{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:29:59Z","timestamp":1793723399798,"version":"4.6.1"},"reference-count":30,"publisher":"The Journal of Health Economics and Outcomes Research","issue":"2","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["jheor.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:sec id=\"background\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Crossover distortion in oncology trials occurs when control-arm patients switch to agent(s) in the experimental arm, potentially attenuating treatment effects in intention-to-treat (ITT) overall survival (OS) analyses. This complicates health technology assessment (HTA) decision-making by masking true treatment benefits. Understanding crossover thresholds compromising ITT OS statistical significance is critical for interpreting trial outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"objective\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aimed to identify minimum threshold beyond which crossover rates are associated with loss of ITT OS statistical significance in advanced\/metastatic breast, colorectal, gastrointestinal stromal, lung, prostate, and renal cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"methods\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic literature review of HTA reports (2013-2024) from NICE-UK, CDA-Canada, HAS-France, G-BA\/IQWiG-Germany, PBAC-Australia, AIFA-Italy, AEMPS-Spain, and ICER-US was conducted. Searches were augmented with information from clinical practice guidelines and product labels from regulatory agencies. Submissions reporting crossover rates, with\/without crossover-mitigation strategies applied, were analyzed to quantify the relationship between crossover rates and ITT OS statistical significance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"results\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fifty unique trials from 114 submissions reported crossover rates (NICE\u2009=\u200925, HAS\u2009=\u200919, CDA\u2009=\u200915, PBAC\u2009=\u200913, G-BA\/IQWiG\u2009=\u200932, AEMPS\u2009=\u20099, ICER\u2009=\u20091), with crossover-mitigation strategies applied in 26 trials. A hypothesis-generating minimum benchmark of crossover rate (the ratio of control-arm participants switching to agent(s) in the experimental arm) ~42.7% was identified above which ITT OS lost statistical significance. Trials with high crossover rates (42.7%-88%) showed nonsignificant OS improvements, whereas lower rates (&lt;42.5%) demonstrated significant OS benefits. Higher crossover rates were observed in trials with built-in vs natural crossover (52.9% vs 8.1%). In first-line setting, crossover rates &gt;42.5% typically diluted OS benefit. In later-line and refractory diseases, OS significance often persisted beyond 42.7% threshold due to limited confounding by post-progression treatment options and faster death event accrual.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"conclusion\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Crossover impact varied by tumor type, treatment line, crossover type, and trial maturity. Crossover &gt;42.7% generally compromised ITT OS significance; however, OS maturity attained in the trial or sustained efficacy of the intervention beyond progression may preserve statistical significance despite high crossover. A crossover rate exceeding 42.7% was associated with nonsignificant ITT OS outcomes in most trials, particularly in first-line settings. OS benefits may persist in later-line settings with fewer post-progression treatment alternatives. This evidence supports contextual interpretation of crossover-affected OS during HTA decision-making.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.36469\/001c.163160","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:45:45Z","timestamp":1783442745000},"update-policy":"https:\/\/doi.org\/10.36469\/00001","source":"Crossref","is-referenced-by-count":0,"title":["Identifying Minimum Threshold Level of Trial Crossover Rates Yielding Nonsignificant Overall Survival Benefit Associated with Cancer Treatments: A Systematic Literature Review of HTA Submissions"],"prefix":"10.36469","volume":"13","author":[{"given":"Anandaroop","family":"Dasgupta","sequence":"first","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Kaushik","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barinder","family":"Singh","sequence":"additional","affiliation":[{"name":"Pharmacoevidence, Mohali, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2921-745X","authenticated-orcid":false,"given":"Sumeet","family":"Attri","sequence":"additional","affiliation":[{"name":"Pharmacoevidence, Mohali, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billy","family":"Amzal","sequence":"additional","affiliation":[{"name":"Phastar, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Gluz","sequence":"additional","affiliation":[{"name":"Breast Center Niederrhein, Evangelical Hospital Johanniter Bethesda, Moenchengladbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"22273","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref1","article-title":"TA488 Regorafenib for previously treated unresectable or metastatic gastrointestinal stromal tumours","author":"GRID"},{"key":"ref2","article-title":"TA515 Eribulin for treating locally advanced or metastatic breast cancer after 1 chemotherapy regimen","author":"Study301"},{"key":"ref3","article-title":"KEYNOTE-024. 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Isbary","year":"2018","journal-title":"Value Health"},{"issue":"12","key":"ref21","doi-asserted-by":"publisher","first-page":"S374","DOI":"10.1016\/j.jval.2024.10.1931","article-title":"HTA106 How has treatment switching been accounted for? insights from NICE appraisals","volume":"27","author":"G. Kijauskaite","year":"2024","journal-title":"Value Health"},{"key":"ref22","article-title":"NICE DSU Technical Support Document 24: Adjusting survival time estimates in the presence of treatment switching: An update to TSD 16","author":"H. Bell Gorrod","year":"2024"},{"issue":"12","key":"ref23","doi-asserted-by":"publisher","first-page":"S470","DOI":"10.1016\/j.jval.2025.09.2108","article-title":"HTA325 The perils of treatment crossover in clinical trials","volume":"28","author":"M. R. Nikolopoulou","year":"2025","journal-title":"Value Health"},{"key":"ref24","article-title":"KEYNOTE-355. [A21-145] Pembrolizumab (breast cancer, triple-negative, locally recurrent\/metastatic, in combination with chemotherapy) - Benefit assessment according to \u00a735a Social Code Book V"},{"key":"ref25","article-title":"COU-AA-302. CT14126 ZYTIGA (ac\u00e9tate d'abirat\u00e9rone\/ abirat\u00e9rone (ac\u00e9tate d')\/ abit\u00e9rone)"},{"key":"ref26","article-title":"LAURA. 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