FDA approves generic Lovenox® (enoxaparin) representing a major policy advancement for naturally-sourced generic drugs and possibly biosimilars.
On July 23, 2010 the FDA approved the first generic enoxaparin product in a major policy advancement that will likely impact a number of other naturally sourced generic drugs and possibly biosimilars. Enoxaparin is the generic name for Lovenox® which is manufactured by Sanofi Aventis. The drug is a low molecular weight heparin, derived from cleavage of large heparin strands. It is an injectable anticoagulant (blood thinner) indicated for the prevention and treatment of deep vein thromboses (blood clots). The drug was approved under an Abbreviated New Drug Application (ANDA) submitted by Sandoz Inc. Lovenox® was originally approved in March 1993 under a New Drug Application (NDA) by Sanofi Aventis.
What makes this matter so important is enoxaparin is a naturally-derived product, more closely related to biologic drugs such as monoclonal antibodies than conventional drugs like aspirin and Lipitor.® These products pose a number of important challenges in the generic review and approval process, unlike conventional drugs. For example the characterization of these products is often difficult and generic versions pose important immunogenicity concerns and greater batch-to-batch variability.
In 2003 counsel for Sanofi Aventis submitted a citizens petition to the FDA urging the agency to not approve a generic version of the drug until a number of requirements were met, in attempts to exclude competition. Specifically, they expressed concerns with characterization of the drug and how the FDA would ensure equivalency. They requested the FDA require the generic to follow the same manufacturing practices as Sanofi Aventis or else require full-scale clinical testing to demonstrate equivalent safety and efficacy. Moreover, Sanofi Aventis requested the FDA require the generic be a specific chemical profile, that is to contain a 1,6 anhydro ring structure at the reducing ends of between 15 percent and 25 percent of its poly(oligo)saccharide chains.
Simultaneous with the approval, on July 23, 2010 the FDA released their response to the petition. The agency granted the petition insofar as requiring the generic to meet the chemical profile type, but denied the petition insofar as requiring the manufacturing practice to be equivalent or else require full-scale clinical investigation. Instead the FDA established that enoxaparin has been adequately characterized and sameness of the generic to the brand would be met based on the following five criteria.
- Equivalence of heparin source material and mode of depolymerization
- Equivalence of physiochemical properties
- Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species
- Equivalence in biological and biochemical assays
- Equivalence of in vivo pharmacodynamic profile
Essentially, by demonstrating compliance with the above standards of identity, a generic drug could prove equivalent to the brand drug without the need for full-scale clinical investigation, complete characterization, and with variances in the manufacturing process.
The approval now means that pharmacists may substitute the generic drug for the brand, providing cost-savings to the patient and the healthcare system as a whole. More importantly, the approval represents an important policy development by the FDA. The FDAs establishment of criteria for sameness suggests the FDA is prepared to move on additional naturally-derived generic applications. Furthermore, the approval suggests that the FDA will not require full-scale clinical trials for biosimilars and may approve them, even with notable differences in the manufacturing process if certain criteria are met. Biosimilars are follow-on versions of complex naturally-derived products. The 2010 health reform bill, the Patient Protection and Affordable Care Act, for the first time authorizes the FDA to approve biosimilar drugs in the United States under Title VII-Biologics Price Competition and Innovcation Act. Prior to this enactment there was no real mechanism to approve biosimilar products for drugs approved under a Biologic License Application (BLA), as authorized by section 351 of the Public Health Service Act (PHS).
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