title: Statistical issues in first-in-human studies on BIA 10-2474: Neglected comparison of protocol against practice.
abstract: By setting the regulatory-approved protocol for a suite of first-in-human studies on BIA 10-2474 against the subsequent French investigations, we highlight 6 key design and statistical issues, which reinforce recommendations by a Royal Statistical Society Working Party, which were made in the aftermath of cytokine release storm in 6 healthy volunteers in the United Kingdom in 2006. The 6 issues are dose determination, availability of pharmacokinetic results, dosing interval, stopping rules, appraisal by safety committee, and clear algorithm required if combining approvals for single and multiple ascending dose studies.
authors.affiliation: MRC Biostatistics Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Sheila M
authors.identifier: 0000-0001-6378-8382
authors.initials: SM
authors.lastname: Bird
authors.affiliation: School of Mathematics and Statistics, University of St Andrews, St Andrews, UK.
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Bailey
authors.affiliation: ICON plc, Marlow, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Grieve
authors.affiliation: Competence Center for Methodology and Statistics, Luxembourg Institute of Health, Strassen, Luxembourg.
authors.forename: Stephen
authors.identifier: 0000-0002-7558-8473
authors.initials: S
authors.lastname: Senn
mesh_terms: D000465:Algorithms; D003497:Cyclic N-Oxides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016207:Cytokines / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004335:Drug and Narcotic Control; D005602:France; D006801:Humans; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012107:Research Design; D006113:United Kingdom
chemical_list: C000612073:BIA 10-2474; D003497:Cyclic N-Oxides; D016207:Cytokines; D011725:Pyridines
keywords: combined approvals; first-in-human; healthy volunteer; protocol; recommendations; study design