FDA Takes Action on LOVENOX Citizen Petition and Approves Sandoz ANDA

By Kurt R. Karst –

Earlier today, FDA issued its long-awaited response (45 pages) to a February 2003 citizen petition submitted to the Agency on behalf of Aventis Pharmaceuticals, Inc. (“Aventis”) concerning the approval of generic versions of the company’s anti-coagulant drug LOVENOX (enoxaparin sodium injection).  FDA approved LOVENOX in March 1993 under NDA No. 20-164.

Aventis requested that FDA not approve an ANDA for generic LOVENOX unless certain conditions are met – specifically, (1) “until enoxaparin has been fully characterized . . . unless the manufacturing process used to create the generic drug product is determined to be equivalent to Aventis’s manufacturing process for enoxaparin or the application is supported by proof of equivalent safety and effectiveness demonstrated through clinical trials;” and (2) “unless the generic product contains a 1,6 anhydro ring structure at the reducing ends of between 15 percent and 25 percent of its poly(oligo)saccharide chains.”  FDA granted Aventis’s petition with respect to item (2), and denied the petition in all other respects.  At the same time, FDA approved Sandoz Inc.’s ANDA (which presumably contains a 1,6 anhydro ring structure in the proper position and which will presumably be “AB” rated to LOVENOX in the Orange Book).  Sandoz is not a first-filer, and therefore, will not be awarded 180-day exclusivity.  As FDA explains in the Sandoz approval letter, 180-day exclusivity for generic LOVENOX, which is governed by the pre-Medicare Modernization Act version of FDC Act § 505(j), was triggered by a court decision and has since expired. 

Briefly, FDA explained in its petition response that the FDC Act:

does not require ANDA applicants to (1) completely characterize all the different polysaccharides of enoxaparin by isolating, purifying, and sequencing each of its unique polysaccharide chains and determining their relative abundance, (2) use the same manufacturing process as that used for the RLD, or (3) conduct clinical studies to demonstrate equivalent safety and effectiveness. 

For an ANDA applicant to demonstrate sameness of its active ingredient as compared to LOVENOX, the Agency considers five criteria (i.e., standards for identity): (1) equivalence of physicochemical properties; (2) equivalence of heparin source material and mode of depolyierization; (3) equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species; (4) equivalence in biological and biochemical assays; and (5) equivalence of in vivo pharacodynamic profile.  According to FDA, a robust showing on all five of these factors by a generic applicant would demonstrate that the molecular diversity of the generic is equivalent to that of enoxaparin, including with respect to the 1,6 anhydro ring structure. 

FDA’s petition response may have implications on other complex drug products for which ANDAs are pending at FDA.  While FDA claims that the Agency’s approach to determining enoxaparin sameness is consistent with the Agency’s previous ANDA approval decisions for heterogeneous polysaccharides, such as heparin and hetastarch, we would not be surprised if FDA is sued over its petition response and ANDA approval.

ADDITIONAL READING:

• FDA, Generic Enoxaparin Questions and Answers

• FDA, Establishing Active Ingredient Sameness for a Generic Enoxaparin Sodium, a Low Molecular Weight Heparin