Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Estimation in AB/BA cross-over trials with application to bioequivalence studies with incomplete and complete data designs
AU - Jaki, Thomas
AU - Pallmann, Philip
AU - Wolfsegger, Martin J.
PY - 2013/12/30
Y1 - 2013/12/30
N2 - Crossover studies are frequently used in clinical research as they allow within-subject comparisons instead of the between-subject evaluation of parallel group designs. Estimation of interesting parameters from such designs is, however, not trivial. We provide three methods for estimating treatment effects and associated standard errors from an AB/BA crossover trial. Assuming at least asymptotic normality, we can obtain the confidence intervals for single parameters as well as for differences or ratios of treatment effects. The latter is particularly useful in a pharmacokinetic context to establish bioequivalence using area under the concentration versus time curves (AUCs). In this work, we will illustrate how Fieller-type confidence intervals can be constructed for the ratio of AUCs estimated using a noncompartmental approach in a sparse sampling setting from a two-treatment, two-period, two-sequence crossover trial. In particular, we will discuss a flexible batch design, which includes traditional serial sampling and complete data designs as special cases. Via simulation, we show that the proposed intervals have nominal coverage and keep the type I error even for small sample sizes. Moreover, we illustrate the methodology in a real data example.
AB - Crossover studies are frequently used in clinical research as they allow within-subject comparisons instead of the between-subject evaluation of parallel group designs. Estimation of interesting parameters from such designs is, however, not trivial. We provide three methods for estimating treatment effects and associated standard errors from an AB/BA crossover trial. Assuming at least asymptotic normality, we can obtain the confidence intervals for single parameters as well as for differences or ratios of treatment effects. The latter is particularly useful in a pharmacokinetic context to establish bioequivalence using area under the concentration versus time curves (AUCs). In this work, we will illustrate how Fieller-type confidence intervals can be constructed for the ratio of AUCs estimated using a noncompartmental approach in a sparse sampling setting from a two-treatment, two-period, two-sequence crossover trial. In particular, we will discuss a flexible batch design, which includes traditional serial sampling and complete data designs as special cases. Via simulation, we show that the proposed intervals have nominal coverage and keep the type I error even for small sample sizes. Moreover, we illustrate the methodology in a real data example.
KW - 2 × 2 × 2 crossover
KW - bioequivalence
KW - area under the concentration versus time curve
KW - noncompartmental
KW - PK parameter
KW - Satterthwaite's approximation
U2 - 10.1002/sim.5886
DO - 10.1002/sim.5886
M3 - Journal article
VL - 32
SP - 5469
EP - 5483
JO - Statistics in Medicine
JF - Statistics in Medicine
SN - 0277-6715
IS - 30
ER -