{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:55:03Z","timestamp":1790794503418,"version":"4.1.0"},"reference-count":148,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>Preclinical drug development has long relied on animal models to predict safety and efficacy before agents enter human trials, despite critical differences between human and animal model physiology. The withdrawal of rosiglitazone, rofecoxib, and terfenadine due to cardiovascular toxicity exemplifies the translational cost of this mismatch. Alternative, human-based systems enable more accurate modeling of cardiometabolic diseases in a dish; in 2025, the US FDA\u2019s new approach methodologies (NAMs) roadmap authorized the submission of results from human-relevant models. The roadmap encourages utilizing biological and digital twins as part of an integrated, context-specific, fit-for-purpose strategy. A \u201cbiological twin\u201d is a human-derived in vitro system that captures the physiology of a patient and can be used to assess potential cardiotoxicity by drug metabolites. A \u201cdigital twin\u201d is the computational counterpart trained on clinical drug response results that can further interpret biological twin data at the patient scale and predict pharmacological parameters. NAMs are no longer experimental but are not yet fully validated as replacements for animal models; major challenges remain before they can be effectively incorporated into the cardiometabolic disease drug discovery pipeline. Addressing these challenges head-on is essential for improving drug development and prediction of their cardiovascular safety.<\/jats:p>","DOI":"10.1172\/jci209668","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:01:22Z","timestamp":1790791282000},"source":"Crossref","is-referenced-by-count":0,"title":["Clinical trials in a dish: cardiometabolic drug development with biological and digital twins"],"prefix":"10.1172","volume":"136","author":[{"given":"Debarun","family":"Patra","sequence":"first","affiliation":[{"name":"Stanford Cardiovascular Institute and"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim M.","family":"Sayed","sequence":"additional","affiliation":[{"name":"Greenstone Biosciences, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravichandra","family":"Venkateshappa","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute and"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latha","family":"Palaniappan","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-8041","authenticated-orcid":true,"given":"Joseph C.","family":"Wu","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute and"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105447"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000450"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.7008"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.54707"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1166"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2019.10.008"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.10.007"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/ame2.12223"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-025-01182-9"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202522276"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2026.02.012"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.aeb0045"},{"key":"B13","unstructured":"US Food & Drug Administration. New Approach Methods (NAMs). https:\/\/www.fda.gov\/science-research\/science-and-research-special-topics\/new-approach-methodologies-nams Updated July 28, 2026. Accessed August 3, 2026"},{"key":"B14"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2022.02.002"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI175824"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-025-03344-6"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.019"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.1188302"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1923-7"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00466-9"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-022-00882-6"},{"key":"B23","unstructured":"US Food & Drug Administration. FDA\u2019s ISTAND Pilot Program Accepts a Submission of First Organ-on-a-Chip Technology Designed to Predict Human Drug-Induced Liver Injury (DILI). https:\/\/www.fda.gov\/drugs\/drug-alerts-and-statements\/fdas-istand-pilot-program-accepts-submission-first-organ-chip-technology-designed-predict-human-drug Updated September 16, 2025. Accessed August 3, 2026"},{"key":"B24","unstructured":"US Food & Drug Administration. Drug-Induced Liver Injury Severity and Toxicity (DILIst) Dataset. https:\/\/www.fda.gov\/science-research\/liver-toxicity-knowledge-base-ltkb\/drug-induced-liver-injury-severity-and-toxicity-dilist-dataset Updated September 2, 2023. Accessed August 3, 2026"},{"key":"B25","unstructured":"US Food & Drug Administration. FDA Announces Plan to Phase Out Animal Testing Requirement for Monoclonal Antibodies and Other Drugs. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-announces-plan-phase-out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs Updated April 10, 2025. Accessed August 3, 2026"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav9051"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202001517"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj6152"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0016-3"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1612906114"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201701000"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.125.326720"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.125.325497"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2018.07.062"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1039\/D3LC00745F"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.124.011690"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-025-01166-4"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1118624"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1039\/D4LC00848K"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38704-1"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01731-9"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.03.001"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.01.010"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-026-02071-4"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab370"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.02.012"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-320622"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2025.05.004"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(25)00323-1"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2018.10.007"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.125.325492"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.03.042"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.020894"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.015308"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-025-01150-9"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn0910"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.09.014"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1172\/JCI186420"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2024.2324015"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70161"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2010.00137"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.667010"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1063\/5.0048986"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/srep20030"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08879-x"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab006"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2004.042473"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.08.079"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00668"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfw200"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2020.104756"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12674"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3389\/fddsv.2025.1679626"},{"key":"B74","doi-asserted-by":"crossref","unstructured":"Simpson NE, et al. In vitro cardiac new approach methodologies predict clinical cardiovascular repolarization risk comparable to non-clinical animal studies [published June 4, 2026]. Br J Pharmacol. https:\/\/doi.org\/10.1111\/bph.70509","DOI":"10.1111\/bph.70509"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd12080285"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.894725"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.90954"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2016.03.020"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.05.043"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3390\/cells12091293"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.138305"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202516114"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.09.055"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf2584"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.851941"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.738848"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.667252"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2024.08.002"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19197-8"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.124.321804"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2023.122450"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1038\/nature24998"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2021.08.003"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318241"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy531"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.032037"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01152-0"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2014.09.001"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2022.0523"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13504"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107925"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adq0143"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202503173"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00401.2023"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.012272"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22168994"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.100976"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd1817"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2023.106853"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-22749-0"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00674-3"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.reth.2025.04.023"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202503273"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-92264-2"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-33293-2"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahjo.2024.100386"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.061732"},{"key":"B118"},{"key":"B119","doi-asserted-by":"crossref","unstructured":"Ahuja N, et al. Utilising the digital twin for disease prevention, treatment and in silico research [published online June 12, 2026]. BMJ Digit Health AI. https:\/\/doi.org\/10.1136\/bmjdh-2026-000031","DOI":"10.1136\/bmjdh-2026-000031"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1016\/j.patter.2024.101028"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.3389\/fdgth.2026.1753906"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2024.09.030"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae619"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaa159"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12678"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202413405"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08829-y"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.124.070413"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1528748"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2532645122"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-024-00450-5"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2025.105904"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2023.105345"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.1002\/admt.202201435"},{"key":"B135","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adm9281"},{"key":"B136","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51698-8"},{"key":"B137","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.120.090472"},{"key":"B138","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2025.12.004"},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.4.2.175"},{"key":"B140","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.03.020"},{"key":"B141","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfaf064"},{"key":"B142","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109909"},{"key":"B143","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.042317"},{"key":"B144","unstructured":"National Toxicology Program. Validation & Qualification of New Methods. https:\/\/ntp.niehs.nih.gov\/whatwestudy\/niceatm\/resources-for-test-method-developers\/submissions Updated June 25, 2026. Accessed August 3, 2026"},{"key":"B145","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110643"},{"key":"B146","doi-asserted-by":"publisher","DOI":"10.1113\/EP086581"},{"key":"B147","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-025-01933-0"},{"key":"B148","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2026.115896"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/209668\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:02:12Z","timestamp":1790791332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/209668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":148,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,8,11]]},"published-print":{"date-parts":[[2026,10,1]]}},"alternative-id":["10.1172\/JCI209668"],"URL":"https:\/\/doi.org\/10.1172\/jci209668","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"e209668"}}