Bioequivalence and Bioavailability Forum

❝ Or do I get that completely wrong?

Not quite. I try to summarize my personal account:

• C_min was never a primary PK metric in any regulation.
  
• Some alternative PK metrics for MR products were explored in the mid 1990s. BTW, C_min was none of them (for obvious reasons I concur). I would not bet that EMA’s “experts” have read these papers. Given that C_min is a single point metric and likely the con­centration with the highest vari­ability of the entire profile powering a study for BE is a nightmare.
  
• Is there any evidence that a product passing conventional PK metrics would fail on C_min in a properly powered BE study? I doubt it. There are more generics on the US market than in the EU. The FDA never required it. Even more: Only SD studies are required. Any problems? Is there any substantial risk?
  
• Analyzing BE of C_min first appeared in EMA’s IR draft in 2008 after some concerns for oxycodone. However, It was dropped from the final IR GL.
  
• At the first conference about the MR GL (Barcelona, Feb 2011) Alfredo García Arieta of the Spanish agency suggested C_τ as an additional metric in SD in order to waive MD studies.
  I strongly opposed that, but …
  
• … Paixão et al. (from the Portuguese agency and the University of Lisbon) showed in extensive simulations that it would work. They explored different type of MR formulations (IR+CR, osmotic pumps, biphasic systems). The main author received the “AAPS Outstanding Manuscript Award in Modeling and Simulation” in 2012. I was convinced.
  
• In the meantime A. García Arieta changed his mind as well and published a bizarre cherry-picking paper. I regularly peer-review papers and this one should have been rejected because the conclusions were exactly the opposite of the reported results. Obviously a man on a mission.
  
• Normally a draft GL is published when members of the PKWP agree at the end (or are so bugged out that they start a trial ballon). In this case there was a vote and the majority was for waiving MD studies + C_τ in SD. Can you guess who insisted in “The discussion of the opportunity of using equivalence in C_τ in single dose studies as basis for waiving the multiple dose study has been recog­nized. However, there is not considered to be sufficient scientific evidence at the moment to encourage this approach”?
  
• At the next conference (Bonn, June 2013) the introduction of a new PK metric with­out justified relevance / discriminatory power was challenged by many participants. Alfredo told me “I don’t believe [sic] in simu­la­tions.” Henning Blume and I suggested to that it should be mandatory to submit the data, but not base the BE decision on it. A similar approach was used by the FDA when they were interested in the subject-by-formulation interaction. For two years all MR studies had to be performed in a replicate design and after analyzing them the FDA decided that S×F is not an issue.
  It felt like talking to a pile of bricks.
  
• Numerous people sent comments to EMA.
  
• The éminence grise of the PKWP showed us the finger. Comments on the draft – which likely would show that many people did not agree – not published…

Slowly I’m loosing confidence in this entire system of (pseudo-)transparency.

Go ahead, collect data (I’m not very optimistic that you will find sufficiently powered studies). Don’t count on me. After six years of opposing C_min I’m running out of steam.