{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:26:55Z","timestamp":1790472415684,"version":"4.1.0"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T00:00:00Z","timestamp":1568764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T00:00:00Z","timestamp":1568764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Res Methodol"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>When conducing Phase-III trial, regulatory agencies and investigators might want to get reliable information about rare but serious safety outcomes during the trial. Bayesian non-inferiority approaches have been developed, but commonly utilize historical placebo-controlled data to define the margin, depend on a single final analysis, and no recommendation is provided to define the prespecified decision threshold. In this study, we propose a non-inferiority Bayesian approach for sequential monitoring of rare dichotomous safety events incorporating experts\u2019 opinions on margins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A Bayesian decision criterion was constructed to monitor four safety events during a non-inferiority trial conducted on pregnant women at risk for premature delivery. Based on experts\u2019 elicitation, margins were built using mixtures of beta distributions that preserve experts\u2019 variability. Non-informative and informative prior distributions and several decision thresholds were evaluated through an extensive sensitivity analysis. The parameters were selected in order to maintain two rates of misclassifications under prespecified rates, that is, trials that wrongly concluded an unacceptable excess in the experimental arm, or otherwise.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The opinions of 44 experts were elicited about each event non-inferiority margins and its relative severity. In the illustrative trial, the maximal misclassification rates were adapted to events\u2019 severity. Using those maximal rates, several priors gave good results and one of them was retained for all events. Each event was associated with a specific decision threshold choice, allowing for the consideration of some differences in their prevalence, margins and severity. Our decision rule has been applied to a simulated dataset.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In settings where evidence is lacking and where some rare but serious safety events have to be monitored during non-inferiority trials, we propose a methodology that avoids an arbitrary margin choice and helps in the decision making at each interim analysis. This decision rule is parametrized to consider the rarity and the relative severity of the events and requires a strong collaboration between physicians and the trial statisticians for the benefit of all. This Bayesian approach could be applied as a complement to the frequentist analysis, so both Data Safety Monitoring Boards and investigators can benefit from such an approach.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12874-019-0826-5","type":"journal-article","created":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T13:04:57Z","timestamp":1568811897000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Bayesian non-inferiority approach using experts\u2019 margin elicitation \u2013 application to the monitoring of safety events"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7482-0405","authenticated-orcid":false,"given":"Camille","family":"Aupiais","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Alberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Baud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moreno","family":"Ursino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Zohar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,18]]},"reference":[{"key":"826_CR1","unstructured":"U S Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Non-Inferiority Clinical Trials to Establish Effectiveness - Guidance for Industry; 2016."},{"issue":"2","key":"826_CR2","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1177\/009286151004400208","volume":"44","author":"A Sorbello","year":"2010","unstructured":"Sorbello A, Komo S, Valappil T. Noninferiority Margin for Clinical Trials of Antibacterial Drugs for Nosocomial Pneumonia. Drug Inf J. 2010; 44(2):165\u201376.","journal-title":"Drug Inf J"},{"issue":"11","key":"826_CR3","first-page":"1067","volume":"103","author":"C Aupiais","year":"2018","unstructured":"Aupiais C, Zohar S, Taverny G, Le Roux E, Boulkedid R, Alberti C. Exploring how non-inferiority and equivalence are assessed in paediatrics: a systematic review. Arch Dis Child. 2018; 103(11):1067\u201375.","journal-title":"Arch Dis Child"},{"issue":"1","key":"826_CR4","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1002\/sim.2528","volume":"26","author":"MJ Bradburn","year":"2007","unstructured":"Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007; 26(1):53\u201377.","journal-title":"Stat Med"},{"issue":"5","key":"826_CR5","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1080\/10543406.2015.1074920","volume":"26","author":"Margaret Gamalo-Siebers","year":"2015","unstructured":"Gamalo-Siebers M, Gao A, Lakshminarayanan M, Liu G, Natanegara F, Railkar R, et al.Bayesian methods for the design and analysis of noninferiority trials. J Biopharm Stat. 2016; 26(5):823\u201341.","journal-title":"Journal of Biopharmaceutical Statistics"},{"issue":"3","key":"826_CR6","doi-asserted-by":"publisher","first-page":"357","DOI":"10.2307\/2983527","volume":"157","author":"DJ Spiegelhalter","year":"1994","unstructured":"Spiegelhalter DJ, Freedman LS, Parmar MKB. Bayesian Approaches to Randomized Trials. J R Stat Soc Ser A (Stat Soc). 