Equivalence test case
Lessons from FDA approval of generic version of sanofi-aventis' Lovenox
While FDA's response to a Citizen's Petition lodged by sanofi-aventis Group specifically addresses the requirements for demonstrating the equivalence of enoxaparin products, it sheds light on the technical rigor that is likely to be necessary for approval of copies of other complex molecules, including biologics.
The document was released on July 23, the same day FDA approved the first ANDA for a generic enoxaparin, which was developed by Momenta Pharmaceuticals Inc. and Sandoz Inc., the generics unit of Novartis AG.
The response was a long time coming. sanofi-aventis filed the petition in 2003 asking FDA not to approve a generic copy of the pharma's blockbuster anticoagulant Lovenox enoxaparin unless the generic was fully characterized, used the same manufacturing process as that used for Lovenox or had demonstrated equivalent safety and efficacy in clinical trials.
FDA now has denied those requests, and instead provided a detailed 45-page explanation of five criteria it considers adequate to demonstrate equivalence of enoxaparin products, including methods for determining that the generic product has a chemical signature sanofi-aventis claims is important to Lovenox's efficacy.
By doing so, the agency established a threshold for the amount of scientific evidence required to demonstrate equivalence of products consisting of complex mixtures. The agency also refuted assertions that it is necessary for a generic manufacturer to know how the innovator manufactures its product, or to demonstrate equivalent safety and efficacy in trials just because the product has not been completely characterized.
FDA did reiterate that ANDA applicants must demonstrate their generic enoxaparin does not pose any more risk of immunogenicity than Lovenox. But in this case, at least, the approval showed this can be accomplished without clinical trials beyond the kinds of bioequivalence studies performed for other ANDAs.
More specifically, FDA's decision to approve Sandoz's ANDA provides validation for Momenta's core technology for characterizing complex carbohydrates. Whether and how other companies seeking to market generic versions of enoxaparin can meet the criteria laid out in FDA's response to the petition remains to be seen. Two other ANDAs seeking approval of generic enoxaparin are still pending, one from Teva Pharmaceutical Industries Ltd. and another from Amphastar Pharmaceuticals Inc.
Momenta President and CEO Craig Wheeler told BioCentury the feat is not impossible to duplicate without the biotech's proprietary technologies, but that the bar has been set very high.