Asymmetric inner wedge group sequential tests with applications to verifying whether effective drug concentrations are similar in adults and children

Hampson, Lisa Victoria and Fisch, Roland and Van, Linh M. and Jaki, Thomas Friedrich (2017) Asymmetric inner wedge group sequential tests with applications to verifying whether effective drug concentrations are similar in adults and children. Statistics in Medicine, 36 (3). pp. 426-441. ISSN 0277-6715

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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.

Item Type: Journal Article
Journal or Publication Title: Statistics in Medicine
Additional Information: This is the peer reviewed version of the following article: Hampson, L. V., Fisch, R., Van, L. M., and Jaki, T. (2017) Asymmetric inner wedge group sequential tests with applications to verifying whether effective drug concentrations are similar in adults and children. Statist. Med., 36: 426–441. doi: 10.1002/sim.7154 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/sim.7154/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Uncontrolled Keywords: /dk/atira/pure/subjectarea/asjc/2600/2613
Subjects:
Departments: Faculty of Science and Technology > Mathematics and Statistics
ID Code: 83692
Deposited By: ep_importer_pure
Deposited On: 19 Dec 2016 11:22
Refereed?: Yes
Published?: Published
Last Modified: 23 Feb 2020 03:48
URI: https://eprints.lancs.ac.uk/id/eprint/83692

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