FDA Approves Momenta/Sandoz' Lovenox Generic Without Need For Clinical Studies

Agency's five criteria for determining "sameness" of generic enoxaparin to Sanofi-Aventis's low molecular weight heparin could serve as guideposts for future biosimilar approvals.

FDA approval of Momenta's and Sandoz' generic version of Sanofi-Aventis' Lovenox (enoxaparin) suggests the agency is willing to find a way around requiring clinical efficacy and safety data for future biosimilar approvals.

In granting approval of the first low molecular weight heparin generic on July 23, FDA rejected Sanofi-Aventis' arguments asserted in a citizen petition that enoxaparin ANDA filers should be required to conduct clinical trials to establish and safety and effectiveness of their products.

Instead, FDA laid out five criteria that it used to make a "sameness" determination for Momenta/Sandoz' enoxaparin sodium. Though FDA's response to Sanofi's citizen petition was limited to the context of enoxaparin generics, the five principles could be viewed as guideposts to the level of evidence needed for future biosimilar approvals.

The five criteria used to demonstrate active ingredient sameness involve equivalence of:

# the physical and chemical characteristics of enoxaparin;

# the nature of the source material and the method used to break up the polysaccharide chains into smaller fragments;

# the nature and arrangement of components that constitute enoxaparin;

# certain laboratory measurements of anticoagulant activity; and

# certain aspects of the drug's effect in humans.

"These five criteria together comprise a robust test that provides overlapping evidence by which an ANDA applicant for enoxaparin can demonstrate active ingredient sameness for enoxaparin within the meaning of the [FD&C] Act and FDA regulations," the agency says in its response to the citizen petition.

This five-pronged approach to determining active ingredient sameness was vetted by various units within the Center for Drug Evaluation and Research, including the Office of Generic Drugs, Office of New Drug Quality Assessment and Office of Biotechnology Products, all housed within the Office of Pharmaceutical Science, as well as the Office of New Drugs' Division of Gastrointestinal and Coagulation Drug Products and the Division of Medical Imaging/Hematology Products.

The agency cautions that its criteria are not set in stone. "As with all complex scientific issues, it is possible that with improvement in the understanding of the biological and clinical properties of enoxaparin and/or advances in the analytical technologies that might be used to characterize enoxaparin, other approaches might emerge to establish ... sameness."

EU Requirements

In a Q&A document on the generic enoxaparin approval, FDA goes to great lengths to explain why it is allowing approval of generic low molecular weight heparin without requiring clinical studies even though the European Medicines Agency has issued guidelines requiring clinical data for this class of medicines (Also see "Generic Lovenox In EU Will Require Clinical Data, Shrinking Sandoz’s Opportunity" - Pink Sheet, 15 Jun, 2009.).

In contrast to the FDA requirements for "sameness," the EMA guidelines only require that products contain a "similar" active ingredient as that of the reference listed drug, FDA says. This similarity requirement means there could be uncertainties as to whether the two products are the same with regard to safety and effectiveness, thus explaining the need for clinical trials to show comparable safety and effectiveness.

FDA says that with its approach of applying the five criteria, in addition to evaluating immunogenicity of the generic product, "there is no scientific need to perform additional clinical studies to demonstrate equivalence of clinical effectiveness and safety of generic enoxaparin to Lovenox."

During a conference call, Momenta CEO Craig Wheeler said he was pleased with the thoroughness of FDA's response to the citizen petition, which he described as an aggressive and rigorous look at the issues. The agency's response, he said, suggests it will set a "high bar" for biosimilar versions of complex molecules under the abbreviated approval pathway created through the recently enacted health care reform legislation.

De Facto Exclusivity

Wheeler said Momenta's marketing partner, Novartis's Sandoz unit, has been preparing to launch the generic, referred to as M-enoxaparin, upon approval, although he would not say exactly when product would begin shipping.

Momenta's generic carries an AB rating, and approval did not include any postmarketing study commitments or requirements.

Though it is the first to win ANDA approval, the Momenta/Sandoz product will not receive 180-day marketing exclusivity. Generic exclusivity for drug products referencing Lovenox was triggered on Oct. 2, 2008, the date a federal appeals court mandate issued finding two Lovenox patents unenforceable due to inequitable conduct by Sanofi-Aventis's predecessor, Aventis. The 180-day exclusivity period expired on March 31, 2009.

Even though it has no statutory exclusivity, the Momenta/Sandoz product appears likely to hold de facto generic marketing exclusivity for some time by virtue of the fact that the agency did not simultaneously approve the ANDAs of either Teva or Amphastar. Both companies filed their ANDAs in 2003, ahead of the 2005 filing by Momenta/Sandoz.

In 2007 the Momenta/Sandoz ANDA received a "not approvable" letter in which FDA cited concerns about immunogenicity with M-enoxaparin. Sandoz submitted new safety data in 2008.

Teva believes it has demonstrated that its enoxaparin meets FDA's five-pronged criteria and that the pending ANDA is approvable. Approval is appropriate, Teva said, because the active ingredient in enoxaparin is significantly better characterized than active ingredients of more complex molecules, pharmacologically active portions of enoxaparin can be identified and replicated, and in vitro and in vivo pharmacodynamic tests are rapidly indicative of drug efficacy and safety.

"Teva recognizes and supports FDA authority and discretion to make generic drug approvals on a case-by-case basis considering drug complexity, patient efficacy and safety outcomes," the company said.

The company distinguished the approval criteria for generic enoxaparin from those it believes are required for ANDAs referencing its own branded multiple sclerosis therapy, Copaxone (glatiramer). The complexity of Copaxone and the serious degenerative nature of the disease warrant full-scale, placebo controlled clinical trials with measured clinical endpoints to establish safety, efficacy and immunogenicity of generic glatiramer in the MS patient population, the company said.

As for Amphastar, the company has alleged CDER Director Janet Woodcock's ties to Momenta, in connection with research into the contamination of heparin raw ingredient from China, resulted in extra immunogenicity testing requirements being placed on its own ANDA (Also see "As Device Center Director Gets The Hook, Spotlight Turns To CDER's Woodcock" - Pink Sheet, 17 Aug, 2009.).

FDA's response to Sanofi-Aventis' citizen petition was signed not by Woodcock, but rather by CDER Deputy Director Douglas Throckmorton.

-Sue Sutter ([email protected])