1994; 157(3):357\u2013416.","journal-title":"J R Stat Soc Ser A (Stat Soc)"},{"issue":"5","key":"826_CR7","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1080\/10543406.2011.589646","volume":"21","author":"MA Gamalo","year":"2011","unstructured":"Gamalo MA, Wu R, Tiwari RC. Bayesian approach to noninferiority trials for proportions. J Biopharm Stat. 2011; 21(5):902\u201319.","journal-title":"J Biopharm Stat"},{"issue":"1","key":"826_CR8","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12884-019-2206-x","volume":"19","author":"T Schmitz","year":"2019","unstructured":"Schmitz T, Alberti C, Ursino M, Baud O, Aupiais C, BETADOSE study group and the GROG(GroupedeRechercheenGyn\u00e9cologie Obst\u00e9trique). Full versus half dose of antenatal betamethasone to prevent severe neonatal respiratory distress syndrome associated with preterm birth: study protocol for a randomised, multicenter, double blind, placebo-controlled, non-inferiority trial (BETADOSE). BMC Pregnancy Childbirth. 2019; 19(1):67.","journal-title":"BMC Pregnancy Childbirth"},{"issue":"4","key":"826_CR9","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1542\/peds.50.4.515","volume":"50","author":"GC Liggins","year":"1972","unstructured":"Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972; 50(4):515\u201325.","journal-title":"Pediatrics"},{"key":"826_CR10","unstructured":"Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consens Statement. 1994; 12(2):1\u201324."},{"issue":"3","key":"826_CR11","first-page":"334","volume":"64","author":"ACOG committee opinion","year":"1999","unstructured":"ACOG committee opinion. Antenatal corticosteroid therapy for fetal maturation. Number 210, October 1998 (Replaces Number 147, December 1994). Committee on Obstetric Practice. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet. 1999; 64(3):334\u20135.","journal-title":"Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet"},{"issue":"7 Suppl","key":"826_CR12","first-page":"5S105","volume":"31","author":"MV Senat","year":"2002","unstructured":"Senat MV. Corticosteroid for fetal lung maturation: indication and treatment protocols. J Gynecol Obstet Biol Reprod. 2002; 31(7 Suppl):5S105\u2013113.","journal-title":"J Gynecol Obstet Biol Reprod"},{"key":"826_CR13","unstructured":"Royal College of Obstetricians & Gynaecologists. Green-top Guideline No 7: Antenatal corticosteroids to reduce neonatal morbidity and mortality. London; 2010."},{"key":"826_CR14","first-page":"CD004454","volume":"3","author":"D Roberts","year":"2006","unstructured":"Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006; 3:CD004454. http:\/\/dx.doi.org\/10.1002\/14651858.cd004454.pub2 .","journal-title":"Cochrane Database Syst Rev"},{"key":"826_CR15","first-page":"CD006764","volume":"8","author":"FC Brownfoot","year":"2013","unstructured":"Brownfoot FC, Gagliardi DI, Bain E, Middleton P, Crowther CA. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2013; 8:CD006764. http:\/\/dx.doi.org\/10.1002\/14651858.cd006764 .","journal-title":"Cochrane Database Syst Rev"},{"key":"826_CR16","first-page":"CD003935","volume":"7","author":"A Crowther","year":"2015","unstructured":"Crowther A, McKinlay CJD, Middleton P, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev. 2015; 7:CD003935. http:\/\/dx.doi.org\/10.1002\/14651858.cd003935.pub3 .","journal-title":"Cochrane Database Syst Rev"},{"key":"826_CR17","doi-asserted-by":"crossref","unstructured":"Ancel PY, Goffinet F, EPIPAGE-2 Writing Group, Kuhn P, Langer B, Matis J, et al.Survival and morbidity of preterm children born at 22 through 34 weeks\u2019 gestation in France in 2011: results of the EPIPAGE-2 cohort study. JAMA Pediatr. 2015; 169(3):230\u20138.","DOI":"10.1001\/jamapediatrics.2014.3351"},{"key":"826_CR18","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing; 2017. https:\/\/www.R-project.org\/ ."},{"issue":"11","key":"826_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v048.i11","volume":"48","author":"B Gr\u00fcn","year":"2012","unstructured":"Gr\u00fcn B, Kosmidis I, Zeileis A. Extended Beta Regression in R: Shaken, Stirred, Mixed, and Partitioned. J Stat Softw. 2012; 48(11):1\u201325.","journal-title":"J Stat Softw"},{"key":"826_CR20","unstructured":"Stan Development Team. RStan: the R interface to Stan. 2018. R package version 2.11.1. http:\/\/mc-stan.org\/ ."},{"key":"826_CR21","doi-asserted-by":"crossref","unstructured":"Carpenter B, Gelman A, Hoffman MD, Lee D, Goodrich B, Betancourt M, et al.Stan: A Probabilistic Programming Language. J Stat Softw. 2017; 76(1):1\u201332.","DOI":"10.18637\/jss.v076.i01"},{"issue":"2","key":"826_CR22","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1177\/0962280217726803","volume":"28","author":"PF Thall","year":"2019","unstructured":"Thall PF, Ursino, M, Baudouin V, Alberti C, Zohar S. Bayesian treatment comparison using parametric mixture priors computed from elicited histograms. Stat Methods Med Res. 2019; 28(2):404\u201318.","journal-title":"Stat Methods Med Res"}],"container-title":["BMC Medical Research Methodology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12874-019-0826-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12874-019-0826-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12874-019-0826-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T23:54:20Z","timestamp":1664409260000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedresmethodol.biomedcentral.com\/articles\/10.1186\/s12874-019-0826-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,18]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["826"],"URL":"https:\/\/doi.org\/10.1186\/s12874-019-0826-5","relation":{},"ISSN":["1471-2288"],"issn-type":[{"value":"1471-2288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,18]]},"assertion":[{"value":"22 January 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declared declare that they have no competing interests with respect to the research, authorship, and\/or publication of this article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"187"}}