{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:59:19Z","timestamp":1790618359582,"version":"4.1.0"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pebble Institute"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Preclinical animal studies are considered essential for therapeutic development, yet translation to human benefit remains poor. The commonly cited translation rate of approximately 20% conflates trial entry with regulatory approval and may substantially overestimate the predictive validity of animal models for specific therapeutic indications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine, for preclinical acute injury studies in small animal models: (a) the proportion progressing to human clinical trials; (b) the proportion achieving regulatory approval for the tested indication; (c) whether approvals represented novel translations or repurposed\/class-effect approvals; and (d) post-market safety outcomes for translational successes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Systematic review following PRISMA 2020 and SYRCLE guidance. We included controlled preclinical studies in small animal models (rats, mice, guinea pigs, hamsters, rabbits) of acute injury that tested a therapeutic intervention not already in routine clinical use, published 1990\u20132010. MEDLINE (via PubMed) was searched on 22 March 2022; full strategy in S1 File, Section S3. Five reviewers independently screened records in duplicate. Risk of bias was assessed with the SYRCLE tool. Therapies were grouped by active ingredient and classified against pre-specified regulatory categories by two reviewers blinded to post-market safety, with a third adjudicating. Post-market safety used five pre-defined criteria. Translation rates were synthesised descriptively as proportions with 95% Wilson score confidence intervals; no meta-analysis was performed. The review was registered on OSF (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/osf.io\/w97fd\" xlink:type=\"simple\">https:\/\/osf.io\/w97fd<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 3,847 records identified, 1,257 studies met inclusion criteria, yielding 100 distinct therapies with sufficient clinical outcome data (83 drugs, 17 devices\/physical interventions). Translation-to-trial was 20.0% (251\/1,257; 95% CI 17.9\u201322.4%). Among 83 drug therapies, only 3 (3.6%; 95% CI 1.2\u201310.1%) achieved first-in-class regulatory approval for the tested indication; 15 (18.1%) definitively failed in clinical trials. In an exploratory post-market analysis, 86% of drugs meeting any definition of translational success subsequently demonstrated major safety concerns; only beractant (Survanta\u00ae) remains in routine clinical use for the tested indication without major caveats, and this was not a novel first-in-class translation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec005\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Within acute injury research, the true regulatory success rate for novel preclinical therapies is 3.6%, likely an upper bound given publication bias. Most approved drugs subsequently experienced serious post-market safety concerns. Small rodent models have limited demonstrated predictive validity for human therapeutic outcomes in this domain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec006\">\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p>\n                      Open Science Framework,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/osf.io\/w97fd\" xlink:type=\"simple\">https:\/\/osf.io\/w97fd<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0358773","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:23:36Z","timestamp":1790616216000},"page":"e0358773","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["From preclinical promise to regulatory reality: translation of small rodent acute injury therapies to human approval and safety outcomes: A systematic review"],"prefix":"10.1371","volume":"21","author":[{"given":"Timothy R.","family":"Entwistle","sequence":"first","affiliation":[{"name":"Pebble Institute","place":["Manchester, United Kingdom"]},{"name":"Pebble Biotechnology Laboratories","place":["Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Cowey","sequence":"additional","affiliation":[{"name":"Pebble Institute","place":["Manchester, United Kingdom"]},{"name":"Pebble Biotechnology Laboratories","place":["Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza","family":"Stokoe","sequence":"additional","affiliation":[{"name":"Pebble Institute","place":["Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9452-2843","authenticated-orcid":true,"given":"John P.","family":"Stone","sequence":"additional","affiliation":[{"name":"Pebble Institute","place":["Manchester, United Kingdom"]},{"name":"Pebble Biotechnology Laboratories","place":["Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Fildes","sequence":"additional","affiliation":[{"name":"Pebble Institute","place":["Manchester, United Kingdom"]},{"name":"Pebble Biotechnology Laboratories","place":["Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"pone.0358773.ref001","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jhealeco.2016.01.012","article-title":"Innovation in the pharmaceutical industry: New estimates of R&D costs","volume":"47","author":"JA DiMasi","year":"2016","journal-title":"J Health Econ"},{"issue":"7","key":"pone.0358773.ref002","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.jacbts.2019.10.008","article-title":"Limitations of animal studies for predicting toxicity in clinical