TY - JOUR

T1 - Asymmetric inner wedge group sequential tests with applications to verifying whether effective drug concentrations are similar in adults and children

AU - Hampson, Lisa Victoria

AU - Fisch, Roland

AU - Van, Linh M.

AU - Jaki, Thomas Friedrich

N1 - 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.

PY - 2017/2/10

Y1 - 2017/2/10

N2 - 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.

AB - 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.

U2 - 10.1002/sim.7154

DO - 10.1002/sim.7154

M3 - Journal article

VL - 36

SP - 426

EP - 441

JO - Statistics in Medicine

JF - Statistics in Medicine

SN - 0277-6715

IS - 3

ER -