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FDA provides guidance on biosimilars
March 2012
by Lloyd Dunlap  |  Email the author


WASHINGTON, D.C.—The U.S. Food and Drug Administration (FDA) has issued three draft guidance documents on biosimilar product development to assist the industry in securing approval for such products in the United States.  
The long-awaited guidelines for the introduction of lower-cost versions of biotechnology drugs leave open the possibility that some products might not need to be tested in humans. However, the proposed rules require studies showing that the generic copies are "highly similar" to the originals, but there are several ways—short of clinical studies—that this might be proven.  
"We're trying to send the signal that it's not one- size-fits-all. It's product-by-product," Rachel Sherman, director of the FDA's office of medical policy, told the press.  
The FDA said it would decide on the "extent and scope of animal and clinical studies" needed for approval once it has considered other analytical data. The agency said it has yet to receive an application for a biosimilar drug, but nine applications have been filed for clinical trials. Makers of branded biotech drugs have argued that full-scale human trials need to be conducted before a rival version of an existing biologic drug should be allowed on the market.  
The worldwide market for copies of biotech medicines will grow to $3.7 billion by 2015, from just $243 million in 2010, as more than 30 branded biologics with sales of $51 billion lose patent exclusivity, according to market analysis firm Datamonitor. Biosimilar drugs are expected to sell at discounts of 25 to 45 percent compared to branded rivals. The Congressional Budget Office has estimated that the United States could save $25 billion from the use of biosimilars over 10 years.  
In one of the guidance documents, "Quality Considerations in Demonstrating Biosimilarity to a Reference Product," the FDA identifies nine structural and functional characteristics that will help determine whether or not further studies are needed to demonstrate biosimilarity. These are: expression system; manufacturing process; physiochemical properties; functional activities; receptor binding and immunochemical properties; impurities; reference product and reference standards; drug product; and stability.  
David Rosen, co-chair of the law firm Foley & Lardner's Life Sciences Industry Team and member of the firm's Government & Public Policy Practice, worked for the FDA for 14 years, where he was a top-level generic official between 1980 to 1989 and one of the principal authors of the Orange Book in 1980. Under the U.S. healthcare reform law passed in 2010, he notes, brand-name biopharmaceuticals were granted a 12-year period of market exclusivity, after which generic versions can be sold. His view of the FDA's first step at providing clarification regarding the approval process such biosimilars will be subjected to is generally positive, but he notes that the guidances don't provide a lot of answers.
"It's more of a framework for thinking about these issues," he says. "We now have a roadmap, but developers will need to consult with the FDA often."
He adds that a user fee is likely to be put in place that could be an order of magnitude more expensive than the one for conventional small-molecule drugs.  
The FDA has suggested that advances in analytical science and manufacturing may facilitate fingerprint-like analysis of biotherapeutic products, which may allow for a more selective approach to any animal or human studies. To develop such fingerprints, Rosen counts off a number of studies that would likely be required: structural analysis, amino acid sequencing, folding, phosphorylation, changes in protein crosslinking and pegylation.
Manufacturers will have the option of asking the FDA to classify their biosimilars as "interchangeable " with a brand-name drug, but the agency said that would require additional clinical studies. The FDA will also require that biosimilar manufacturers provide a post-marketing safety monitoring program, which in some cases may include long-term clinical studies.
Jennifer Fox, who focuses her practice at Brinks Hofer Gilson & Lione on counseling small-to-midsize pharmaceutical and biotechnology companies in patent and related matters and whose career includes more than 15 years of experience in the pharmaceutical and biotechnology industries as both a research scientist and a patent attorney, sees the issue of branding versus biosimilarity as the horns of a dilemma.
"Based on the uncertainty surrounding the biosimilar application pathway (i.e., it is not known just how much will be necessary with respect to animal studies and more important, human clinical studies), it is difficult for a company to commit to a biosimilar pathway unless it is certain that development costs will be so much less that the very limited exclusivity given for a biosimilar, if any, is enough to recoup the development costs, as compared to the possible 12 years that the company might obtain if it files its own BLA.  
"The FDA has left itself a lot of wiggle room," she observes, and asks exactly what "interchangeable" means. "Businesses need motivation to take risk."
Animal and human studies may still be required, she notes, because there are no in-vitro or animal tests that can speak to the critical aspect of immunogenicity.
"From a business strategy standpoint, why not file a BLA and get 12 years of patent protection?" Fox asks.
Code: E031225



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