{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T02:10:14Z","timestamp":1785550214053,"version":"3.56.0"},"reference-count":33,"publisher":"American Medical Association (AMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>The US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy\u2013designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy\u2013designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Descriptive analyses were used to characterize the breakthrough therapy\u2013designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments.<\/jats:p><\/jats:sec>Results<\/jats:title>From 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this cross-sectional study of original FDA breakthrough therapy\u2013designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy\u2013designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.30486","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T15:01:15Z","timestamp":1724770875000},"page":"e2430486","source":"Crossref","is-referenced-by-count":12,"title":["Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies"],"prefix":"10.1001","volume":"7","author":[{"given":"Maryam","family":"Mooghali","sequence":"first","affiliation":[{"name":"Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut"},{"name":"Yale Collaboration for Regulatory Rigor, Integrity and Transparency, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Wallach","sequence":"additional","affiliation":[{"name":"Yale Collaboration for Regulatory Rigor, Integrity and Transparency, Yale School of Medicine, New Haven, Connecticut"},{"name":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Ross","sequence":"additional","affiliation":[{"name":"Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut"},{"name":"Yale Collaboration for Regulatory Rigor, Integrity and Transparency, Yale School of Medicine, New Haven, Connecticut"},{"name":"Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut"},{"name":"Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reshma","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut"},{"name":"Yale Collaboration for Regulatory Rigor, Integrity and Transparency, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2024,8,27]]},"reference":[{"issue":"4","key":"zoi240921r1","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1001\/jama.2013.282034","article-title":"Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.","volume":"311","author":"Downing","year":"2014","journal-title":"JAMA"},{"issue":"4","key":"zoi240921r2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.3284","article-title":"Assessment of clinical trials supporting US Food and Drug Administration approval of novel therapeutic agents, 1995-2017.","volume":"3","author":"Zhang","year":"2020","journal-title":"JAMA Netw Open"},{"key":"zoi240921r5","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.102283","article-title":"A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.","volume":"65","author":"Ciani","year":"2023","journal-title":"EClinicalMedicine"},{"issue":"7","key":"zoi240921r8","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1002\/ijc.v144.7","article-title":"Association between progression-free survival and patients\u2019 quality of life in cancer clinical trials.","volume":"144","author":"Hwang","year":"2019","journal-title":"Int J Cancer"},{"key":"zoi240921r9","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2020.100332","article-title":"Evaluating the evidence behind the surrogate measures included in the FDA\u2019s table of surrogate endpoints as supporting approval of cancer drugs.","volume":"21","author":"Gyawali","year":"2020","journal-title":"EClinicalMedicine"},{"issue":"8","key":"zoi240921r10","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1001\/jamainternmed.2015.2829","article-title":"The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses.","volume":"175","author":"Prasad","year":"2015","journal-title":"JAMA Intern Med"},{"issue":"19","key":"zoi240921r11","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1001\/jama.2024.4175","article-title":"Associations between surrogate markers and clinical outcomes for nononcologic chronic disease treatments.","volume":"331","author":"Wallach","year":"2024","journal-title":"JAMA"},{"issue":"8","key":"zoi240921r15","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.31753","article-title":"Use of expedited regulatory programs and clinical development times for FDA-approved novel therapeutics.","volume":"6","author":"Wong","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"3","key":"zoi240921r16","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1001\/jama.2018.7619","article-title":"Clinical trial evidence supporting FDA approval of drugs granted breakthrough therapy designation.","volume":"320","author":"Puthumana","year":"2018","journal-title":"JAMA"},{"issue":"9","key":"zoi240921r17","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1002\/phar.2018.38.issue-9","article-title":"FDA breakthrough therapy designation: evaluating the quality of the evidence behind the drug approvals.","volume":"38","author":"Herink","year":"2018","journal-title":"Pharmacotherapy"},{"issue":"11","key":"zoi240921r18","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1056\/NEJMp2306872","article-title":"The accelerated approval program for cancer drugs\u2014finding the right balance.","volume":"389","author":"Gyawali","year":"2023","journal-title":"N Engl J Med"},{"key":"zoi240921r23","doi-asserted-by":"publisher","first-page":"k2031","DOI":"10.1136\/bmj.k2031","article-title":"Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis.","volume":"361","author":"Wallach","year":"2018","journal-title":"BMJ"},{"issue":"7","key":"zoi240921r25","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1001\/jamainternmed.2019.0462","article-title":"Assessment