Written by Bob Pollock • April 11, 2014

   OGD approved another “complex” drug product and brings a happy closure to an ANDA submitted in November 2008. By no means a record in terms of length of approval, this ANDA has been percolating for 65 months since submission and represents another in a string of complex products that OGD has tackled and approved. Thus, the first generic for Lovaza will likely hit the market soon as Teva’s ANDA # 091028 for Omega-3 – Acid Ethyl Esters gained approval on April 7, 2014.

    Fish oil – why such a problem? First there is the problem of characterization. Because an ANDA must have the same active ingredient as the reference listed drug (RLD) it relies upon for approval, OGD first must know what is actually in the fish oil. In describing its denial of New Chemical Entity (NCE) status for Vascepa (Icosapent Ethyl) in a February 21, 2014 letter FDA noted: “On November 10, 2004, more than 7 years prior to FDA's approval of Vascepa, FDA approved NDA 021654 for Lovaza, which lists "Omega-3 acid ethyl esters" as its active ingredient. The relevant monograph defines "Omega-3 acid ethyl esters" as a mixture containing, among other things, seven distinct omega-3 fatty acid ethyl esters obtained from fish oil (the Lovaza mixture). Two of the seven omega-3 acid ethyl esters, the ethyl esters of EPA and docosahexaenoic acid (DHA), make up approximately 85% of the Lovaza mixture. Similarly Lovaza's labeling describes its composition as follows: "Each 1 gram capsule of LOVAZA contains at least 900 mg of the ethyl esters of omega 3 fatty acids sourced from fish oils. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA- approximately 465 mg) and docosahexaenoic acid (DHA - approximately 375 mg)." The "Description" section of the Lovaza labeling further gives the empirical formulas, molecular weights and structural formulas of EPA ethyl ester and DHA ethyl ester, respectively, without referring to any other component of the Lovaza mixture.” Thus, while much of the Lovaza contents are well characterized, there are other components that are not. And while the NCE issue is certainly a blog-worthy topic, the concept of how the FDA arrives at its decision on what the active ingredient actually is really the story here.

     This decision is never easy and usually lengthy as evidenced by OGD’s 7 year struggle to come to grips with the composition and approval of a generic enoxaparin and is also reflected in OGD’s current deliberations, now at 6.5 years and counting, surrounding their review of glatiramer (the generic for Copaxone). The key for OGD in the Lovaza situation was first to define what is in the other 15% of the Lovaza product. While OGD took their time in terms of providing guidance to the industry on this issue, as well as how to establish bioequivalence of the product, OGD knows they have to get it right to avoid any potential problems once they approve an ANDA. Why? Because if OGD gets it wrong and the product does not preform the way the RLD does, then the credibility of the ANDA approval process gets called into question. Complex synthetic and naturally occurring products give the Agency the most problems. And the problem OGD faces with the current approval approach is that full characterization for these complex products are not necessarily established during the NDA approval process.

      Drug products subject to NDAs must demonstrate they are safe and effective, but often the work to characterize products with complex mixture is not always necessary at the NDA stage, as long as the firm can define the manufacturing process, establish appropriate controls and specifications to assure that each batch manufactured will produce a consistent and reproducible product. The job of full characterization is, thus, often left to prospective generic competitors seeking to gain approval of the product.

       Anyway, I think you can see that the process of establishing that an ANDA for a complex product has the “same” active ingredient as the RLD is essential for OGD to be able to approve the product, and the job of establishing sameness becomes a team effort between the ANDA applicants and the OGD reviewers. There is a lot of back and forth and OGD learns much from multiple ANDA submissions for the product as it pieces information and data together to establish the appropriate methods, tests procedures, specifications and techniques to measure and define the “active ingredient” and the best methods to establish bioequivalence. For complex products, this task is difficult and represents perhaps the biggest challenge to the approval process. But time and time again OGD seems to succeed. Keep your eyes on the prize, but remember we are still waiting for a Premarin generic so the work, so to speak, is never really done!