FDA Issues Draft Guidance for Demonstrating Biosimilarity

Biological products—a category that includes proteins, such as antibodies, vaccines, blood products, and serums—are becoming increasingly important in the treatment of disease. In 2010, President Obama signed into law the Biologics Price Competition and Innovation Act ("BPCI Act"). This act is broadly similar to the 1984 Hatch-Waxman amendments, and it may in the long run prove to be of equal significance in reshaping the marketplace for medicines. The Hatch-Waxman amendments permit generic drugs an "abbreviated" pathway for gaining approval, through proof that the generic is "bioequivalent" to an already approved pioneer drug. The BPCI Act similarly allows the Food and Drug Administration ("FDA") to approve a biological product upon proof that it is "biosimilar" to or "interchangeable" with a licensed reference product. Both acts also contain elaborate (although very different) mechanisms for determining whether patents bar approval of the generic or biosimilar product.

One of the major questions arising from the BPCI Act is how the FDA is to determine whether a biological product is biosimilar to or interchangeable with the reference product. Given the differences between biological products and other drugs, the answer is far from obvious. Compared to most drugs (often called "small-molecule" drugs), biological products, or biologics, are usually much larger, and much more complex. Furthermore, while most small-molecule drugs are manufactured through chemical synthesis, most biological products are produced in living cells, generally using recombinant DNA technologies.

The BPCI Act contains some clues as to how biosimilarity is to be determined. A product is "biosimilar" to the reference if it is "highly similar" and there are "no clinically meaningful differences … in terms of the safety, purity, and potency of the product." Proof of biosimilarity will usually require analytical, animal, and clinical studies. A product is interchangeable with the reference product—a designation that would allow substitution between the products without a doctor's prescription—if it is biosimilar, if it can be expected to produce the same clinical result as the reference product, and, for a product that is administered multiple times to an individual, if there is no danger posed from switching between the two products.

Even before developing any rules or guidances, the FDA was encouraging manufacturers to take advantage of the biosimilarity approval pathway. Some companies have been doing so. As of February 3, 2012, the FDA had received nine Investigational New Drug ("IND") applications for potential biosimilars products. (An IND presents preclinical data that would allow one to conduct the clinical studies necessary, in these cases, to prove biosimilarity.) The FDA also reported receiving 35 requests for pre-IND biosimilars meetings, and it has held 21 such meetings.

Yesterday, on February 9, 2012, the FDA issued highly anticipated draft guidance documents for implementing the BPCI Act: "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product"; "Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product"; and "Guidance for Industry on Biosimilars: Q & As Regarding Implementation of the BPCI Act of 2009."

The drafts set out general approaches the FDA recommends biosimilars sponsors follow for demonstrating biosimilarity, and provide some suggested methodologies, but they set forth few requirements. Specifically, the FDA recommends that a stepwise approach be devised for developing the evidence needed to demonstrate biosimilarity, wherein each step in the process can address any residual uncertainty that might remain from the previous step. The FDA will then evaluate the data and information submitted using a "risk-based, totality-of-the-evidence approach." While acknowledging that a proposed biosimilar can be found interchangeable with a reference biological product, the drafts merely state that the FDA is continuing to consider the type of information that would be sufficient to enable such a determination. Although the drafts focus on methodologies for demonstrating biosimilarity of therapeutic proteins, they point out that similar methodologies may apply to other biological products.         

While very general, the drafts do provide some useful guideposts. For example, with respect to the stepwise approach, the guidance states—not surprisingly—that demonstration of biosimilarity should begin with extensive structural and functional characterization of the proposed biosimilar and the reference biological product. The guidances also suggest performing toxicity and immunogenicity studies, and comparative pharmacokinetic and pharmacodynamic studies in an appropriate population. With respect to its totality-of-the-evidence analysis, while providing no detailed discussion of its criteria, the FDA states that biosimilarity may be demonstrated even if there are formulation or minor structural differences in the proposed biosimilar relative to the reference biological product, provided sufficient data and information is submitted to demonstrate that the differences are not clinically meaningful. Along with more technical information, the draft guidances provide, for example:

  • Biosimilar products need not seek licensure for all routes of administration, all presentations, or all conditions of use that have been approved for the reference.
  • To prove biosimilarity, one can rely (at least in part) on evidence that compares the product to a non-U.S.-licensed product.
  • Evidence of biosimilarity regarding one condition of use can sometimes be extrapolated to show biosimilarity regarding other conditions of use.

The FDA's interpretation of the "biosimilar" and "interchangeable" requirements will have a tremendous impact upon how quickly biosimilar products can gain approval, the cost of seeking approval, and perhaps the safety of the resulting products.

The new guidance documents are drafts. The FDA is soliciting comments on them. Interested parties should study the drafts and make their views known to the FDA. Time is of the essence, since the comment period will be open only for 60 days (a period that could end as early as April 13).

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