The impact of period effects on dose level contrasts in alternating cross-over designs for first-time-in-human studies.
For first-time-in-human studies with small molecules alternating cross-over designs are often employed and at study end are analyzed using linear models. We discuss the impact of including a period effect in the model on the precision with which dose level contrasts can be estimated and quantify the bias of least squares estimators if a period effect is inherent in the data that is not accounted for in the model. We also propose two alternative designs that allow a more precise estimation of dose level contrasts compared with the standard design when period effects are included in the model.
Novartis Pharma AG, Basel, Switzerland. stephan.koehne-voss@novartis.com
Stephan
S
Koehne-Voss
Heinz
H
Schmidli
David M
DM
Smith
Iris
I
Pigeot
D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D018592:Cross-Over Studies; D003710:Demography / Q000706:statistics & numerical data*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D012107:Research Design