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. Although new legislation is needed to address that issue, generic-drug advocates believe that Hatch–Waxman should apply
to biologics such as insulin and human growth hormone that are regulated as drugs. FDA has drafted guidances for developing
generic versions of these products, but has not released them, despite demands from members of Congress, state governors,
and generics manufacturers to do so. In response to a call from several governors for FDA to "help states reduce the burden
of excessive pharmaceutical costs," the agency said in April 2006 that it was holding off on product-specific guidances for
biogenerics to draft broad requirements for approving all follow-on biologics.
Action on Omnitrope
While efforts to clarify FDA regulatory policy have been on hold, the agency was compelled to consider approval of a follow-on
version of the human growth hormone "Omnitrope" from Novartis's generics unit Sandoz. FDA approved this first biotechnology
therapy made by another manufacturer last May, but this was almost three years after Sandoz submitted its application and
only when a federal court ruled that the agency must stop stalling and act on the submission.
Sandoz adopted the 505(b)(2) application route, which permits a manufacturer to tap publicly available data about a reference
product instead of duplicating all preclinical and clinical studies. FDA explained that it approved the application because
Omnitrope is a well-characterized product with a well-known primary structure and mechanism of action and publicly available
bioassays and biomarkers. The agency determined that it was sufficient for Sandoz to document the safety and effectiveness
of its own system for the cell expression, fermentation, isolation, and purification of the active ingredient, instead of
demonstrating that Omnitrope has the same active ingredient as its reference drug (Pfizer's "Genotropin"), as is required
for conventional ANDAs.
Moreover, Sandoz conducted several clinical trials to demonstrate a similar safety and efficacy profile plus a sufficiently
low level of immunogenicity. 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.
At the same time, the agency did not rate Omnitrope as equivalent to Genotropin. And, FDA emphasized that this approval does
not establish a pathway for other biotechnology products to come to market, including other proteins regulated as drugs.
In explaining its action on Omnitrope, FDA reiterated its request for new legislation to clarify its legal authority to approve
follow-on versions of any biotechnology therapies. Just before Congress recessed in October, three leading Democratic legislators
offered a proposal to move the debate forward. Rep. Henry Waxman of California and Sens. Charles Schumer and Hillary Rodham
Clinton of New York introduced the "Access to Life-Saving Medicine Act" (HR 6257) that describes an approach for approving
copies of biopharmaceuticals. Although the legislators acknowledge that more complicated scientific issues are involved in
demonstrating that a generic version of a biotechnology drug is the same as the branded product, they assert that the Omnitrope
approval shows that such action is "scientifically feasible."
The bill authorizes FDA to approve abbreviated applications for biological products that are "comparable" with previously
approved (reference) biologics. FDA will determine on a case-by-case basis which clinical and preclinical studies are necessary
to establish comparability, and all applicants for follow-on biologics would pay user fees.
A summary of the bill emphasizes the importance of technical and scientific expertise for documenting comparability. The manufacturer
must show that its product shares the "principal molecular structural features" and has the same mechanism of action (if known),
route of administration, dosage form, and strength. Manufacturing controls must be established to ensure product identity,
strength, quality, and purity.