trials: Is it time to rethink our current approach?","volume":"4","author":"GA Van Norman","year":"2019","journal-title":"JACC Basic Transl Sci"},{"issue":"1","key":"pone.0358773.ref003","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1186\/s12967-018-1678-1","article-title":"Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail","volume":"16","author":"P Pound","year":"2018","journal-title":"J Transl Med"},{"issue":"2","key":"pone.0358773.ref004","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nrn3407","article-title":"Animal models of traumatic brain injury","volume":"14","author":"Y Xiong","year":"2013","journal-title":"Nat Rev Neurosci"},{"issue":"3","key":"pone.0358773.ref005","first-page":"207","article-title":"The Mighty Mouse: the impact of rodents on advances in biomedical research","volume":"110","author":"EC Bryda","year":"2013","journal-title":"Mo Med"},{"issue":"3","key":"pone.0358773.ref006","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1000245","article-title":"Can animal models of disease reliably inform human studies?","volume":"7","author":"HB van der Worp","year":"2010","journal-title":"PLoS 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Downing","year":"2017","journal-title":"JAMA"},{"key":"pone.0358773.ref017","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"MJ Page","year":"2021","journal-title":"BMJ"},{"key":"pone.0358773.ref018","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1471-2288-14-43","article-title":"SYRCLE\u2019s risk of bias tool for animal studies","volume":"14","author":"CR Hooijmans","year":"2014","journal-title":"BMC Med Res Methodol"},{"issue":"1","key":"pone.0358773.ref019","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ebm2.7","article-title":"A protocol format for the preparation, registration and publication of systematic reviews of animal intervention studies","volume":"2","author":"RBM de Vries","year":"2015","journal-title":"Evid Based Preclin Med"},{"issue":"1","key":"pone.0358773.ref020","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s13643-017-0644-y","article-title":"Optimal database combinations for literature searches in systematic reviews: a prospective exploratory study","volume":"6","author":"WM Bramer","year":"2017","journal-title":"Syst Rev"},{"key":"pone.0358773.ref021","article-title":"Automated Paper Screening for Clinical Reviews Using Large Language Models: Data Analysis Study","volume":"26","author":"E Guo","year":"2024","journal-title":"J Med Internet Res"},{"issue":"2","key":"pone.0358773.ref022","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1179\/2049396713Y.0000000020","article-title":"Staff report on Medtronic\u2019s influence on INFUSE clinical studies","volume":"19","author":"United States Senate Finance Committee","year":"2013","journal-title":"Int J Occup Environ Health"},{"issue":"26","key":"pone.0358773.ref023","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1056\/NEJMoa1404304","article-title":"Very early administration of progesterone for acute traumatic brain injury","volume":"371","author":"DW Wright","year":"2014","journal-title":"N Engl J Med"},{"issue":"26","key":"pone.0358773.ref024","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1056\/NEJMoa1411090","article-title":"A clinical trial of progesterone for severe traumatic brain injury","volume":"371","author":"BE Skolnick","year":"2014","journal-title":"N Engl J Med"},{"issue":"11","key":"pone.0358773.ref025","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3109\/02699052.2015.1065344","article-title":"Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials","volume":"29","author":"DG Stein","year":"2015","journal-title":"Brain Inj"},{"key":"pone.0358773.ref026","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1093\/brain\/aws072","article-title":"Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury","volume":"135","author":"S Casha","year":"2012","journal-title":"Brain"},{"issue":"5","key":"pone.0358773.ref027","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1161\/01.STR.0000125719.25853.20","article-title":"Pooling of animal experimental data reveals influence of study design and publication bias","volume":"35","author":"MR Macleod","year":"2004","journal-title":"Stroke"},{"key":"pone.0358773.ref028","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jneumeth.2013.09.010","article-title":"Meta-analysis of data from animal studies: a practical guide","volume":"221","author":"HM Vesterinen","year":"2014","journal-title":"J Neurosci Methods"},{"issue":"6","key":"pone.0358773.ref029","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.spinee.2011.04.023","article-title":"A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned","volume":"11","author":"EJ Carragee","year":"2011","journal-title":"Spine J"},{"issue":"12","key":"pone.0358773.ref030","doi-asserted-by":"crossref","first-page":"890","DOI":"10.7326\/0003-4819-158-12-201306180-00006","article-title":"Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis","volume":"158","author":"R Fu","year":"2013","journal-title":"Ann Intern Med"},{"issue":"12","key":"pone.0358773.ref031","doi-asserted-by":"crossref","first-page":"877","DOI":"10.7326\/0003-4819-158-12-201306180-00005","article-title":"Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data","volume":"158","author":"MC Simmonds","year":"2013","journal-title":"Ann Intern Med"},{"key":"pone.0358773.ref032","unstructured":"Schultz DG. FDA Public Health Notification: Life-threatening Complications Associated with Recombinant Human Bone Morphogenetic Protein in Cervical Spine Fusion. 