Replies to post #101019 on Biotech Values

[RockRat]

"Here it is. 7 pages, so it was short and sweet." And old, but I still hadn't seen it.

"Let me know what you think it means in regard to Teva's current application. "

As I said before in the post Dew stickied a few days ago, I think the problem is reverse engineering the process engineering to get the fragments needed. The same mode of depolymerization can be used, but process variations (temp, pH, depolymerization time) can give rise to different fragments, even if the same sequence is still there. Alkaline beta-elimination, the mode used for enoxaparin, cleaves w/o preference to the presence or absence of a 2-O-sulfo group in the iduronic acid, whereas other depolymerization methods can be more rigid -- but yield different terminal ends. The example given in the response to the CP says that a chain with the sequence ABCEDA can be cleaved into AB and CDEDA with a process that biases cleavage at the C unit, whereas a process that biases cleavage at the D unit will yield ABC, DE, and DA. Sequence is the same but distribution of the short chains making it up are now different. I believe this is the sticking point for Teva and other applicants. Their methods of characterizing these oligosaccharide units are so much slower than MNTA's that it takes them a long time to know if they've got a match or not. Most likely not, so then they have to change a parameter of the process, say the pH, and try again. The stuff at the terminal ends is relatively easy, and Teva has apparently done that long ago, so that's not the issue (i.e. the 1,6 anhydrous ring at the reducing end in about 20% of the mixture).

"Results for polysaccharide chains with molecular mass less than 3,600 Da. indicate that both enoxaparin products show essentially the same variability." (quote from Teva's response)

But showing the same variability in the oligosaccharide chains is not the same as showing the same chains, which is what FDA is asking for in its response to the CP.

"Additional characterization studies are ongoing, and it is Teva’s intention to submit these studies for Agency review as part of our pending ANDA for enoxaparin sodium injection." (quote from Teva's response)

Yeah, yeah. Plod on, boys.

Aside to everyone else. Thanks for being a sounding board for dissecting my various worries on other subjects.

Regards, RockRat

[jbog]

Tinker,

It's interesting to see all the gov. notes and explainations.



http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm220018.htm

[ThomasS]

MNTA: The following excerpts are very telling, imo:

"Aventis thus essentially asks FDA to categorically stop all review of enoxaparin ANDAs until such time (which may never come) that Aventis believes enoxaparin has been “adequately” characterized."
{IMO, Teva admits that it cannot characterize: "which may never come."}

"Teva, the world’s leading generic drug manufacturer, and the holder of hundreds of approved ANDAs, recognizes that compliance to compendial tests and specifications is not necessarily sufficient for approval of any ANDA, and that FDA may require additional tests and specifications beyond those mandated by the USP. However, as discussed below, Teva has conducted adequate and appropriate tests, and submitted the results of those tests to FDA via its ANDA, to demonstrate that its enoxaparin product is sufficiently the “same” as Lovenox® in all relevant respects to allow ANDA approval."
{"sufficiently the "same"" admits again the above lack of full characterization.}

"Teva’s enoxaparin oligosaccharide profile has been compared to that of Aventis’ Lovenox® using ion-pair HPLC- separation with TOF-MS methodology/detection. Results for polysaccharide chains with molecular mass less than 3,600 Da. indicate that both enoxaparin products show essentially the same variability. Moreover, the amino sugar composition of Teva’s enoxaparin has been compared to that of Aventis’ Lovenox® using HPLC methodology analysis of hydrolyzed enoxaparin preparations with post-column derivatization. Results show essentially identical amino sugar composition for both products..."
{Again, the verbage "essentially identical... essentially the same variability."}

"Nothing in Aventis’ petition provides a basis for FDA to refuse to review such data and approve Teva’s ANDA if, as expected, the results of Teva’s tests reveal sufficient sameness (but not necessarily exact chemical identicality) to Lovenox®."
{"But not necessarily exact..." This says it all, imo... that MNTA has raised the bar to exclude Teva. The best Teva can hope for is a generic which is not AB-rated.}

C. The Lack Of “Full Characterization” Of Enoxaparin Does Not Bar Generic Approvals
{Same as above comment. They may get a "Generic Approval," but perhaps not AB-rated.}

"Americans need generic drugs more than ever…” The economic benefits of availability of generic equivalents to Lovenox® can be estimated..."
{Irrelevant argument which belies Teva's unsuitability. They are asking the FDA to possibly fudge safety to save Americans $$$. If MNTA has an AB-rated product, the FDA cannot approve Teva as AB-rated unless they have fully characterized to the same extent as MNTA, even if MNTA did not FULLY characterize.}

[ThomasS]

MNTA: Irt generic enoxaparin, I keep coming back to the same statement from TEVA for insight on suitability, unless and until they have refined their capabilities and resubmitted to the FDA's satisfaction:


C. The Lack Of “Full Characterization” Of Enoxaparin Does Not Bar Generic Approvals


{It may bar Teva if MNTA fully characterized. We don't really know if MNTA was able to, however. On the other hand, it may only be necessary for MNTA to have more fully characterized than Teva, even if not completely.}

{I also found Teva's statement amusing as they seem to be dictating policy to the FDA.}