On a hybrid method in dose finding studies.
OBJECTIVE
Combination of multiple testing and modeling techniques in dose-response studies. Use of hypotheses tests to assess the significance of the dose-response signal associated with a given candidate dose-response model. Estimation of target dose(s) following the previous model selection step. Illustration of the method with a real data example.


METHODS
We assume a set of candidate models potentially reflecting the data generating process. The appropriateness of each individual model is evaluated in terms of contrast tests, where each set of contrast weights describes a specific dose-response shape. Optimum contrast weights are computed, which maximize the non-centrality parameters associated with the contrast tests. A reference set of appropriate candidate models is obtained while controlling the familywise error rate. A single model is then selected from this reference set using standard model selection criteria. The final step is devoted to dose finding by applying inverse regression techniques. This is illustrated for estimating the minimum effective dose.


RESULTS
The method is as powerful as competing standard dose-response tests to detect an overall dose-related trend. In addition, the possibility is given to estimate one or more target doses of interest. The analysis of a real data example confirms the advantages of the proposed hybrid method.


CONCLUSIONS
Combining multiple testing and modeling techniques leads to a powerful tool, which uses the advantages of both approaches: Rigid error control at the significance testing step and flexibility at the dose estimation step. The method can be extended to handle more general linear models including covariates and factorial treatment structures.
Bretz
F
F
Novartis Pharma AG, Basel, Switzerland. frank.bretz@novartis.pharma.com
Pinheiro
J C
JC
Branson
M
M
D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015233:Models, Statistical