评估和验证，这是一项复杂的任务。 这些工作最适合多个利益相关者之间的协作，包括 科学家和组织。该提案包括努力首先定义蜂窝 心血管毒性机制，然后是一个过程，以测试和建立信心， 能够预测所述毒性的体外方法。这项研究的目的是 与FDA的关注领域保持一致，“1。现代化毒理学以提高产品质量 安全。” 熟练的科学协调和管理是高效设计的必要条件， 开展多地点协作科学研究。这对研究来说尤其重要， 这些建议旨在为应用药物开发和药物治疗提供直接价值。 通过公共和私营部门科学家的参与实现安全。这种多部门、多领域的合作， 学科专业知识将使拟议的计划，以有效地界定核心心血管疾病 责任，并就新型体外试验的实用性达成共识， 这些责任。组织经验，除了广泛的科学成员， 给予HESI进行无偏见科学所需的可信度， 社区对这些新检测的信心。HESI是解决这些问题的正确组织 挑战和解决新的和二十一世纪的心血管安全性问题 科学视角

Title: Consortium Led Evaluation of Integrated Human-Relevant Approaches to Identify Drug Induced Cardiovascular Liabilities FOA Title and Number: Validating Human Stem Cell Cardiomyocyte Technology for Better Predictive Assessment of Drug-Induced Cardiac Toxicity (U01 Clinical Trial Not Allowed), RFA- FD-19-002 Proposed project start date: September 30, 2019 Proposed end date: September 30, 2022 Project Summary/Abstract: Cardiovascular drug-induced toxicity remains a major cause of drug attrition in both preclinical and clinical phases of drug development (Laverty et al., 2011). This is likely due to gaps in the traditional preclinical models used to assess cardiotoxicities. Additionally, many of the traditional methods are deployed in later stages of drug development causing costly late stage attrition. Advancements in both in vitro technology platforms and human stem cell-derived cardiomyocytes (hSC-CMs) offer an opportunity to improve the current preclinical testing paradigm by using mechanistically-relevant assays earlier in the drug development process. A paradigm shift like this will require appropriate confidence in the assay platforms, cells and underlying mechanisms associated with the cardiotoxicities, as well as gathering expertise to conduct evaluation and validation, a complex task. These efforts are best suited to a collaborative effort between multiple stakeholders including individual scientists and organizations. This proposal includes an effort to first define cellular mechanisms of cardiovascular toxicity, followed by a process to test and build confidence in the in vitro methods capable of predicting said toxicities. The objective of this proposed research aligns well with the FDA’s area of interest, “1. Modernize Toxicology to Enhance Product Safety.” Skilled scientific coordination and management is a requirement for the efficient design and execution of multi-site collaborative science. This is particularly essential for the studies proposed here that are intended to provide direct value to applied drug development and drug safety via engagement of public and private sector scientists. This multi-sector and multi- disciplinary expertise will allow the proposed program to effectively define core cardiovascular liabilities and build consensus on the utility of novel in vitro assays that provide insights into these liabilities. The organizational experience, in addition to a broad scientific membership, gives HESI the credibility needed to conduct unbiased science and give the drug development community confidence in these new assays. HESI is the right organization to tackle these challenges and address the cardiovascular safety issues from a novel and twenty-first century science perspective.