title: Asymmetric inner wedge group sequential tests with applications to verifying whether effective drug concentrations are similar in adults and children.
abstract: Extrapolating from information available on one patient group to support conclusions about another is common in clinical research. For example, the findings of clinical trials, often conducted in highly selective patient cohorts, are routinely extrapolated to wider populations by policy makers. Meanwhile, the results of adult trials may be used to support conclusions about the effects of a medicine in children. For example, if the effective concentration of a drug can be assumed to be similar in adults and children, an appropriate paediatric dosing rule may be found by 'bridging', that is, by matching the adult effective concentration. However, this strategy may result in children receiving an ineffective or hazardous dose if, in fact, effective concentrations differ between adults and children. When there is uncertainty about the equality of effective concentrations, some pharmacokinetic-pharmacodynamic data may be needed in children to verify that differences are small. In this paper, we derive optimal group sequential tests that can be used to verify this assumption efficiently. Asymmetric inner wedge tests are constructed that permit early stopping to accept or reject an assumption of similar effective drug concentrations in adults and children. Asymmetry arises because the consequences of under- and over-dosing may differ. We show how confidence intervals can be obtained on termination of these tests and illustrate the small sample operating characteristics of designs using simulation. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Medical and Pharmaceutical Statistics Research Unit, Department of Mathematics and Statistics, Lancaster University, Lancaster, LA1 4YF, U.K.
authors.forename: Lisa V
authors.initials: LV
authors.lastname: Hampson
authors.affiliation: Biostatistical Science and Pharmacometrics, Novartis Pharma AG, Basel, CH-4002, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Fisch
authors.affiliation: Biostatistical Science and Pharmacometrics, Novartis Pharmaceutical, Cambridge, 02139, MA, U.S.A.
authors.forename: Linh M
authors.initials: LM
authors.lastname: Van
authors.affiliation: Medical and Pharmaceutical Statistics Research Unit, Department of Mathematics and Statistics, Lancaster University, Lancaster, LA1 4YF, U.K.
authors.forename: Thomas
authors.identifier: 0000-0002-1096-188X
authors.initials: T
authors.lastname: Jaki
mesh_terms: D000328:Adult; D000367:Age Factors; D002648:Child; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D010599:Pharmacokinetics; D013223:Statistics as Topic / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D004364:Pharmaceutical Preparations
keywords: Bayes decision problem; error spending tests; extrapolation; group sequential tests; optimal tests; paediatric clinical trials; pharmacodynamics; pharmacokinetics; verifying assumptions