{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:12:42Z","timestamp":1787065962015,"version":"build-2736575974"},"reference-count":33,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T00:00:00Z","timestamp":1570060800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["EOG111391"],"award-info":[{"award-number":["EOG111391"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Clinical Trials"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5\u2009years of approval by the Food and Drug Administration of 12 anti-cancer \u201cindex\u201d drugs first licensed 2005\u20132007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>We captured 323 published post-approval trials exploring combinations, including 266 unique combination\u2013indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3\u20134 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33\u20131.79) and 1.51 (1.16\u20131.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92\u20131.05) and 0.85 (0.79\u20130.93), respectively. None of the combination\u2013indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5\u2009years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5\u2009years of follow-up, and 22.3% among pairings for which there were 8\u2009years of follow-up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/1740774519873883","type":"journal-article","created":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T09:11:10Z","timestamp":1570093870000},"page":"18-29","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Benefit, burden, and impact for a cohort of post-approval cancer combination trials"],"prefix":"10.1177","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8975-0649","authenticated-orcid":false,"given":"Benjamin Gregory","family":"Carlisle","sequence":"first","affiliation":[{"name":"Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2622-5948","authenticated-orcid":false,"given":"Ad\u00e9la\u00efde","family":"Doussau","sequence":"additional","affiliation":[{"name":"Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1614-6779","authenticated-orcid":false,"given":"Jonathan","family":"Kimmelman","sequence":"additional","affiliation":[{"name":"Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,10,3]]},"reference":[{"key":"bibr1-1740774519873883","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16723"},{"key":"bibr2-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1097\/MJT.0b013e3181ff7e23"},{"key":"bibr3-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1001\/jama.292.4.470"},{"key":"bibr4-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1995.13.5.1062"},{"key":"bibr5-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1067\/mpd.2003.192"},{"key":"bibr6-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsa042220"},{"key":"bibr7-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002505"},{"key":"bibr8-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19980101)82:1<116::AID-CNCR14>3.0.CO;2-5"},{"key":"bibr9-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1179\/1607845414Y.0000000159"},{"key":"bibr10-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31012"},{"key":"bibr11-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0669"},{"key":"bibr12-1740774519873883","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2007.06.004"},{"key":"bibr13-1740774519873883","unstructured":"U.S. Department of Health and Human Services. 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