{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:02:34Z","timestamp":1789614154021,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceutical Statistics"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Sample size re\u2010estimation based on interim data has become an increasingly important component of adaptive clinical trial designs. Many novel anti\u2010cancer therapies under development demonstrate enhanced efficacy in biomarker\u2010defined subpopulations rather than the overall population. To address the inherent uncertainty in the predictive value of biomarkers, biomarker\u2010based adaptive designs have gained considerable interest. Given the complexity of these designs, it is critical to evaluate whether existing sample size re\u2010estimation methods maintain adequate control of the overall Type I error rate. In this paper, we focus on the promising zone method applied within biomarker\u2010based adaptive designs. We show that the promising zone method can produce Type I error inflation when embedded in biomarker\u2010based adaptive designs, with the magnitude of inflation depending on the underlying true treatment effect in the biomarker\u2010positive subgroup and specific design parameters such as the biomarker subgroup prevalence, the interim analysis timing, and the maximum inflation factor. We derive exact analytical results for normally distributed endpoints and extend these findings to time\u2010to\u2010event (TTE) endpoints through the asymptotic normal approximation of the log\u2010rank test statistic, with the conclusions supported by simulation studies. We also discuss regulatory considerations for the implementation of such complex adaptive designs in confirmatory settings.<\/jats:p>","DOI":"10.1002\/pst.70118","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T06:32:58Z","timestamp":1789108378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Applying the Promising Zone Method to Biomarker\u2010Based Adaptive Designs: A Word of Caution"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0094-5685","authenticated-orcid":false,"given":"Jingzhao","family":"Wang","sequence":"first","affiliation":[{"name":"Office of Biostatistics and Clinical Pharmacology, Center for Drug Evaluation National Medical Products Administration  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3818-5875","authenticated-orcid":false,"given":"Ruobing","family":"Li","sequence":"additional","affiliation":[{"name":"Office of Biostatistics and Clinical Pharmacology, Center for Drug Evaluation National Medical Products Administration  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Office of Biostatistics and Clinical Pharmacology, Center for Drug Evaluation National Medical Products Administration  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimin","family":"Tang","sequence":"additional","affiliation":[{"name":"Office of Biostatistics and Clinical Pharmacology, Center for Drug Evaluation National Medical Products Administration  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhong","family":"Pan","sequence":"additional","affiliation":[{"name":"Office of Biostatistics and Clinical Pharmacology, Center for Drug Evaluation National Medical Products Administration  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1688"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4102"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.1999.00853.x"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.2307\/2533441"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.2755"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.1999.01286.x"},{"key":"e_1_2_12_8_1","volume-title":"Adaptive Design Methods in Clinical Trials","author":"Chow S. 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J.","year":"2009","journal-title":"Contemporary Clinical Trials"},{"issue":"13","key":"e_1_2_12_21_1","first-page":"1391","article-title":"Biomarker Enrichment Strategies in Phase III Oncology Trials","volume":"29","author":"Freidlin B.","year":"2010","journal-title":"Statistics in Medicine"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.472"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3559"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0146465"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-020-04931-w"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/19466315.2020.1811145"},{"key":"e_1_2_12_27_1","unstructured":"FDA Adaptive Designs for Clinical Trials of Drugs and Biologics. Guidance for Industry(2019)."},{"key":"e_1_2_12_28_1","unstructured":"EMA Reflection Paper on Methodological Issues in Confirmatory Clinical Trials Planned with an Adaptive Design(2020)."},{"key":"e_1_2_12_29_1","unstructured":"NMPA CDE Guiding Principles for Adaptive Design in Clinical Drug Trials (Trial Version)(2021)."},{"key":"e_1_2_12_30_1","unstructured":"NMPA CDE Guiding Principles for Sample Size Estimation in Clinical Drug Trials (Trial Version)(2024)."}],"container-title":["Pharmaceutical Statistics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pst.70118","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pst.70118","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pst.70118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:28:51Z","timestamp":1789612131000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pst.70118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":29,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/pst.70118"],"URL":"https:\/\/doi.org\/10.1002\/pst.70118","archive":["Portico"],"relation":{},"ISSN":["1539-1604","1539-1612"],"issn-type":[{"value":"1539-1604","type":"print"},{"value":"1539-1612","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2025-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70118"}}