## ANOVA party prevails [BE/BA News]

Dear All,

that makes me dumbfound!
Seems the ANOVA fraction of EMA statisticians has triumphed all along the line. Thus our crossing fingers was of no effect.

To summarize my understanding of this so-called "clarification":
• Method C, the FDA approach, although giving more conservative CIs (Quote: "... Method C gives wider intervals ...", page 23) is dead. It is not named "Compatible with CHMP guideline". Thus we can not go with the same statistical evaluation for the FDA and EMA!
• Method B, simple mixed model assuming equal variabilities for Test and Reference and no formulation-by-subject interaction but random effect for subjects, acceptable if same results as Method A. For me it follows I have to use Method A.
Quote: "... in borderline cases and when there are many included subjects who only provide data for a subset of the treatment periods, additional analysis using method A might be required.", page 25.
• Method A, ANOVA assuming equal variabilities for Test and Reference and no formulation-by-subject interaction and all effects as fixed (including subjects!), is the method of choice to evaluate replicate cross-over studies, which are originally aimed to overcome the impossibility to estimate separate intra-subject variances for Test and Reference in a classical 2x2 cross-over.
• To overcome the flaw in the point above one has to evaluate the intra-subject variability for the Reference with neglecting a considerable part of the data, namely neglecting all data under Test.
• Evaluation of intra-subject variability of Test is not necessary at all (is not mentioned with any word), even in the case of a fully replicate design (data set I).
• Missing data will be handled adequately by the simple ANOVA(?). They termed that "unbalanced" in dataset I.
Do you think I have got their points?

The rationale behind that all I can't and will not discuss seriously .
I thank my God that I'm only a quantum-theoretical chemist educationally and not a statistician. Thus I must not understand .

BTW: The CVWT of Method C from SAS for dataset II is 3.87%.
Proc MIXED is complaining: The Mixed Procedure Convergence criteria met but final hessian is not positive definite.
This is a strong sign of an over-specified model. That may be one of the sources of wider CIs compared to the simpler models.

Regards,

Detlew