Biotech Values

[mouton29]

<<There is nothing I’m aware of in the governing statues that mandates how the FDA should ensure manufacturing purity.>>

The FDA's reasoning is set forth on pages 41 - 42 of their response to the CP, cut and pasted here:

E. Current Approval Requirements for ANDAs for Enoxaparin are Scientifcally Appropriate and Address the Safety Proïie of Enoxaparin.

The North American Thrombosis Foru (NATF), for example, states that current guidelines for generic drug approval may not be applicable for the approval of therapeutic agents that are biologically based. In particular, NATF and other comments state that there is the potential for unanticipated adverse events or immune response, and that clinical testing is essential (February 22,2010 and March 2,2010, NATF Comments; May 26,2010, Society of Hospital Medicine Comment; and May 28, 2010, Victor Tapson, Duke University Medical Center Comment).

It is important that ANDA applicants assess the potential of the generic product to generate a greater immune response as compared to the RLD, Lovenox.126 In the case of enoxaparin, an immune response can be generated that may lead to a known adverse event, thrombocytopenia. There is evidence that the immune response resulting in thrombocytopenia is stimulated by the active ingredient. The pathogenesis of this response has been extensively investigated and involves a critical step of association of enoxaparn (or other L WMHs) oligo saccharides to platelet factor 4 (PF4) via a non-specific (sequence independent) electrostatic interaction primarily based on oligosaccharide chain length and charge density. Therefore, a demonstration of equivalence of molecular diversity of the generic drug product's enoxaparin to Lovenox's enoxaparin is a strong indication that the generic enoxaparin would not differ from Lovenox with respect to its immunogenicity. Nonetheless, immune responses are very complex and even when they are stimulated by the active ingredient (as is the case with enoxaparin sodium), they may be influenced by impurities or other substances in the product that may modify the immune response to the active ingredient. Given the safety profile of Lovenox, we believe that, in addition to demonstrating sameness of the generic drug product's enoKaparin to Lovenox's enoxaparn, sponsors should submit a comparative assessment of their generic enoxaparin and Lovenox for potential impurities that may have an adverse impact with respect to immunogenicity. Based on review of available data, we have determined that it is possible, by satisfying the five criteria and (as a conservative measure) by conducting in vitro and in vivo assays to address impurities, to provide scientifically appropriate assurance that the risk of immunogenicity due to potential impurities in the generic enoxaparin wil not be greater than that of Lovenox. In such cases, clinical testing to demonstrate safety and effectiveness is not necessary for enoxaparin sodium injection (see also sections VLC. and VLF.). We expect that a generic enoxaparin that meets the requirements for ANDA approval wil be therapeutically equivalent to and can be
substituted for Lovenox with the expectation that it wil produce the same clinical effect and safety profile as Lovenox.