Bioequivalence and Bioavailability Forum

According to ICH E9:

"The statistical model to be adopted for the estimation and testing of treatment effects should be described in the protocol. The main treatment effect may be investigated first using a model which allows for centre differences, but does not include a term for treatment-by-centre interaction. If the treatment effect is homogeneous across centres, the routine inclusion of interaction terms in the model reduces the efficiency of the test for the main effects. In the presence of true heterogeneity of treatment effects, the interpretation of the main treatment effect is controversial."

(...)

"If positive treatment effects are found in a trial with appreciable numbers of subjects per centre, there should generally be an exploration of the heterogeneity of treatment effects across centres, as this may affect the generalisability of the conclusions. Marked heterogeneity may be identified by graphical display of the results of individual centres or by analytical methods, such as a significance test of the treatment-by-centre interaction. When using such a statistical significance test, it is important to recognise that this generally has low power in a trial designed to detect the main effect of treatment."

I believe this subject has already been discussed elsewhere (not sure in what post).

Imo, multicentre effect should be handled the same way as the group effect in BABE studies. The model would include centre, centre*form and subject(sequence*centre). Additionally, you should include center as a block factor in randomization to acchieve balanced sequences between centres.

Dear Yura,

as you probably know, Belarus is a member of Eurasian Economic Union.
I don't know did the rules of medicines circulation come into force in Belarus or not, but I would suggest to use it. As far as I know the BEQ guideline for EEU was developed by experts in Belarus.

So you can download it here and open the page 44 (47 Adobe speaking).
The point 94 says that the BEQ study conducted in different sites are suspicious (sic!) and you need to discuss the design with expert first.

I'm also wondering regarding the sentence in the previous point of Guideline:
'Especially during the model building it should be taken into account the fact that periods of 1st group are not the same as periods of the second'

Hmmm... Does that mean that we need to add Period*Group statement?
Let's see our Guru's opinion!