{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:35:28Z","timestamp":1760189728621,"version":"3.40.5"},"reference-count":27,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T00:00:00Z","timestamp":1583971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Single\u2010arm trials are currently an accepted study design to investigate the efficacy of novel therapies (NT) in non\u2010muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette\u2010Gu\u00e9rin (BCG) immunotherapy as randomized controlled trials are either unfeasible (comparator: early radical cystectomy; ERC), or unethical (comparator: placebo). To guide the design of such single\u2010arm trials, expert groups published recommendations for clinically meaningful outcomes. The aim of this study was to quantitatively verify the appropriateness of these recommendations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a discrete event simulation framework in combination with a supercomputer to find the required efficacy at which a NT can compete with ERC when it comes to quality\u2010adjusted life expectancy (QALE). In total, 24 different efficacy thresholds (including the recommendations) were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After ascertaining face validity with content experts, repeated verification, external validation, and calibration we considered our model valid. Both recommendations rarely showed an incremental benefit of the NT over ERC. In the most optimistic scenario, an increase in the IBCG recommendation by 10% and an increase in the FDA\/AUA recommendation by 5% would yield results at which a NT could compete with ERC from a QALE perspective.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This simulation study demonstrated that the current recommendations regarding clinically meaningful outcomes for single\u2010arm trials evaluating the efficacy of NT in BCG\u2010unresponsive NMIBC may be too low. Based on our quantitative approach, we propose increasing these thresholds to at least 45%\u201055% at 6\u00a0months and 35% at 18\u201024\u00a0months (complete response rates\/recurrence\u2010free survival) to promote the development of clinically truly meaningful NT.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.2980","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T16:51:36Z","timestamp":1584031896000},"page":"3287-3296","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Required efficacy for novel therapies in BCG\u2010unresponsive non\u2010muscle invasive bladder cancer: Do current recommendations really reflect clinically meaningful outcomes?"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1378-3625","authenticated-orcid":false,"given":"Marian S.","family":"Wettstein","sequence":"first","affiliation":[{"name":"Division of Urology Department of Surgery Princess Margaret Cancer Centre University Health Network University of Toronto Toronto Ontario Canada"},{"name":"Department of Urology University Hospital of Zurich University of Zurich Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Naimark","sequence":"additional","affiliation":[{"name":"Division of Nephrology Department of Medicine Sunnybrook Health Sciences Centre Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Hermanns","sequence":"additional","affiliation":[{"name":"Department of Urology University Hospital of Zurich University of Zurich Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6793-4404","authenticated-orcid":false,"given":"Jaime O.","family":"Herrera\u2010Caceres","sequence":"additional","affiliation":[{"name":"Division of Urology Department of Surgery Princess Margaret Cancer Centre University Health Network University of Toronto Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ardalan","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Division of Urology Department of Surgery Princess Margaret Cancer Centre University Health Network University of Toronto Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7162-5380","authenticated-orcid":false,"given":"Michael A.S.","family":"Jewett","sequence":"additional","affiliation":[{"name":"Division of Urology Department of Surgery Princess Margaret Cancer Centre University Health Network University of Toronto Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Girish S.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Division of Urology Department of Surgery Princess Margaret Cancer Centre University Health Network University of Toronto Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,3,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2017.16"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.05.041"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2008.07.031"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0302-2838(02)00351-2"},{"volume-title":"Center for Drug Evaluation and Research","year":"2018","author":"United States Food and Drug Administration","key":"e_1_2_9_6_1"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.4070"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2013.10.030"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v090.i02"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1088\/1742-6596\/256\/1\/012026"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","unstructured":"PonceM RvZ NorthrupS et al.Deploying a Top\u2010100 Supercomputer for Large Parallel Workloads: the Niagara Supercomputer. 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