Bioequivalence and Bioavailability Forum

Hi MGR,

❝ Can we do a partial replicate study for Canada submission ?

Why didn’t you search the Guidelines / Guidances first? HC’s Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies states in Section 2.3.1:

Replicated cross-over designs may also be used, where the formulations are tested more than once in the same subjects.

❝ If so what will be the procedure we have to follow?

Section 2.7.4.2:

By definition the cross-over design is a mixed effects model with fixed and random effects. The basic two period cross-over can be analysed according to a simple fixed effects model and least squares means estimation. Identical results will be obtained from a mixed effects analysis such as Proc Mixed in SAS^®. If the mixed model approach is used, parameter constraints should be defined in the protocol.

Currently HC does not accept reference-scaling (though the “Scientific Advisory Committee on Phar­ma­ceutical Sciences and Clinical Pharmacology“ recommended in the June 2014 meeting FDA’s approach with a minimum sample size of 40 for the partial replicate and 24 for the four-period full replicate). The mixed-effect model (as given for SAS f.i. in FDA’s guidance or EMA’s Q&A-document ‘Method C’) with the FA0(2) parameterization of the covariance structure might fail to converge in partial replicate designs due to the over-spe­ci­fied model (see these posts). Either use FA0(1) instead or opt for a fully replicated three-period design (RTR|TRT).
It is beyond me why the partial replicate is so “popular”. Why do you want to use it?

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Edit: see also this thread.