Replies to post #111674 on Biotech Values

[dewophile]

The five criteria for sameness are the easy part of this narrative; the hard part is understanding the “junk” in the Lovenox mixture and ensuring that it is within the lot-to-lot variation of branded Lovenox.

assessing the "junk", at least for regulatory purposes, is gauged by immunogenicity. there are no other required tests for approval other than the 5 criteria and immunogenicity. my point was not to diminishe the difficulty of the immunogenicity angle, but to point out that the other applicants seem to have developled a manufacturing process that can yeild material that can meet the 5 criteria - which i thought was an additional difficult hurdle. in amphastar's case they still have to work through the supply chain - so they have a ways to go, but over time i think they will get this in place. so imo that leaves immunogenicity as the sole hurdle - so i stand by my post.

now on immunogenicity there is some revealing information in the SNY motion for summary judgement. this is what the FDA requested of MNTA in the 2007 letter denying approval of their ANDA (from page 12 of the motion):

FDA stated that “understanding the potential for your
product to elicit an immune response is critical.” AR 4170. FDA then set forth three groups of
items that Sandoz “need[ed] to address as part of [its] ANDA”: (1) “Studies assessing the
interaction of Enoxaparin with PF4”; (2) “Studies to assess differences in impurities and their
potential affect on immunogenicity”; and (3) “Functional studies to assess differences in
impurities and their potential affect on immunogenicity.” AR 4171-73.

amphastar has already claimed that they can get protein impurities down to very low levels, so i have to think items (2) and (3) are not too difficult. item (1) is another story. these antibodies are formed to the complexes between drug and endogenous PF4 protein (even arixtra, which as you know is synthetic and should have negligible protein impurities - particularly compared to biologically sourced product - elicits anti-heparin-PF4 antibodies). so it very well could be that even though the other applicants are able to generate sample that meets the 5 criteria for sameness, there are items in the soup (or even differences in the active drug product that are not picked up by the 5 criteria threshold) that result in differences in these antibody levels.

my guess is this is where teva is hung up since assays for PF4 are readily available. since levels of these antibodies are felt to be linked to heparin induced thrombocytopenia, i don't think the FDA will allow any flexibility on this issue

[10nisman]

MNTA/TEVA

the hard part is understanding the “junk” in the Lovenox mixture and ensuring that it is within the lot-to-lot variation of branded Lovenox.

With respect to understanding the "junk".... Could Teva obtain approval without understanding the "junk" to the same degree as MNTA? Basically - is MNTA's understanding of the "junk" the bar or the potential ceiling for the FDA?

10nis