Bioequivalence and Bioavailability Forum

Dear Jagankm & Ohlbe!

❝ […] a steady state study is needed for EU submission.

Yes and no (see below).

❝ […] SPC of innovator itself noticing there is no accumulation of metformin after repeated administration. in this regard is it necessary to for steady state study as per guidelines. is there any way to skip to conduct steady state study for metformin for EU submission.

Maybe it’s worthwhile reading this story. In short: No steady state studies were performed since the drug did not accumulate; MA was granted in the EU – despite required by the old (and still current) GL.

According to current thinking of EMA^1,2 (internal draft #8 of the MR-GL as of May 2011) steady state studies will not have to be performed any more – if no accumulation is demonstrated in the single dose study (AUC_t/AUC_∞ > 80%). A justification IMHO will be acceptable only if referring to a pivotal single dose study (not the SPC of the innovator or literature data). It’s up to you to go either for a (nonbinding, of course) scientific advice, or simply go ahead with a justification in the application. I think that in the light of international harmonisation this section will ‘make it’ through the official draft to the final version, because:

• FDA requires multiple dose studies only in exceptional cases (mainly studies in patients).
  
• A similar POV about accumulation in Canada.

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1. Christoph Baumgärtel [AGES PharmMed, Raporteur of the CHMP Pharmacokinetics Working Party (PKWP)]
   Bioequivalence requirements for MR products: Current regulatory thinking and open issues
   EUFEPS BABP Network Open Discussion Forum. Revision of BE Requirements for Modified Release Products
   Barcelona, Spain, 24 February 2011
   
2. Jan Neuhauser (AGES PharmMed)
   Understanding the proposed guideline for modified release
   7^th Annual Bioavailability/Bioequivalence and Dissolution Testing Conference
   Budapest, Hungary, 18 May 2011