ICH E9 has the answer [Regulatives / Guidelines]
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.
"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.
Complete thread:
- multicenter crossover bioequivalent study Yura 2016-08-29 08:10 [Regulatives / Guidelines]
- ICH E9 has the answerDavidManteigas 2016-08-29 13:55
- please explain your opinion regarding ICH E9 mittyri 2016-08-29 15:12
- please explain your opinion regarding ICH E9 DavidManteigas 2016-09-01 13:47
- ICH E9 has the answer Yura 2016-08-29 15:16
- ICH E9 has the answer BE-proff 2016-08-30 08:31
- please explain your opinion regarding ICH E9 mittyri 2016-08-29 15:12
- Winter is coming to EEU mittyri 2016-08-29 15:03
- ICH E9 has the answerDavidManteigas 2016-08-29 13:55