of the clinical benefit of cancer drugs receiving accelerated approval.","volume":"179","author":"Gyawali","year":"2019","journal-title":"JAMA Intern Med"},{"issue":"1","key":"zoi240921r27","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/s12916-017-0902-9","article-title":"Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?","volume":"15","author":"Kemp","year":"2017","journal-title":"BMC Med"},{"key":"zoi240921r28","doi-asserted-by":"publisher","first-page":"f457","DOI":"10.1136\/bmj.f457","article-title":"Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study.","volume":"346","author":"Ciani","year":"2013","journal-title":"BMJ"},{"issue":"4","key":"zoi240921r29","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2023.7110","article-title":"Breakthrough therapy cancer drugs and indications with FDA approval: development time, innovation, trials, clinical benefit, epidemiology, and price.","volume":"22","author":"Michaeli","year":"2024","journal-title":"J Natl Compr Canc Netw"},{"issue":"15","key":"zoi240921r30","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1056\/NEJMhpr1713338","article-title":"The FDA breakthrough-drug designation\u2013four years of experience.","volume":"378","author":"Darrow","year":"2018","journal-title":"N Engl J Med"},{"key":"zoi240921r31","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2023-076138","article-title":"US FDA breakthrough therapy designation and consumer drug advertising: a recipe for confusion.","volume":"384","author":"Patel","year":"2024","journal-title":"BMJ"},{"issue":"1","key":"zoi240921r32","doi-asserted-by":"publisher","first-page":"e85","DOI":"10.1093\/oncolo\/oyab021","article-title":"Physician perceptions of the FDA\u2019s breakthrough therapy designation: an update.","volume":"27","author":"Paquin","year":"2022","journal-title":"Oncologist"},{"issue":"6","key":"zoi240921r33","doi-asserted-by":"publisher","DOI":"10.1001\/jamahealthforum.2023.1313","article-title":"Extending the US Food and Drug Administration\u2019s postmarket authorities.","volume":"4","author":"Fernandez Lynch","year":"2023","journal-title":"JAMA Health Forum"},{"key":"zoi240921r3","unstructured":"CFR\u2014Code of Federal Regulations Title 21. US Food and Drug Administration. January 15, 2024. Accessed January 15, 2024. https:\/\/www.accessdata.fda.gov\/scripts\/cdrh\/cfdocs\/cfcfr\/cfrsearch.cfm?fr=314.126"},{"key":"zoi240921r4","unstructured":"Surrogate endpoint resources for drug and biologic development. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/drugs\/development-resources\/surrogate-endpoint-resources-drug-and-biologic-development"},{"key":"zoi240921r6","unstructured":"Project Confirm: promoting the transparency of accelerated approval for oncology indications. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/about-fda\/oncology-center-excellence\/project-confirm"},{"key":"zoi240921r7","unstructured":"Table of surrogate endpoints that were the basis of drug approval or licensure. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/drugs\/development-resources\/table-surrogate-endpoints-were-basis-drug-approval-or-licensure"},{"key":"zoi240921r12","unstructured":"Guidance for industry: expedited programs for serious conditions\u2014drugs and biologics. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/media\/86377\/download"},{"key":"zoi240921r13","unstructured":"Breakthrough therapy. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/patients\/fast-track-breakthrough-therapy-accelerated-approval-priority-review\/breakthrough-therapy"},{"key":"zoi240921r14","unstructured":"Frequently asked questions: breakthrough therapies. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/regulatory-information\/food-and-drug-administration-safety-and-innovation-act-fdasia\/frequently-asked-questions-breakthrough-therapies"},{"key":"zoi240921r19","unstructured":"Breakthrough therapy approvals. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/drugs\/nda-and-bla-approvals\/breakthrough-therapy-approvals"},{"key":"zoi240921r20","unstructured":"Drugs@FDA: FDA-approved drugs. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm"},{"key":"zoi240921r21","unstructured":"Postmarketing requirements and commitments: introduction. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/drugs\/guidance-compliance-regulatory-information\/postmarket-requirements-and-commitments"},{"key":"zoi240921r22","unstructured":"Postmarket requirements and commitments. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/pmc\/index.cfm"},{"key":"zoi240921r24","unstructured":"Postmarketing requirements and commitments: frequently asked questions (FAQ). US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/drugs\/postmarket-requirements-and-commitments\/postmarketing-requirements-and-commitments-frequently-asked-questions-faq"},{"key":"zoi240921r26","unstructured":"FDA Facts: biomarkers and surrogate endpoints. US Food and Drug Administration. Accessed January 15, 2024. https:\/\/www.fda.gov\/about-fda\/innovation-fda\/fda-facts-biomarkers-and-surrogate-endpoints"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2822865\/mooghali_2024_oi_240921_1724178872.23412.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T15:01:19Z","timestamp":1724770879000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2822865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,27]]},"references-count":33,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2024.30486","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,27]]}}}