{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T01:48:40Z","timestamp":1775872120960,"version":"3.50.1"},"reference-count":26,"publisher":"Wiley","issue":"28-30","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V038419\/1"],"award-info":[{"award-number":["MR\/V038419\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC\u2216_UU\u2216_00002\/14"],"award-info":[{"award-number":["MC\u2216_UU\u2216_00002\/14"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC\u2216_UU\u2216_00040\/03"],"award-info":[{"award-number":["MC\u2216_UU\u2216_00040\/03"]}],"id":[{"id":"10.13039\/501100000265","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":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Clinical trials conducted during the COVID\u201019 pandemic demonstrated the value of adaptive design methods in emerging disease settings, when there can be considerable uncertainty around disease natural history, anticipated endpoint effect sizes and population size. In such settings, there may also be uncertainty regarding the most appropriate primary endpoint. This might lead to an externally\u2010driven decision to change the primary endpoint during the course of an adaptive trial. If information on the new primary endpoint is already being collected, initially as a secondary endpoint, the trial could continue with a new primary endpoint. In this case it is unclear how statistical inference on the final primary endpoint should be adjusted for interim analyses monitoring the initial primary endpoint so as to control the overall type I error rate as adjusting for monitoring as if this was based on the new endpoint could be conservative whereas failing to make any adjustment could lead to type I error rate inflation if the new and original endpoint are correlated. This paper shows how group\u2010sequential methods can be modified to control the type I error rate for the analysis of the new primary endpoint irrespective of the true treatment effect on the initial primary endpoint. The method is illustrated using a simulated data example based on a clinical trial of remdesivir in COVID\u201019. Construction of critical values for the test of the new primary endpoint require a value for the correlation between this and the initial primary endpoint. We present simulation studies to demonstrate that the type I error rate is controlled when this value is estimated from the data on the two endpoints obtained from the trial.<\/jats:p>","DOI":"10.1002\/sim.70337","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T16:45:09Z","timestamp":1765385109000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Group\u2010Sequential Designs With an Externally\u2010Driven Change of Primary Endpoint"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7435-6632","authenticated-orcid":false,"given":"Amin","family":"Yarahmadi","sequence":"first","affiliation":[{"name":"Clinical Trials Unit Warwick Medical School  University of Warwick, Coventry UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3433-5429","authenticated-orcid":false,"given":"Lori E.","family":"Dodd","sequence":"additional","affiliation":[{"name":"Clinical Trials Research and Statistics Branch National Institute of Allergy and Infectious Diseases  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9822-1586","authenticated-orcid":false,"given":"Peter","family":"Horby","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, Nuffield Department of Medicine University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1096-188X","authenticated-orcid":false,"given":"Thomas","family":"Jaki","sequence":"additional","affiliation":[{"name":"Faculty of Informatics and Data Science University of Regensburg  Regensburg Germany"},{"name":"MRC Biostatistics Unit University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7781-1512","authenticated-orcid":false,"given":"Nigel","family":"Stallard","sequence":"additional","affiliation":[{"name":"Clinical Trials Unit Warwick Medical School  University of Warwick, Coventry UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119524687"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2007764"},{"key":"e_1_2_10_4_1","unstructured":"World Health Organization \u201cWHO R&D Blueprint: Novel coronavirus. COVID\u201019 Therapeutic Trial Synopsis \u201d2020 https:\/\/www.who.int\/publications\/i\/item\/covid\u201019\u2010therapeutic\u2010trial\u2010synopsis."},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/19466315.2020.1790415"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1997.10473654"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1997.10473655"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2307\/2336502"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/74.1.149"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780091207"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1201\/9780367805326"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4202"},{"key":"e_1_2_10_13_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2021"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.2307\/2533535"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/1740774520939938"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543409608835149"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/03610929808832161"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.2307\/2532704"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1852"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/83.2.453"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/asy004"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.9605"},{"key":"e_1_2_10_23_1","unstructured":"Food and Drug Administration \u201cMultiple Endpoints in Clinical Trials: Guidance for Industry \u201d2022 https:\/\/www.fda.gov\/media\/162416\/download."},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-017-4802-4"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-018-0601-z"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.4103\/2045-8932.109920"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-024-08302-7"}],"container-title":["Statistics in Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sim.70337","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/sim.70337","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sim.70337","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T00:58:59Z","timestamp":1775869139000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/sim.70337"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":26,"journal-issue":{"issue":"28-30","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/sim.70337"],"URL":"https:\/\/doi.org\/10.1002\/sim.70337","archive":["Portico"],"relation":{},"ISSN":["0277-6715","1097-0258"],"issn-type":[{"value":"0277-6715","type":"print"},{"value":"1097-0258","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70337"}}