{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T10:48:58Z","timestamp":1782211738738,"version":"3.54.5"},"reference-count":30,"publisher":"Wiley","issue":"13-14","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1AI068635"],"award-info":[{"award-number":["UM1AI068635"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Statistics in Medicine"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Active\u2010controlled trials with non\u2010inferiority objectives are often used when effective interventions are available, but new options may offer advantages or meet public health needs. In these trials, participants are randomized to an experimental intervention or an active control. The traditional non\u2010inferiority criterion requires that the new intervention preserve a substantial proportion of the active control effect. A key challenge is the absence of a placebo arm, which necessitates reliance on historical data to estimate the active control effect and assumptions about how well this effect applies to the target population. Another challenge arises when the active control is highly effective, as the new intervention may still be valuable even if it does not meet the traditional criterion. This has motivated alternative criteria based on sufficient efficacy relative to a hypothetical placebo. In this work, we propose a general framework for designing and evaluating non\u2010inferiority trials that integrates all existing analytical methods and accommodates both traditional and alternative success criteria. The framework enables the systematic comparison of methods in terms of type I error, power, and robustness to misspecification of the active control effect. We illustrate its applicability in the design of a future HIV prevention trial with a highly effective active control. In this application, our framework identifies methods that provide greater efficiency and robustness than commonly used approaches and demonstrates practical advantages of the alternative non\u2010inferiority criterion. Overall, this framework offers a comprehensive toolkit for rigorous non\u2010inferiority trial design, supporting method selection and the evaluation of new interventions.<\/jats:p>","DOI":"10.1002\/sim.70618","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T14:32:21Z","timestamp":1779805941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A General Framework for Designing and Evaluating Active\u2010Controlled Trials with Non\u2010Inferiority Objectives"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2779-0068","authenticated-orcid":false,"given":"Antonio","family":"Olivas\u2010Martinez","sequence":"first","affiliation":[{"name":"Department of Biostatistics University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6797-5468","authenticated-orcid":false,"given":"Fei","family":"Gao","sequence":"additional","affiliation":[{"name":"Bioinformatics and Epidemiology Program Vaccine and Infectious Disease Division Fred Hutch Cancer Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Janes","sequence":"additional","affiliation":[{"name":"Bioinformatics and Epidemiology Program Vaccine and Infectious Disease Division Fred Hutch Cancer Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_2_12_2_1","volume-title":"Design and Analysis of Non\u2010Inferiority Trials","author":"Rothmann M. 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