2017-05-16 20:33
(2327 d 09:09 ago)

Posting: # 17359
Views: 6,210

 Generic product of fixed dose combination product [Regulatives / Guidelines]

Hi all,

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

Assuming RAB is the FDC reference product with corresponding individual reference product RA and RB; TAB the test FDC product intended to be generic version of RAB.

For developing FDC generic product, it used to be simple. Conduct BE study comparing TAB to RAB 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. TAB vs RAB as usual, and
  2. RAB vs (RA + RB)
What's the criteria? Is it mandatory to pass BE for both 1 and 2 to be generic? What if TAB is BE to RAB but RAB is not BE to (RA + RB)? Ask originator to recall the FDC product? :-D

The point 2 doesn't seem right to me. Or should one interpret the wording as follows?
  1. TAB vs RAB as usual, and
  2. TAB vs (RA + RB)
If so, what if TAB is BE to (RA + RB) but not BE to RAB? 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 TAB/RAB vs (RA + RB). Maybe it's clear to everyone except me? What's your experience about generic FDC development under new guideline?

All the best,

2017-05-16 21:17
(2327 d 08:25 ago)

@ Shuanghe
Posting: # 17360
Views: 5,197

 Generic product of fixed dose combination product

"...In this case two pharmacokinetics bridges may need to be built..."

Emphasis on may, I guess ;-)

Would strongly depend on the clinical data available for R(AB), I assume, if you have to go this way.

You could offer some food offerings to the oracle or some thousand bugs for an SA, to get the official answer to your questions. In fact I believe, you need both BE studies of your option 1 to pass plus an explanation for "no drift relevant" in practice, if you have clinical data only for combi of the monopreparations. FDC can be real pain...

Edit: Please don’t shout! [Helmut]

Kindest regards, nobody

2017-11-30 12:03
(2129 d 16:39 ago)

@ Shuanghe
Posting: # 18026
Views: 4,454

 Generic product of fixed dose combination product

Dear All,

We seek further clarity on this topic,

As per post of Shuanghe, new guideline has an additional requirement of demonstration FDC BE against the individual subtances, this could be done by following options

option 01

1. TAB vs RAB as usual, and
2. RAB vs (RA + RB)- evidence based approach

option 02

1. TAB vs RAB as usual, and
2. TAB vs (RA + RB)

But if we refer section 4.6. Bridging the evidence base to the fixed combination medicinal product
Clinical data establishing the contribution of each active substance and the positive benefit-risk are often obtained from the combined use of individual active substances. In this case demonstration of similar pharmacokinetics (usually through demonstrating bioequivalence) of the fixed combination medicinal product versus its individual active substances taken simultaneously is required. This is to satisfy the third basic requirement for an MAA for fixed combination medicinal products. An efficient study design is to compare AB versus concurrent administration of A and B as individual active substance products, in which case bioequivalence can be evaluated for each active substance separately considering individual active substance product characteristics characteristics; e.g. highly variable drug, narrow therapeutic index, biopharmaceutics classification system (BCS) classification, appropriate sampling schedule, and release mechanism (requirements differ for immediate- and modified-release products).

If we refer above paragraph from the guideline, then is it concluding to prove BE of FDC as follows

1. TAB vs RAB as usual, and
2. TAB vs (RA + RB)


Can we do BE of FDC as TAB vs RAB, and provide evidence base data for RAB vs (RA + RB) from innovator published studies or PAR or scientific discussion to support to clinical dossier.

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