The impact of period effects on dose level contrasts in alternating cross-over designs for first-time-in-human studies
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Stephan Koehne-Voss1, Heinz Schmidli, David M Smith
1Novartis Pharma AG, Basel, Switzerland. stephan.koehne-voss@novartis.com
Abstract:
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.
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