Although the Food and Drug Administration (FDA) has been slow to articulate a regulatory pathway for follow-on protein products (FDA's preferred term), several developments are moving the debate forward. A federal court compelled the agency to act on an application for a follow-on biologic earlier this year. And that action prompted members of Congress to introduce legislation laying out a possible regulatory approach. All signs point to extended debate on the issue in the coming year, particularly with Democrats gaining control of Congress.
MANUFACTURING ISSUES KEYWhile economic forces drive the clamor for generic versions of biologics and other drug dosage forms, more efficient and technically advanced analytical and production systems are key to producing follow-on versions of complex drugs. Demonstrating comparability of large molecules requires an understanding of molecular structure, heterogeneity profile, impurities, and degradation patterns. Manufacturing systems have to be high quality and well-controlled. Because production of therapies from living cell cultures can be variable, even politicians recognize that it may not be possible to develop identical or therapeutically equivalent biotech generics. Nevertheless, the prospect of any cost savings has been fueling efforts to establish a pathway for follow-on biopharmaceuticals once patents expire.
FDA has held meetings on the scientific and technical issues related to developing follow-on protein products, but the political infighting has delayed a long-promised white paper on the relevant regulatory issues. A key point of contention is whether generic firms would have to conduct a full battery of clinical trials to document that a follow-on product has a similar efficacy and immunogenicity profile as a reference product. Biotech and pharma companies insist that another manufacturer cannot access proprietary clinical or manufacturing data on biologics and that new legislation is needed to clarify FDA's regulatory authority in this area.
The Hatch-Waxman Act of 1984 established a legal process for developing generic versions of conventional drugs regulated by the Food, Drug and Cosmetic Act, but does not apply to proteins and other biologics that fall under the Public Health Service Act. While new legislation is needed to address the issue, generic drug advocates believe that Hatch-Waxman should cover those few biologics that are regulated as drugs, such as insulin and human growth hormone. FDA has drafted guidances for developing generic versions of these products, but said in April 2006 it was holding off on product-specific guidances for biogenerics, in order to draft an approval requirement for all follow-on biologics.
ACTION ON OMNITROPE
While everyone is waiting for such guidance, the agency was compelled to move forward and evaluate an application for a follow-on version of the human growth hormone Omnitrope from Sandoz, Novartis' generics unit. FDA approved the application last May, nearly three years after Sandoz filed it and only when a federal court ruled that the agency had to stop stalling and act .
Sandoz opted for the 505(b)(2) application route, which permits a manufacturer to tap publicly available data on a reference product instead of duplicating all preclinical and clinical studies. In approving the application, FDA noted that it did so because Omnitrope is a well-characterized product with a well-known primary structure and mechanism of action and publicly available bioassays and biomarkers. FDA determined that it was sufficient for Sandoz to document safety and effectiveness of its own system for cell expression, fermentation, isolation, and purification of the active ingredient, instead of proving that Omnitrope has the same active ingredient as its reference drug (Pfizer's Genotropin), as is required for conventional abbre- viated new drug applications.
Moreover, Sandoz conducted a number of clinical trials to demonstrate a similar safety and efficacy profile plus a low, acceptable immunogenicity level. Even though the scope and duration of these studies represents a modified clinical program, the trials avoided reliance on innovators' proprietary data. FDA thus rejected petitions opposing the approval from Pfizer, Genentech, and the Biotechnology Industry Organization (BIO).
At the same time, the agency did not rate Omnitrope as equivalent to Genotropin. FDA emphasized that the approval does not establish a pathway for other biotech products to come to market, including other proteins regulated as drugs.