Teva’s entry into the hepatitis C market (see yesterday’s post) comes at a time of increased attention to the uncharted path to regulatory approval for generic versions of biologics – drugs made from living organisms (i.e., cells), such as interferon.
Biologics often require injection, and are typically several times more expensive than other types of drugs made solely from chemicals. Several biologics cost well over a thousand dollars a month for a course of treatment; at the high end, Imclone's Erbitux (used for colon cancer) can cost $20,000 a month. Biologics make up a rapidly growing proportion of drug costs, and have spurred debate among cancer doctors over whether the costs of these treatments exceeds the benefits to patients. While the expense of biologics in part reflects their higher manufacturing costs, the lack of competition ensures that companies can price their drugs as high as the market will bear. The call for generic biologics reflects these skyrocketing prices and pressures on insurers, government payers, and patients.
The FDA has claimed that it cannot approve any generic (or, to use their term, “follow-on”) biologic products until there’s more clarity on legal and scientific issues. The legal issues hinge on whether the FDA currently has regulatory authority to approve generic biologics under the 505(b)(2) provision of the Hatch-Waxman amendment to the Federal Food, Drug and Cosmetic Act. The 1984 legislation (formally known as the Drug Price Competition and Patent Term Restoration Act) established a new and simplified regulatory framework to guide the approval of generic versions of original (“brand-name” or “innovator”) drugs.
In short, generic versions no longer had to duplicate the results of clinical trials (studies that test a drug’s safety and efficacy in patients) that were conducted for the approval of the original drug. Generic companies simply had to demonstrate “bioequivalence” – that the generic drug behaved the same way in the body as the original drug. The theory was that the active chemical ingredient was identical, so safety and efficacy should be the same as long as the drugs were bioequivalent (for more background on Hatch-Waxman, and its effect on competition and pricing, see this 1998 report from the Congressional Budget Office [PDF version]).
However, this bioequivalence model has not been tested for biologics, where the same “active chemical” (which in this case could be a protein such as interferon or antibodies, or genetic material – e.g., RNA or DNA) could in theory behave differently in the body depending on how it’s manufactured.
Sandoz, the generics division of Novartis, recently forced the question by submitting Omnitrop, a generic version of human growth hormone (somatropin), for approval in Europe and the United States. Omnitrop would compete with brand-name versions of human growth hormone from Serono and Genentech.
In April, the European Agency for the Evaluation of Medical Products (EMEA – the European equivalent of the FDA) rejected Omnitrop, citing “filing irregularities” in the application – despite the recommendation for approval [http://www.emea.eu.int/pdfs/human/opinion/318403en.pdf] by the EMEA’s own Committee for Proprietary Medicinal Products in June of 2003 (see article from The Scientist for more detail).
In early September, Sandoz announced that the FDA had “completed its review of Omnitrope and did not identify any deficiencies in the application. However, the agency stated it had been unable to reach a final decision on the application due to uncertainty regarding scientific and legal issues.” [PDF of Sandoz press release]
Since then, the FDA held a public workshop on September 14th and 15th to discuss “Scientific Considerations Related to Developing Follow-On Protein Products” [announcement; PDF version]. The workshop aimed to “solicit the scientific and technological perspectives of manufacturers, academia, and other interested persons to determine the state of the science as it relates to protein characterization, production, and assessment of similarity.” This input would be used by the FDA to develop guidance on scientific requirements for approving generic biologics, to be issued some time next year (guidance that was originally expected to be issued this year).
The FDA requested comments on the following topics:
A. Manufacturing Issues
1. What aspects of the manufacturing process determine the characteristics of a protein product whether produced through biotechnology or derived from natural sources?
2. What parts of the manufacturing process should the agency focus on when assessing similarity between products?
1. What is the capability of current analytical technology to adequately characterize protein products?
2. Are there new technologies that hold promise for helping to characterize proteins?
3. What factors, including quality attributes, impurity profiles, and changes in the manufacturing process, should be considered when assessing similarity of different protein products?
4. Is it possible to accurately predict safety and efficacy from analytical studies?
1. How, and to what extent, should immunogenicity be evaluated for a follow-on protein product?
2. Under what circumstances should comparative immunogenicity studies be conducted?
D. Preclinical and Clinical
1. When and how would it be appropriate to streamline or eliminate certain animal or human studies during development of a follow-on protein product?
E. Potency and Surrogates for Efficacy and Safety
1. What factors should be considered regarding bioactivity and potency assays used for comparing two products?
2. What is the role of in vitro and in vivo assays for use as surrogates in establishing safety and efficacy?
1. Please comment on the appropriateness of this notice's working definition of “follow-on protein” as a protein that is intended to be a similar version or copy of an already approved or licensed protein pharmaceutical product.
2. Please comment on this notice's working definition of a “second-generation protein product” as a product similar to an already approved or licensed product but which has been deliberately modified to change one or more of the product's characteristics (e.g., to provide more favorable pharmacokinetic parameters or to decrease immunogenicity).
The FDA is soliciting written comments on these questions through November 12th.
Notably, the FDA workshop did not address “legal or regulatory issues” and many observers predict that an approval process for generic biologics will ultimately require legislative action from Congress. The Senate’s Committee on the Judiciary, chaired by Sen. Orrin Hatch (the co-author of the Hatch-Waxman amendment), held a hearing on generic biologics in June (see hearing notice, with witness list, links to testimony, and a webcast of the hearing – in particular see the FDA’s Acting Commissioner Lester Crawford’s testimony on legal and regulatory authority and uncertainties).
In the meantime, the manufacturers of brand-name biologics are fighting to keep generics off the market. More tomorrow.
Follow-on biologics: The next frontier - Drug Topics, 4/2/04
Biotech Cost Control - Motley Fool (via Yahoo Finance), 8/10/04
Genentech's Generic Battle - Forbes, 5/5/04
Biotechnology Companies Try to Ward Off Generic Drugs - New York Times, 12/28/00
Biogenerics Are Coming and They're Not the Generics We Know - In Vivo, December 2002