{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T19:03:46Z","timestamp":1789844626700,"version":"4.0.1"},"reference-count":14,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100006229","name":"Oak Ridge Institute for Science and Education","doi-asserted-by":"publisher","award":["CDER-OND-M-24-11192"],"award-info":[{"award-number":["CDER-OND-M-24-11192"]}],"id":[{"id":"10.13039\/100006229","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drug Saf"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Based on the late Dr. Hyman Zimmerman\u2019s observation that hepatocellular drug-induced liver injury (DILI) leading to jaundice carries a \u2265 10% fatality risk (coined as Hy\u2019s law by others), evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) continues to play a central role in the assessment of a study drug\u2019s liability for acute hepatocellular DILI. The eDISH identifies drugs in clinical trials with DILI fatality (death or transplant) risk that may be unacceptable in a post-market setting. As a two-dimensional graph that plots peak total bilirubin (TB) versus peak serum aminotransferase levels for each patient during study drug or comparator treatment, eDISH identifies potential cases of acute, modest, and serious hepatocellular DILI for in-depth analysis of liver tests (LT) and clinical course so that the likelihood of causal association with the study drug can be determined. Unfortunately, the generalizable utility of this tool only pertains to trials enrolling patients with normal or near normal (NNN) baseline (BL) serum LTs. The eDISH does not necessarily apply to trials of patients with abnormal baseline (ABN-BL) LTs that often coincide with underlying liver disorders. Because drug development programs being reviewed by the FDA increasingly target liver disorders, we are often challenged to evaluate DILI risk in trials of patients with ABN-BL LTs. Also, the high background prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) means patients with LTs above NNN may need to be enrolled in trials treating non-liver disorders to reflect the target population. Such study populations create challenges for industry and regulators because eDISH may not reliably categorize or identify potential cases of DILI for further analysis, as it so efficiently does in NNN-BL trials. We describe the main functionalities of eDISH in NNN-BL trials to understand what should be emulated by new tools or eDISH modifications. We then discuss non-eDISH\u2013based plots that may be useful in ABN-BL trials.<\/jats:p>","DOI":"10.1007\/s40264-024-01511-8","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T16:06:17Z","timestamp":1739289977000},"page":"443-453","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Emerging Tools to Support DILI Assessment in Clinical Trials with Abnormal Baseline Serum Liver Tests or Pre-existing Liver Diseases"],"prefix":"10.1007","volume":"48","author":[{"given":"Jasmine","family":"Amirzadegan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bereket","family":"Tesfaldet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Veronica","family":"Pei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen","family":"Navarro Almario","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark I.","family":"Avigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5371-1020","authenticated-orcid":false,"given":"Paul H.","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"issue":"Suppl 1","key":"1511_CR1","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1007\/s40264-014-0182-7","volume":"37","author":"JR Senior","year":"2014","unstructured":"Senior JR. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Drug Saf. 2014;37(Suppl 1):S9-17. https:\/\/doi.org\/10.1007\/s40264-014-0182-7. (published Online First: 2014\/10\/30).","journal-title":"Drug Saf"},{"issue":"5","key":"1511_CR2","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1002\/hep.22633","volume":"48","author":"PB Watkins","year":"2008","unstructured":"Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to learn more about acute drug-induced liver injury. Hepatology. 2008;48(5):1680\u20139. https:\/\/doi.org\/10.1002\/hep.22633.","journal-title":"Hepatology"},{"issue":"2","key":"1511_CR3","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1055\/s-0034-1375961","volume":"34","author":"MI Avigan","year":"2014","unstructured":"Avigan MI. DILI and drug development: a regulatory perspective. Semin Liver Dis. 2014;34(2):215\u201326. https:\/\/doi.org\/10.1055\/s-0034-1375961. (published Online First: 20140531).","journal-title":"Semin Liver Dis"},{"key":"1511_CR4","doi-asserted-by":"crossref","unstructured":"Avigan M, Munoz, MA. Perspectives on the Regulatory and Clinical Science of Drug-induced Liver Injury. Drug-Induced Liver Toxicity: Springer Protocols, 2018:367-93.","DOI":"10.1007\/978-1-4939-7677-5_18"},{"key":"1511_CR5","unstructured":"Drug-induced liver injury (DILI): Current status and future directions for drug development and the post-market setting. A consensus by a CIOMS Working Group.; 2020; Geneva, Switzerland. Council for International Organizations of Medical Sciences (CIOMS), https:\/\/cioms.ch\/publications\/product\/drug-induced-liver-injury\/. Accessed 12 Jun 2024."