{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:13:29Z","timestamp":1788412409263,"version":"build-2803163510"},"reference-count":34,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100020098","name":"Innovative Health Initiative","doi-asserted-by":"publisher","award":["101165912"],"award-info":[{"award-number":["101165912"]}],"id":[{"id":"10.13039\/100020098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Stat Methods Med Res"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>Even in rare diseases, where the sample size is limited and blinding is less frequently implemented, randomized controlled trials are considered the gold standard to prove efficacy. Randomization is used to mitigate bias and regulatory guidance recommend the investigation of the impact of bias on the test decision. We quantified how allocation bias affects the test decision in small-sample two-arm group sequential trials under a biasing policy based on the Blackwell\u2013Hodges convergence strategy. Type I error and power were evaluated under Lan\u2013DeMets spending (Pocock-, O\u2019Brien\u2013Fleming-, Wang\u2013Tsiatis-type functions), with and without futility (non-binding, binding), varying interim timing, number of looks and stage-wise restarting of randomization. Allocation bias inflated type I error most for more restrictive randomization procedures, especially permuted blocks with small block sizes. Spending more alpha at interim reduced inflation. Non-binding futility reduced type I error, while binding increased type I error inflation for more aggressive stopping boundaries. Stage-wise restarting modestly reduced inflation for most procedures. Overall, group sequential choices had secondary effect and did not rescue a predictable randomization scheme. When allocation bias cannot be ruled out (e.g. open-label trials), we recommend less restrictive randomization procedures (e.g. big stick design) or, if using permuted blocks, large block sizes.<\/jats:p>","DOI":"10.1177\/09622802261442914","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:55:34Z","timestamp":1777528534000},"page":"1295-1309","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["When randomization is not random: Allocation bias in small sample, group sequential randomized clinical trials"],"prefix":"10.1177","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1051-5713","authenticated-orcid":false,"given":"Daniel","family":"Bodden","sequence":"first","affiliation":[{"name":"RWTH Aachen University"},{"name":"Medical School, Sigmund Freud Private University, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5945-1119","authenticated-orcid":false,"given":"Ralf-Dieter","family":"Hilgers","sequence":"additional","affiliation":[{"name":"RWTH Aachen University"},{"name":"Medical School, Sigmund Freud Private University, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6893-3304","authenticated-orcid":false,"given":"Franz","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Medical University of Vienna"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"e_1_3_2_2_2","unstructured":"US Food and Drug Administration. Providing clinical evidence of effectiveness for human drug and biological products. Guidance for Industry 1998."},{"key":"e_1_3_2_3_2","unstructured":"International Conference on Harmonisation (ICH). ICH harmonised tripartite guideline: E9 statistical principles for clinical trials https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-e-9-statistical-principles-clinical-trials-step-5_en.pdf (1998)."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1214\/aoms\/1177706973"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/ebmed-2017-110882"},{"key":"e_1_3_2_6_2","unstructured":"International Conference on Harmonisation (ICH). ICH Harmonised Tripartite Guideline E10: choice of control group and related issues in clinical trials https:\/\/database.ich.org\/sites\/default\/files\/E10_Guideline.pdf (2000). Step 4 version."},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2021.09.009"},{"key":"e_1_3_2_8_2","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne JAC","year":"2019","unstructured":"Sterne JAC, Savovi\u0107 J, Page MJ, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.","journal-title":"BMJ"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","unstructured":"Shao H Rosenberger WF. Properties of the random block design for clinical trials. In: Kunert J M\u00fcller CH and Atkinson AC (eds) mODa 11\u2014advances in model-oriented design and analysis. Contributions to Statistics. Cham: Springer 2016 pp. 207\u2013215. DOI: 10.1007\/978-3-319-31266-8_26.","DOI":"10.1007\/978-3-319-31266-8_26"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-017-0428-z"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1177\/0962280219846146"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-024-02335-x"},{"key":"e_1_3_2_13_2","unstructured":"EMA\/CHMP. Guideline on clinical trials in small populations https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-clinical-trials-small-populations_en.pdf (2006)."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0931-2"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-014-0170-0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/64.2.191"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.2307\/2530245"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0325333"},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","unstructured":"Wassmer G Brannath W. Group sequential and confirmatory adaptive designs in clinical trials. Springer Series in Pharmaceutical Statistics. Springer International Publishing 2016.","DOI":"10.1007\/978-3-319-32562-0"},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","unstructured":"Jennison C Turnbull B. Group sequential methods with applications to clinical trials. Chapman & Hall\/CRC Interdisciplinary Statistics. CRC Press 1999.","DOI":"10.1201\/9781584888581"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.2307\/2336502"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.2307\/2531959"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1177\/2168479015604181"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1177\/0962280216653778"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2007.02.006"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1080\/10543406.2020.1730878"},{"key":"e_1_3_2_27_2","unstructured":"Anderson K. gsDesign: group sequential design https:\/\/keaven.github.io\/gsDesign\/ (2023)."},{"key":"e_1_3_2_28_2","unstructured":"Wassmer G Pahlke F. rpact: confirmatory adaptive clinical trial design and analysis https:\/\/www.rpact.org (2025)."},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v085.i08"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-021-01303-z"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.3414\/ME11-01-0043"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0312936"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1756-5391.2009.01023.x"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/sim.10117"},{"key":"e_1_3_2_35_2","unstructured":"International Council for Harmonisation (ICH). ICH E20: guideline on adaptive designs for clinical trials \u2013 step 2b (draft) 2025."}],"container-title":["Statistical Methods in Medical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/09622802261442914","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/09622802261442914","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/09622802261442914","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T22:06:39Z","timestamp":1782079599000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/09622802261442914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":34,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1177\/09622802261442914"],"URL":"https:\/\/doi.org\/10.1177\/09622802261442914","relation":{},"ISSN":["0962-2802","1477-0334"],"issn-type":[{"value":"0962-2802","type":"print"},{"value":"1477-0334","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]}}}