FDA provides guidance on biosimilars

WASHINGTON, D.C.—The U.S. Food and Drug Administration (FDA)has issued three draft guidance documents on biosimilar product development toassist the industry in securing approval for such products in the UnitedStates.

The long-awaited guidelines for the introduction oflower-cost versions of biotechnology drugs leave open the possibility that someproducts might not need to be tested in humans. However, the proposed rulesrequire studies showing that the generic copies are "highly similar" to theoriginals, but there are several ways—short of clinical studies—that this mightbe proven.

"We're trying to send the signal that it's notone-size-fits-all. It's product-by-product," Rachel Sherman, director of theFDA's office of medical policy, told the press.

The FDA said it would decide on the "extent and scope ofanimal and clinical studies" needed for approval once it has considered otheranalytical data. The agency said it has yet to receive an application for abiosimilar drug, but nine applications have been filed for clinical trials.Makers of branded biotech drugs have argued that full-scale human trials needto be conducted before a rival version of an existing biologic drug should beallowed on the market.

The worldwide market for copies of biotech medicines willgrow to $3.7 billion by 2015, from just $243 million in 2010, as more than 30branded biologics with sales of $51 billion lose patent exclusivity, accordingto market analysis firm Datamonitor. Biosimilar drugs are expected to sell atdiscounts of 25 to 45 percent compared to branded rivals. The CongressionalBudget Office has estimated that the United States could save $25 billion fromthe use of biosimilars over 10 years.

In one of the guidance documents, "Quality Considerations inDemonstrating Biosimilarity to a Reference Product," the FDA identifies ninestructural and functional characteristics that will help determine whether ornot further studies are needed to demonstrate biosimilarity. These are:expression system; manufacturing process; physiochemical properties; functionalactivities; 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'sLife Sciences Industry Team and member of the firm's Government & PublicPolicy Practice, worked for the FDA for 14 years, where he was a top-levelgeneric official between 1980 to 1989 and one of the principal authors of theOrange Book in 1980. Under the U.S. healthcare reform law passed in 2010, henotes, brand-name biopharmaceuticals were granted a 12-year period of marketexclusivity, after which generic versions can be sold. His view of the FDA'sfirst step at providing clarification regarding the approval process suchbiosimilars will be subjected to is generally positive, but he notes that theguidances 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 theFDA often."

He adds that a user fee is likely to be put in place thatcould be an order of magnitude more expensive than the one for conventional small-moleculedrugs.

The FDA has suggested that advances in analytical scienceand manufacturing may facilitate fingerprint-like analysis of biotherapeuticproducts, which may allow for a more selective approach to any animal or humanstudies. To develop such fingerprints, Rosen counts off a number of studiesthat 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 toclassify their biosimilars as "interchangeable" with a brand-name drug, but theagency said that would require additional clinical studies. The FDA will alsorequire that biosimilar manufacturers provide a post-marketing safetymonitoring program, which in some cases may include long-term clinical studies.

Jennifer Fox, who focuses her practice at Brinks HoferGilson & Lione on counseling small-to-midsize pharmaceutical andbiotechnology companies in patent and related matters and whose career includesmore than 15 years of experience in the pharmaceutical and biotechnologyindustries as both a research scientist and a patent attorney, sees the issueof branding versus biosimilarity as the horns of a dilemma.

"Based on the uncertainty surrounding the biosimilarapplication pathway (i.e., it is notknown just how much will be necessary with respect to animal studies and moreimportant, human clinical studies), it is difficult for a company to commit toa biosimilar pathway unless it is certain that development costs will be somuch less that the very limited exclusivity given for a biosimilar, if any, isenough to recoup the development costs, as compared to the possible 12 yearsthat the company might obtain if it files its own BLA.

"The FDA has left itself a lot of wiggle room," sheobserves, and asks exactly what "interchangeable" means. "Businesses needmotivation to take risk."

Animal and human studies may still be required, she notes,because there are no in-vitro or animaltests that can speak to the critical aspect of immunogenicity.

"From a business strategy standpoint, why not file a BLA andget 12 years of patent protection?" Fox asks.