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.