Bioequivalence and Bioavailability Forum

Hi all,

I have some questions about EMA’s new fixed dose combination (FDC) guideline.

Assuming R_AB is the FDC reference product with corresponding individual reference product R_A and R_B; T_AB the test FDC product intended to be generic version of R_AB.

For developing FDC generic product, it used to be simple. Conduct BE study comparing T_AB to R_AB and period. However, the wording in section 4.5 of the new guideline is a bit confusing.

"Also, for generic fixed combination medicinal products it needs to be verified that the evidence base that may have been generated for the reference product with individual active substances (rather than with the fixed combination medicinal product, to which reference is being made) applies to the generic fixed combination medicinal product. In this case two pharmacokinetics bridges may need to be built, one between the reference fixed combination medicinal product and its active substances and one between the generic and reference fixed combination medicinal product. A justification should be provided why ‘drifting’ of bioavailability is not considered relevant and hence why the original demonstration of efficacy and safety is relevant to the generic."

So now it seems we have to do:

1. T_AB vs R_AB as usual, and
   
2. R_AB vs (R_A + R_B)

What's the criteria? Is it mandatory to pass BE for both 1 and 2 to be generic? What if T_AB is BE to R_AB but R_AB is not BE to (R_A + R_B)? Ask originator to recall the FDC product?

The point 2 doesn't seem right to me. Or should one interpret the wording as follows?

1. T_AB vs R_AB as usual, and
   
2. T_AB vs (R_A + R_B)

If so, what if T_AB is BE to (R_A + R_B) but not BE to R_AB? Or vice versa?

I know at Biobridge Prague in September last year there's discussion of "drifting" but I thought this was still an issue to be discussed; but it seems it has been implemented in the final guide.

I searched the forum and I'm surprised that no one seems to talk about the additional T_AB/R_AB vs (R_A + R_B). Maybe it's clear to everyone except me? What's your experience about generic FDC development under new guideline?