{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:22:18Z","timestamp":1792815738460,"version":"4.5.0"},"reference-count":18,"publisher":"BMJ","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate the regulatory handling of cancer drugs that were granted accelerated approval by the US Food and Drug Administration (FDA) but failed to improve the primary endpoint in post-approval trials and to evaluate the extent to which negative post-approval trials changed the recommendations in treatment guidelines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Retrospective observational study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>FDA and National Comprehensive Cancer Network (NCCN) reports.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Included drugs<\/jats:title>\n                    <jats:p>Cancer drugs that received accelerated approval from the FDA and had negative post-approval trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main outcome measures<\/jats:title>\n                    <jats:p>Regulatory outcomes, including withdrawal, conversion to regular approval, and no action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>18 indications for 10 cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials were identified. Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA. Of the 11 withdrawals, six occurred in 2021 alone. The remaining six (33%) indications remain on the label. The NCCN guidelines provide a high level of endorsement (category 1 endorsement for one and category 2A endorsement for seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Cancer drug indications that received accelerated approval often remained on formal FDA approved drug labelling and continued to be recommended in clinical guidelines several years after statutorily required post-approval trials showed no improvement in the primary efficacy endpoint. Clinical guidelines should better align with the results of post-approval trials of cancer drugs that received accelerated approval.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmj.n1959","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T21:35:17Z","timestamp":1631136917000},"page":"n1959","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":92,"title":["Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study"],"prefix":"10.1136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7444-8594","authenticated-orcid":false,"given":"Bishal","family":"Gyawali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin N","family":"Rome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron S","family":"Kesselheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,9,8]]},"reference":[{"key":"2021090822250590000_374.sep08_4.n1959.1","unstructured":"FDA-NIH Biomarker Working Group . BEST (Biomarkers, EndpointS, and other Tools) Resource. US Food and Drug Administration, National Institutes of Health, 2016."},{"key":"2021090822250590000_374.sep08_4.n1959.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2020.100332"},{"key":"2021090822250590000_374.sep08_4.n1959.3","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31957"},{"key":"2021090822250590000_374.sep08_4.n1959.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0066-3"},{"key":"2021090822250590000_374.sep08_4.n1959.5","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.5618"},{"key":"2021090822250590000_374.sep08_4.n1959.6","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2019.0462"},{"key":"2021090822250590000_374.sep08_4.n1959.7","doi-asserted-by":"publisher","DOI":"10.1111\/1468-0009.12413"},{"key":"2021090822250590000_374.sep08_4.n1959.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1107201"},{"key":"2021090822250590000_374.sep08_4.n1959.9","unstructured":"US Food and Drug Administration. FDA In Brief: FDA Oncologic Drugs Advisory Committee to Review Status of Six Indications Granted Accelerated Approval. 2021. https:\/\/www.fda.gov\/news-events\/fda-brief\/fda-brief-fda-oncologic-drugs-advisory-committee-review-status-six-indications-granted-accelerated."},{"key":"2021090822250590000_374.sep08_4.n1959.10","unstructured":"US Food and Drug Administration. 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Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. https:\/\/www.fda.gov\/drugs\/development-resources\/table-surrogate-endpoints-were-basis-drug-approval-or-licensure."},{"key":"2021090822250590000_374.sep08_4.n1959.16","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2019.7345"},{"key":"2021090822250590000_374.sep08_4.n1959.17","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2021.4604"},{"key":"2021090822250590000_374.sep08_4.n1959.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1700446"}],"container-title":["BMJ"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/data.bmj.org\/tdm\/10.1136\/bmj.n1959","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmj.n1959","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T01:25:16Z","timestamp":1631150716000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.bmj.com\/lookup\/doi\/10.1136\/bmj.n1959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,8]]},"references-count":18,"alternative-id":["10.1136\/bmj.n1959"],"URL":"https:\/\/doi.org\/10.1136\/bmj.n1959","relation":{},"ISSN":["1756-1833"],"issn-type":[{"value":"1756-1833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,8]]}}}