{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:27:52Z","timestamp":1790836072824,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>This study evaluated human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes (hiPSC\u2010CMs) as a non\u2010animal, new approach methodology for assessing cardiovascular repolarization risk, comparing hiPSC\u2010CM data with traditional non\u2010clinical methods (hERG assays and animal studies) to support regulatory decisions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>A pilot study of over\u200920 Investigational New Drug applications submitted to the FDA between 2020 and 2023 were retrospectively analysed, comparing hiPSC\u2010CM studies using multielectrode array and voltage sensing optical platforms to traditional methods. Analysis focused on concordance between methods and their ability to predict clinical QT prolongation risk for five clinical QT positive and 18 clinical QT negative drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>hiPSC\u2010CMs displayed greater overall concordance (0.71\u20130.82) relative to non\u2010clinical animal studies than hERG studies (0.54\u20130.64). hiPSC\u2010CMs demonstrated comparable likelihood ratios and overall accuracy (0.83) in predicting clinical QT prolongation relative to single\u2010dose in vivo non\u2010rodent QT (0.74) and other animal studies (0.78). Inclusion of additional animal studies had negligible impact on overall concordance, supporting the 3Rs. Approximately 50% of non\u2010clinical in vivo QT studies tested concentrations at or below clinical Cmax, while in vitro assays generally evaluated higher exposures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>hiPSC\u2010CMs offer a promising alternative to extensive animal testing for cardiovascular risk assessment. Limitations include small sample size, low prevalence of clinical QT true positives (though each non\u2010clinical assay's higher negative predictive value versus positive predictive value provided higher confidence in negative QTc signals), early\u2010phase data, and variability in hiPSC\u2010CM study rigour. Examples for implementation were provided, but further research is needed to integrate hiPSC\u2010CMs more broadly into regulatory workflows.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70509","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:10:51Z","timestamp":1780629051000},"page":"5300-5314","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In vitro cardiac new approach methodologies predict clinical cardiovascular repolarization risk comparable to non\u2010clinical animal studies"],"prefix":"10.1111","volume":"183","author":[{"given":"Natalie E.","family":"Simpson","sequence":"first","affiliation":[{"name":"Immediate Office, Office of New Drug, Center for Drug Evaluation and Research U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tromondae K.","family":"Feaster","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Sciences, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ksenia","family":"Blinova","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Sciences, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nakissa","family":"Sadrieh","sequence":"additional","affiliation":[{"name":"Immediate Office, Office of New Drug, Center for Drug Evaluation and Research U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70231"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.08.079"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfw200"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-019-6413-7"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehi092"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfu198"},{"key":"e_1_2_12_8_1","unstructured":"FDA. (2025).FDA Roadmap to Reducing Animal Testing in Preclinical Safety Studieshttps:\/\/www.fda.gov\/news-events\/press-announcements\/fda-announces-plan-phase-out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs"},{"key":"e_1_2_12_9_1","unstructured":"FDA S7A. (2001).S7A Safety Pharmacology Studies for Human Pharmaceuticalshttps:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/s7a-safety-pharmacology-studies-human-pharmaceuticals"},{"key":"e_1_2_12_10_1","unstructured":"FDA S7B. (2005).S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticalshttps:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/s7b-nonclinical-evaluation-potential-delayed-ventricular-repolarization-qt-interval-prolongation"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2010.08.008"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2020.104756"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00310-2"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2024.117135"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70249"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.15.2004"},{"key":"e_1_2_12_17_1","unstructured":"ICH. 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