This week, the FDA issued a non-approvable letter to Momenta Pharmaceuticals as outlined in a press release from the company. The approvable letter was issued to Momenta and its partner, Sandoz, Inc, which is a generics manufacturing division of Novartis. The focus of the letter was an abbreviated application for Enoxaparin Sodium Injection – labeled by the company as a "technology-enabled generic version of LOVENOX®. LOVENOX® is manufactured by Sanofi-Aventis and is a chemical treatment for Deep Vein Thrombosis.
While a non-approvable letter is nothing unusual, especially in the current FDA environment, it was notable because "the application does not adequately address the potential for immunogenicity of the drug product and suggested a meeting with the FDA’s Office of Generic Drugs.
This raised a few questions in my mind. First – why did the FDA send an non-approval letter instead of an approvable letter if the agency was going to refer the sponsor to the FDA for consultation on how to address the agency’s concern. If the FDA’s concern can be addressed, shouldn’t it be an approvable rather than non-approval? Investors, after all, react strongly to these letters and yet there is, at least on the face of it, a lack of clarity about when an approvable letter is being issued versus a non-approval.
The other question that is of import relates to the issue of immunogenicity. Immunogenicity is a key concern related to the approval of follow-on-biologics. Since the basis of this non-approval is immunogenicity, there may be insights in the experience of Momenta and Sandoz to gain approval of their generic version of LOVENOX®. Here is what Dr. Janet Woodcock recently said about the issue of immunogenicity and follow-on-biologics in testimony before the Subcommittee on Health, Committee on Energy and Commerce entitled "Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States" on May 2, 2007:
"The ability to predict immunogenicity of a protein product, particularly the more complex proteins, is extremely limited. Therefore, some degree of clinical assessment of a new product’s immunogenic potential will ordinarily be needed. The extent of independent testing needed will again depend on a variety of scientific factors such as the indication, whether the product is to be administered chronically, the overall assessment of the product’s immunogenic potential, and whether there is the possibility of generating a cross-reaction with an important endogenous molecule.
A finding by the Agency that a follow-on protein product may be approved as safe and effective is distinct from a determination that the follow-on protein product would be substitutable for the referenced protein product. To establish that two protein products would be substitutable, the sponsor of a follow-on product would need to demonstrate through additional clinical data that repeated switches from the follow-on product to the referenced product (and vice versa) would have no negative effect on the safety and/or effectiveness of the products as a result of immunogenicity. For many follow-on protein products — and in particular, the more complex proteins – there is a significant potential for repeated switches between products to have a negative impact on the safety and/or effectiveness. Therefore, the ability to make determinations of substitutability for follow-on protein products may be limited."
It appears that there are two tasks to be considered. One is immunogenicity and another is for interchangeability. According to the Momenta release, the FDA concerns are solely focused on the former, but there could nevertheless be some serious clues in the treatment of this application for future applications for follow-on-biologics.