Bioequivalence and Bioavailability Forum

Dear All,

I'm Stefano Vezzoli, biostatistician at CROS NT, a CRO based in Verona, Italy. Most of my (little: I'm just 28) experience is with Phase III trials, but I'm currently working on a pilot bioavailability study. In this forum I have already found a lot of useful suggestions and provocative thoughts, and I hope that my questions will lead to equally interesting discussions.

My question concerns the inclusion of sequence effect in models used to analyse pharmacokinetic parameters. I know this is a very debated issue. For this reason, I tried to gather as much information as possible from previous topics and available resources. The model described by Helmut Schütz in his excellent lecture (pag. 15) does not include sequence effect. I think that the reasons behind this choice are fully explained in the following section (pag. 44-50) of the same presentation. However, as noted in the slides, EMEA Draft GL on BE explicitly requests sequence effect to be included in the model (line 509). The same model is described by the FDA guideline Statistical Approaches to Establishing Bioequivalence (section VI.B.1.b, pag. 10). But in the section VII.B (pag. 13) of the same document, it is stated that in a 2X2 crossover design "the only statistical test available for the presence of unequal carryover effects is the sequence test", and circumstances are provided under which "the possibility of unequal carryover effects is considered unlikely in a BE study".

My question is the following: if the conditions defined in the FDA GL, the inclusion of the sequence effect is mandatory?

Thank you very much for your help.