US Pharm. 2009;34(6)(Generic Drug Review suppl):22-23.
Biological products can cost anywhere from $15,000 to $150,000 per year. In 2006, U.S. sales of biologics were about $40 billion.1 It is estimated that these sales could increase to about $60 billion in 2010. Currently in the U.S., major patents for some first-generation biologics have expired and will continue to expire over several years. With the consideration of upcoming patent expirations and costs of these products, there is a push for an abbreviated approval of follow-on biologics.
The term follow-on biologic is the one most used by the FDA. Since the replication of therapeutic biologic products can be very complex and cannot be performed in the same precise manner as for chemical compounds, the term generic has been deemed inappropriate. Other terms such as biosimilars (European term) and follow-on protein products have been used. Follow-on biologics, therefore, are referred to as lower cost copies of biotech drugs (biologics or biopharmaceuticals).
Proving Safety and Efficacy
The controversy with follow-on biologics lies with whether or not clinical trials should be performed and, if the trial process is bypassed, with the safety of these products. Since these are large molecular drugs, they are regulated by the Public Health Service Act (PHSA) under section 351 (rather than the Food, Drug, and Cosmetic Act [FDCA]). Under the PHSA, all biologics require full clinical studies to show that they are safe, pure, and effective. Under the FDCA, major barriers are reduced and generic manufacturers can get copies of medicines to market much easier (Hatch-Waxman Act: Public Law 98-417).2 Instead of proving safety and effectiveness, a generic manufacturer can show only that its copy is bioequivalent to a pioneer product and the FDA could, therefore, rely on the pioneer’s safety and efficacy data to approve the copy. There is no abbreviated approval pathway for products licensed under the PHSA.
Biologics, as mentioned above, are large molecular drugs that are drastically different from small molecular drugs called pharmaceuticals (e.g., atorvastatin calcium [Lipitor], fluoxetine hydrochloride [Prozac]). Biologics are manufactured in a living system often produced using recombinant DNA technology. A pharmaceutical is typically manufactured through chemical synthesis and is an ordered process. Biologics, by contrast, are more complex, and the finished product cannot be characterized in the laboratory. The living systems used to produce biologics can also be sensitive to minor changes in the manufacturing process. The FDA’s concerns are based on this information and, therefore, the agency currently scrutinizes the drug application for follow-on biologics. In most instances, clinical trials are required for those companies seeking approval for follow-on biologics.
Abbreviated Approval Process
Nevertheless, follow-on biologics (protein products) have been reviewed and approved using what could appear to be an abbreviated process (which goes against how biologics can seek approval under the PHSA). In 2006, the FDA approved somatropin (Omnitrope), a recombinant human growth hormone that is structurally identical to Pfizer’s Genotropin under the FDCA. This came about after much deliberation between the FDA and Sandoz. The approval of Omnitrope was based on new data specific to Omnitrope (but less new data than would be needed to approve a drug requiring a new drug application) and also relied on the approval of Genotropin.3 This contradicts current regulations under the PHSA. However, in its approval document, the FDA called Sandoz’s Omnitrope a “follow-on protein product,” not a biogeneric, and said its approval “does not create a new pathway for follow-on versions of all protein products.”4 Other follow-on protein products that have been approved in the same manner as Omnitrope are hyaluronidase recombinant human (Hylenex), hyaluronidase (Hydase), calcitonin salmon recombinant (Fortical Nasal Spray), hyaluronidase (Amphadase), and glucagon recombinant for injection (Glucagen).
Over the past 3 years, five bills have been introduced to the U.S. Congress seeking to define a process for the approval of follow-on biologics. Legislation regarding the process is expected to be introduced to Congress this year, and some of the key issues that must be agreed upon include 1) the extent of clinical trial requirements; 2) equivalence and interchangeability; 3) the length of exclusivity periods for both innovator and biosimilar products; and 4) immunogenicity and other safety issues.5 Innovators still maintain that it is impossible to produce a truly “generic” biologic and insist that public safety requires extensive studies to establish safety and efficacy.
The cost of biologics is another controversial area. Governments and consumers alike are in favor of follow-on biologics because of the expense associated with their use. Worldwide, biologics account for one out of eight prescriptions written. Once prescribed for rare genetic disorders, biologics have become common treatments for multiple sclerosis, diabetes, cancer, and rheumatoid arthritis. In the U.S., biologics account for more than 16% of the total drug expenditure (over $45 billion in 2008).5 A few organizations have estimated that passage of a follow-on biologic law could bring about huge health care savings. The Congressional Budget Office (charged with reviewing congressional budgets and other legislative initiatives with budgetary implications) estimates that placing follow-on biologics and their brand-name counterparts in the same billing code under Medicare Part B would have a cost savings of about $10 billion dollars over 10 years.6
Despite the bills that will be introduced to Congress this year and approval of follow-on protein products in the past, the push for an abbreviated pathway for approving these agents appears to be one that will encounter many challenges. President Obama is in favor of follow-on biologics. His current budget plan will “remove barriers to creating generic biologics,” said an administration official. “The money the federal government will save from biogenerics would help pay for a major overhaul of the nation’s health care system.”7 The biotech executives of Genzyme Corporation and Biogen Idec warn that if Congress makes it too easy for generic drug companies to produce biologics, it could possibly discourage them from investing in new life-saving therapies.7
The controversy surrounding biologics may continue for a few more years. Taking into consideration the current state of the economy, many of these bills may not get the full attention they deserve. The role of pharmacists in this controversy is to monitor trends and make recommendations to cut costs when necessary. The ongoing monitoring of use of these agents could aid in reducing health care costs.
1. Dudzinski DM, Kesselheim AS. Scientific and legal viability of follow-on protein drugs. New Engl J Med. 2008;358(8):843-849.
2. The Drug Price Competition and Patent Term Restoration Act: “Hatch-Waxman Act” [Public Law 98-417].
3. Woodcock J. Statement to the House of Representatives. Committee on Oversight and Government Reform. Follow-On Protein Product, Hearing, March 26, 2007. www.hhs.gov/asl/testify/2007/
04/t20070326a.html. Accessed March 9, 2009.
4. Food and Drug Administration. Omnitrope (somatropin [rDNA origin]) Information. May 30, 2006. www.fda.gov/cder/drug/
5. Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting drug expenditures – 2009. Am J Health Syst Pharm. 2009;66:237-257.
6. Taylor N. Ten billion dollar savings from follow-on biologics: CBO report. Inpharma-technologist.com. January 5, 2009. www.inpharmatechnologist.com/
report). Accessed March 9, 2009.
7. Wangsness L, Wallack T. Obama backing generic biologics. The Boston Globe. February 26, 2009. www.boston.com/business/
biologics). Accessed March 9, 2009.
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