BETHESDA, MD 26 August 2010—After much deliberation, FDA on July 23 approved the first generic version of enoxaparin, the drug that has topped the list of highest pharmaceutical expenditures by nonfederal hospitals for the past four years.
Sandoz Inc., sponsor of the recently approved marketing application, described the product as a "more affordable" version of the "leading hospital-based medication."
Sanofi-Aventis, maker of the brand-name product, expressed concern about "potential implications for patient safety" because the newer product did not undergo "extensive clinical trials to demonstrate its efficacy and safety."
The company’s U.S. affiliate in addition said it would suffer "irreparable harm" if FDA’s approval of the generic stands.
A request for a federal court to make FDA retract its approval was filed July 26 by the affiliate. The judge had not reached a decision by presstime.
Complex set of oligosaccharides. Enoxaparin first hit the U.S. market in 1993 when a predecessor of Sanofi-Aventis launched Lovenox in prefilled syringes.
The manufacture of the drug, the labeling states, starts with heparin benzyl ester derived from porcine intestinal mucosa. Alkaline treatment of the ester produces polysaccharide chains having various molecular weights.
According to the United States Pharmacopeia description of enoxaparin sodium, the drug consists of a "complex set of oligosaccharides that have not yet been completely characterized."
But enough is known about its characteristics, FDA said in July, "for the purposes of approving naturally sourced generic enoxaparin."
The agency explained that the sponsor of an application to market generic enoxaparin can demonstrate the "sameness" of that substance to Lovenox’s enoxaparin by showing that the two are equivalent in physicochemical properties, heparin source material, mode of heparin depolymerization, disaccharide building blocks, oligosaccharide fragment mapping profile, sequence of oligosaccharide species, biological assays, biochemical assays, and in vivo pharmacodynamic profile.
Use of the same "process conditions" as for the manufacture of Lovenox’s enoxaparin is not necessary, FDA said.
Sameness of the active ingredient. Sandoz developed its enoxaparin product in collaboration with Momenta Pharmaceuticals Inc., which specializes in the analysis and characterization of complex drugs, including heparin.
That collaboration dates back to 2003, several years before Momenta researchers helped FDA identify oversulfated chondroitin sulfate as a contaminant in heparin.
In comments about FDA’s approval of the new enoxaparin product, the nonprofit North American Thrombosis Forum (NATF) said clinicians prescribing that generic product "can . . . expect the exact same levels of anticoagulation (and hopefully antithrombotic) outcomes, as were reported with the brand name products."
NATF, in its 2009 annual report, acknowledged several manufacturers of brand-name antithrombotics, including Sanofi-Aventis, as providers of educational grants.
Unlike FDA, NATF considers enoxaparin and other low-molecular-weight heparins to be biological products.
"The only way to establish parity of structure and equivalence of function and safety for the biologics is through carefully conducted clinical trials," NATF said.
That criterion, said NATF Vice President Jawed Fareed, has not been applied to the newly approved enoxaparin product.
Fareed is a professor of pathology and pharmacology at Loyola University in Chicago and the director of the Hemostasis and Thrombosis Research Unit at Loyola University Medical Center. He has worked on the preclinical and clinical development of anticoagulant drugs, in particular low-molecular-weight heparins and related substances.
"From what I understand," Fareed said, "that in lieu of clinical trials, the FDA has approved the drug based on the scientific information provided to them, which, I think, based on the FDA’s expertise—the chemists and so forth—is most likely valid."
If the new generic product turns out not to be the same as the brand-name product, one of two problems can arise, he said: "Either there may be a safety problem or there may be an efficacy problem."
The safety problem would be bleeding or thrombocytopenia, he said.
Bleeding or thrombocytopenia can occur during enoxaparin therapy. During the various clinical trials of Lovenox, the product’s labeling states, major bleeding episodes occurred in as many as 4% of patients who received the drug. Moderate thrombocytopenia occurred in 1.3% of patients.
The efficacy problem, which would be the generic product not being as effective as the brand-name product, can be observed only after postmarketing surveillance, such as through FDA’s MedWatch program, which NATF strongly endorses, Fareed said.
Lack of clinical validation of efficacy, he added, is true of any new generic product on the market.
The law permitting abbreviated new drug applications for generic versions of drugs approved after 1962 eliminated the need for applicants to include the results of safety and efficacy studies on those generic products.
Changes in contracts. Since 2006, enoxaparin has been the biggest drug expense for hospitals not owned or operated by the federal government, according to the authors who annually publish an article in AJHP on future drug expenditures.
A byproduct of FDA’s decision for at least one group purchasing organization and its member hospitals is a lower contract price for the brand-name product.
"We’ve renegotiated our agreement with Sanofi-Aventis for a sole-source deal" with a substantial decrease in the cost for Lovenox, said Gary Freeman, vice president of pharmacy contracting at Amerinet.
He said hospitals in the group purchasing organization had expressed "lots of interest" in generic enoxaparin.
Amerinet and Sanofi-Aventis signed the agreement on July 23 or thereabouts, he said. Their previous agreement would have expired in October 2011.
A group purchasing organization whose representative said he signed a contract with Sandoz for its generic enoxaparin declined to comment on the matter.
