{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:58:07Z","timestamp":1766145487794,"version":"3.48.0"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F31AG077880"],"award-info":[{"award-number":["F31AG077880"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Adaptive randomization is a clinical trial design feature used to modify treatment allocation probabilities during accrual. In time-to-event trials, the impact of adaptive randomization is less well understood for estimating treatment efficacy in the presence of time-varying effects [e.g., relative risk of progression to acquired immunodeficiency syndrome (AIDS) or death changes over time]. Here, we focus on time-to-event trials where the scientific estimand is a marginal hazard ratio in the absence of intermittent censoring over the support of observed times. We analytically show that adaptive randomization alters censoring patterns and illustrate via Monte Carlo simulations that the Cox proportional hazards estimator can yield biased estimates. As a remedy, we propose a censoring-robust estimator based on reweighting the partial likelihood score by treatment-specific censoring distributions that account for adaptive randomization. We derive the asymptotic properties of the proposed estimator and evaluate its finite sample operating characteristics via simulation. Finally, we apply our proposed method using data from the Community Programs for Clinical Research on AIDS Trial 002.<\/jats:p>","DOI":"10.1093\/biomtc\/ujaf161","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T12:59:42Z","timestamp":1763211582000},"source":"Crossref","is-referenced-by-count":0,"title":["Censoring-robust estimation in fixed sample time-to-event clinical trials with adaptive randomization"],"prefix":"10.1093","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-1438","authenticated-orcid":false,"given":"Navneet R","family":"Hakhu","sequence":"first","affiliation":[{"name":"Harvard T.H. Chan School of Public Health Department of Biostatistics, , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1983-9730","authenticated-orcid":false,"given":"Daniel L","family":"Gillen","sequence":"additional","affiliation":[{"name":"University of California, Irvine Department of Statistics, , Irvine, CA 92697 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"2025121906533155900_bib1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1056\/NEJM199403103301001","article-title":"A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection","volume":"330","author":"Abrams","year":"1994","journal-title":"New England Journal of Medicine"},{"key":"2025121906533155900_bib2","volume-title":"Selected R code functions provided by author and unpublished from censoring-robust treatment effect estimation in clinical trials with time-to-event outcomes","author":"Boyd","year":"2009"},{"key":"2025121906533155900_bib3","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1002\/sim.5440","article-title":"Estimation of treatment effect under non-proportional hazards and conditionally independent censoring","volume":"31","author":"Boyd","year":"2012","journal-title":"Statistics in Medicine"},{"key":"2025121906533155900_bib4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.2517-6161.1972.tb00899.x","article-title":"Regression models and life-tables","volume":"34","author":"Cox","year":"1972","journal-title":"Journal of the Royal Statistical Society: Series B (Methodological)"},{"key":"2025121906533155900_bib5","volume-title":"Counting Processes and Survival Analysis","author":"Fleming","year":"1991"},{"key":"2025121906533155900_bib6","doi-asserted-by":"crossref","DOI":"10.1002\/047005588X","volume-title":"The Theory of Response-Adaptive Randomization in Clinical Trials","author":"Hu","year":"2006"},{"key":"2025121906533155900_bib7","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1080\/01621459.1958.10501452","article-title":"Nonparametric estimation from incomplete observations","volume":"53","author":"Kaplan","year":"1958","journal-title":"Journal of the American Statistical Association"},{"key":"2025121906533155900_bib8","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1200\/JCO.2010.31.1423","article-title":"Outcome-adaptive randomization: is it useful?","volume":"29","author":"Korn","year":"2011","journal-title":"Journal of Clinical Oncology"},{"key":"2025121906533155900_bib9","doi-asserted-by":"crossref","first-page":"djx013","DOI":"10.1093\/jnci\/djx013","article-title":"Adaptive clinical trials: advantages and disadvantages of various adaptive design elements","volume":"109","author":"Korn","year":"2017","journal-title":"Journal of the National Cancer Institute"},{"key":"2025121906533155900_bib19_471_021825","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1177\/17407745211065762","article-title":"Time trends with response-adaptive randomization: The inevitability of inefficiency","volume":"19","author":"Korn","year":"2022","journal-title":"Clinical Trials"},{"key":"2025121906533155900_bib10","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1080\/10543406.2012.676535","article-title":"Adaptive randomization for clinical trials","volume":"22","author":"Rosenberger","year":"2012","journal-title":"Journal of Biopharmaceutical Statistics"},{"key":"2025121906533155900_bib11","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1093\/biomet\/73.2.363","article-title":"Misspecified proportional hazard models","volume":"73","author":"Struthers","year":"1986","journal-title":"Biometrika"},{"key":"2025121906533155900_bib12","article-title":"Survival Analysis, version 3.3-1","author":"The survival package","year":"2022"},{"key":"2025121906533155900_bib13","volume-title":"Adaptive Design Clinical Trials for Drugs and Biologics Guidance for Industry","author":"U.S. Food\u00a0Drug Administration","year":"2019"},{"key":"2025121906533155900_bib14","volume-title":"Benefit-Risk Assessment for New Drug and Biological Products Guidance for Industry","author":"U.S. Food\u00a0Drug Administration","year":"2023"},{"key":"2025121906533155900_bib15","volume-title":"Master Protocols for Drug and Biological Product Development Guidance for Industry","author":"U.S. Food\u00a0Drug Administration","year":"2023"},{"key":"2025121906533155900_bib16","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/biostatistics\/1.4.423","article-title":"Estimating average regression effect under non-proportional hazards","volume":"1","author":"Xu","year":"2000","journal-title":"Biostatistics"},{"key":"2025121906533155900_bib17","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1111\/rssb.12392","article-title":"Robust tests for treatment effect in survival analysis under covariate-adaptive randomization","volume":"82","author":"Ye","year":"2020","journal-title":"Journal of the Royal Statistical Society Series B: Statistical Methodology"},{"key":"2025121906533155900_bib18","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1467-9876.2007.00571.x","article-title":"Response-adaptive randomization for survival trials: the parametric approach","volume":"56","author":"Zhang","year":"2007","journal-title":"Journal of the Royal Statistical Society Series C: Applied Statistics"}],"container-title":["Biometrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biometrics\/article-pdf\/81\/4\/ujaf161\/66032598\/ujaf161.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biometrics\/article-pdf\/81\/4\/ujaf161\/66032598\/ujaf161.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:53:40Z","timestamp":1766145220000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biometrics\/article\/doi\/10.1093\/biomtc\/ujaf161\/8384136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":19,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,10,8]]}},"URL":"https:\/\/doi.org\/10.1093\/biomtc\/ujaf161","relation":{},"ISSN":["0006-341X","1541-0420"],"issn-type":[{"value":"0006-341X","type":"print"},{"value":"1541-0420","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,10,8]]},"article-number":"ujaf161"}}