The pharmacokinetic characteristics to be tested, the test procedure and the norms to be maintained should be specified beforehand in the protocol. A post hoc change of the methods specified for the statistical evaluation is acceptable only if adherence to the protocol would preclude a meaningful evaluation and if such change of procedure has been fully justified.
Concentration dependent data such as AUC and Cmax should be log transformed prior to statistical analysis in order to satisfy the fundamental assumption of variance that effects in the model in an additive rather than a multiplicative manner.
Acceptance ranges for main characteristics
The 90% confidence interval for this measure of relative bioavailability should lie within a bioequivalence range of 0.80-1.25 (see page 118). If therapeutic range is particularly narrow, the acceptance range may need to be reduced. A larger acceptance range may be acceptable if clinically appropriate.
This measure of relative bioavailability is inherently more variable than, for example, the AUC-ratio, and a wider acceptance range may be appropriate. The range used should be justified taking into account safety and efficacy considerations.
Statistical evaluation of tmax only makes sense if there is a clinically relevant claim for rapid release or action or signs for a relation to adverse effects. The non-parametric 90% confidence interval for this measure of relative bioavailability should lie within a clinically relevant range.