2008. Available from: https:\/\/wayback.archive-it.org\/7993\/20170111190511\/http:\/www.fda.gov\/MedicalDevices\/Safety\/AlertsandNotices\/PublicHealthNotifications\/ucm062000.htm"},{"issue":"11","key":"pone.0358773.ref033","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1056\/NEJM199909093411102","article-title":"Increased mortality associated with growth hormone treatment in critically ill adults","volume":"341","author":"J Takala","year":"1999","journal-title":"N Engl J Med"},{"issue":"11","key":"pone.0358773.ref034","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1056\/NEJM199909093411110","article-title":"Growth hormone therapy in critically ill patients","volume":"341","author":"R Demling","year":"1999","journal-title":"N Engl J Med"},{"issue":"6","key":"pone.0358773.ref035","article-title":"Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans","volume":"7","author":"Y Xie","year":"2017","journal-title":"BMJ Open"},{"issue":"2","key":"pone.0358773.ref036","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1001\/jamainternmed.2015.7193","article-title":"Proton pump inhibitor use and the risk of chronic kidney disease","volume":"176","author":"B Lazarus","year":"2016","journal-title":"JAMA Intern Med"},{"issue":"7","key":"pone.0358773.ref037","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1681\/ASN.0000000000000356","article-title":"The effects of pantoprazole on kidney outcomes: post hoc observational analysis from the COMPASS Trial","volume":"35","author":"L Pyne","year":"2024","journal-title":"J Am Soc Nephrol"},{"issue":"3","key":"pone.0358773.ref038","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1097\/00005792-199005000-00003","article-title":"Mannitol-induced acute renal failure","volume":"69","author":"HR Dorman","year":"1990","journal-title":"Medicine (Baltimore)"},{"issue":"6","key":"pone.0358773.ref039","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.3171\/2013.12.JNS13888","article-title":"Increased risk of acute kidney injury associated with higher infusion rate of mannitol in patients with intracranial hemorrhage","volume":"120","author":"MY Kim","year":"2014","journal-title":"J Neurosurg"},{"issue":"8","key":"pone.0358773.ref040","article-title":"Mannitol for acute traumatic brain injury","volume":"2013","author":"A Wakai","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"issue":"1","key":"pone.0358773.ref041","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1227\/NEU.0000000000001432","article-title":"Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition","volume":"80","author":"N Carney","year":"2017","journal-title":"Neurosurgery"},{"issue":"10","key":"pone.0358773.ref042","first-page":"813","article-title":"A systematic review of traumatic brain injury in modern rodent models: current status and future prospects","volume":"13","author":"E Balakin","year":"2024","journal-title":"Biology (Basel)"},{"key":"pone.0358773.ref043","doi-asserted-by":"crossref","first-page":"6","DOI":"10.33696\/Neurol.4.068","article-title":"Current spinal cord injury animal models are too simplistic for clinical translation","volume":"4","author":"L Gliksten","year":"2023","journal-title":"J Exp Neurol"},{"issue":"7","key":"pone.0358773.ref044","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"18","author":"N Percie du Sert","year":"2020","journal-title":"PLoS Biol"},{"issue":"7419","key":"pone.0358773.ref045","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nature11556","article-title":"A call for transparent reporting to optimize the predictive value of preclinical research","volume":"490","author":"SC Landis","year":"2012","journal-title":"Nature"},{"issue":"7391","key":"pone.0358773.ref046","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/483531a","article-title":"Drug development: Raise standards for preclinical cancer research","volume":"483","author":"CG Begley","year":"2012","journal-title":"Nature"},{"issue":"10","key":"pone.0358773.ref047","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.1002273","article-title":"Risk of Bias in reports of in vivo research: A Focus for Improvement","volume":"13","author":"MR Macleod","year":"2015","journal-title":"PLoS Biol"},{"issue":"11","key":"pone.0358773.ref048","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0275962","article-title":"Reporting quality in preclinical animal experimental research in 2009 and 2018: A nationwide systematic investigation","volume":"17","author":"BS Kousholt","year":"2022","journal-title":"PLoS 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anesthesia","volume":"13","author":"V Leung","year":"2018","journal-title":"PLoS One"},{"issue":"7","key":"pone.0358773.ref052","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1016\/j.apsb.2022.02.002","article-title":"Why 90% of clinical drug development fails and how to improve it?","volume":"12","author":"D Sun","year":"2022","journal-title":"Acta Pharm Sin B"},{"issue":"2","key":"pone.0358773.ref053","first-page":"114","article-title":"Lost in translation: animal models and clinical trials in cancer treatment","volume":"6","author":"IW Mak","year":"2014","journal-title":"Am J Transl Res"},{"key":"pone.0358773.ref054","unstructured":"FDA Modernization Act 2.0. 2022."},{"issue":"8","key":"pone.0358773.ref055","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1377\/hlthaff.2014.0122","article-title":"Era of faster FDA drug approval has also seen increased black-box warnings and market withdrawals","volume":"33","author":"C 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