},{"issue":"2","key":"1511_CR6","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1002\/hep.20800","volume":"42","author":"E Bjornsson","year":"2005","unstructured":"Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42(2):481\u20139. https:\/\/doi.org\/10.1002\/hep.20800.","journal-title":"Hepatology"},{"issue":"1","key":"1511_CR7","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1053\/j.gastro.2014.03.050","volume":"147","author":"M Robles-Diaz","year":"2014","unstructured":"Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hy\u2019s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014;147(1):109\u201385. https:\/\/doi.org\/10.1053\/j.gastro.2014.03.050. (published Online First: 20140401).","journal-title":"Gastroenterology"},{"issue":"1","key":"1511_CR8","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1053\/j.gastro.2014.03.045","volume":"147","author":"RJ Fontana","year":"2014","unstructured":"Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147(1):96-108e4. https:\/\/doi.org\/10.1053\/j.gastro.2014.03.045. (published Online First: 20140327).","journal-title":"Gastroenterology"},{"key":"1511_CR9","unstructured":"Food and Drug Administration. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/drug-induced-liver-injury-premarketing-clinical-evaluation. Accessed 12 Jun 2024."},{"issue":"8","key":"1511_CR10","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1002\/hep4.1992","volume":"6","author":"BL Shneider","year":"2022","unstructured":"Shneider BL, Spino CA, Kamath BM, et al. Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome. Hepatol Commun. 2022;6(8):1922\u201333. https:\/\/doi.org\/10.1002\/hep4.1992. ([published Online First: 20220607]).","journal-title":"Hepatol Commun"},{"issue":"6","key":"1511_CR11","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1002\/pds.3405","volume":"22","author":"D Parks","year":"2013","unstructured":"Parks D, Lin X, Painter JL, et al. A proposed modification to Hy\u2019s law and Edish criteria in oncology clinical trials using aggregated historical data. Pharmacoepidemiol Drug Saf. 2013;22(6):571\u20138. https:\/\/doi.org\/10.1002\/pds.3405.","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"1511_CR12","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-024-01425-5","author":"B Tesfaldet","year":"2024","unstructured":"Tesfaldet B, Patel T, Chen M, et al. Composite plot for visualizing aminotransferase and bilirubin changes in clinical trials of subjects with abnormal baseline values. Drug Saf. 2024. https:\/\/doi.org\/10.1007\/s40264-024-01425-5. ([published Online First: 20240420]).","journal-title":"Drug Saf"},{"issue":"2","key":"1511_CR13","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1001\/jama.2021.6986","volume":"326","author":"RS Kearney","year":"2021","unstructured":"Kearney RS, Ji C, Warwick J, et al. Effect of platelet-rich plasma injection vs sham injection on tendon dysfunction in patients with chronic midportion achilles tendinopathy: a randomized clinical trial. JAMA. 2021;326(2):137\u201344. https:\/\/doi.org\/10.1001\/jama.2021.6986.","journal-title":"JAMA"},{"issue":"11","key":"1511_CR14","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1001\/jama.2024.1215","volume":"331","author":"TG Simon","year":"2024","unstructured":"Simon TG, Wilechansky RM, Stoyanova S, et al. Aspirin for metabolic dysfunction-associated steatotic liver disease without cirrhosis: a randomized clinical trial. JAMA. 2024;331(11):920\u20139. https:\/\/doi.org\/10.1001\/jama.2024.1215.","journal-title":"JAMA"}],"container-title":["Drug Safety"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40264-024-01511-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40264-024-01511-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40264-024-01511-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T17:37:29Z","timestamp":1744220249000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40264-024-01511-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,11]]},"references-count":14,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["1511"],"URL":"https:\/\/doi.org\/10.1007\/s40264-024-01511-8","relation":{},"ISSN":["0114-5916","1179-1942"],"issn-type":[{"value":"0114-5916","type":"print"},{"value":"1179-1942","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,11]]},"assertion":[{"value":"11 December 2024","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2025","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Research Participation Program at the U.S. Food and Drug Administration administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (Grant no. CDER-OND-M-24-11192).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors have no conflicts of interest to declare.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The conclusions and views in this manuscript are the authors and do not represent an official position of the Food and Drug Administration.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimer"}},{"value":"Not applicable. Data are not identifiable to any drug product, subject, or patient.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Publication"}},{"value":"Not applicable. Datasets from new drug applications are not publicly available.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of Data"}},{"value":"Composite coding available on GitHub. Other coding to be available on GitHub shortly.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code Availability"}},{"value":"JA: study design, programming, data analysis, manuscript writing; BT: programming, data analysis; YVP: study design, manuscript writing; EN: study design, data analysis, manuscript writing; MIA: Study design, manuscript writing; PHH: study design, data analysis, manuscript. All authors have read and approved the final version.","order":10,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author Contributions"}}]}}