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Apr 15, 2010 (Vol. 30, No. 8)

Complex Biosimilars Demand New Rules

Case-by-Case Decision-Making Process May Be Best Approach for Safe and Efficacious Drugs

  • More than $10 billion worth of biologics are expected to be off-patent by 2010, creating enormous incentives for the development of generic alternatives to these drugs. As a result, it is anticipated that the market for biosimilars will grow significantly in the coming years.  

    For companies with extensive experience in the generic pharmaceutical marketplace, establishing bioequivalence and producing safe and efficacious products has always been key. The lessons that have been learned in this sector, especially as they relate to the Hatch-Waxman approval process, should be used to help establish the framework for biosimilars.

    Based on an article by Henry Grabowski in Health Affairs, according to the Hatch-Waxman Act, in reviewing abbreviated new drug applications (ANDAs), the FDA relies on a prior finding of safety and efficacy for a referenced pioneer drug, with a generic applicant having only to demonstrate bioequivalence between its product and the referenced drug.

    Although Hatch-Waxman provides a clear path for generic drug market entry, it generally does not apply to biologics.  Biologics are generally regulated under the Public Health Service Act, which has no equivalent provision to the ANDA that allows for the expedited approval of generic versions of approved, on-market products. Some early biologics such as human growth hormone, insulin, and conjugated estrogens were approved as drugs under the Food, Drug and Cosmetic Act. ANDAs could be approved for these products, subject to FDA resolution of the scientific and other issues involved.

    As of this writing, Congress is considering legislation that would include an approval pathway for biosimilars and seeks to address the complexity of these biologic-based drug candidates, as compared to the chemistry-based measures of bioequivalence of small molecule drugs covered under the 1984 Hatch-Waxman legislation.

    The legislative proposal would allow the FDA to examine biosimilar products on a case-by-case basis and also make determinations about interchangeability. It will be incumbent on the FDA to gather needed clinical information and set forth a new standard for these complex products.

    Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA, has said that, “Unlike small molecule drugs whose chemical composition can easily be determined to be the same as an approved product, the very nature of protein products makes comparisons of one protein to another, including to establish safety and efficacy, more scientifically challenging.”

    In a September 18, 2008, letter to Representative Frank Pallone Jr., chairman of the Subcommittee on Health, of the Committee on Energy and Commerce, Frank M. Torti, M.D., M.P.H., principal deputy commissioner and chief scientist of the FDA, echoed this concern. 

    In response to Representative Pallone’s question about the FDA’s possible mandatory requirements for clinical trials for all follow-on biologics (FOBs), Dr. Torti wrote that “FDA believes that legislation should require that sponsors of follow-on products meet the same high standards for approval as reference biological products. 

    “For instance, the extent of clinical information required depends on how much is known regarding the mechanism of action, the degree to which structural similarity could be assessed, comparative pharmacokinetic and pharmacodynamic data, and immunogenicity. Given the current level of understanding, at least some clinical information will be needed to assess the safety and efficacy of most FOBs. Legislation should require clinical trials, but FDA should be given the discretion to determine through a transparent and public process what clinical trials are needed to support the licensure of a FOB.”

    Dr. Torti further wrote: “At this time, we have not approved a recombinant protein (as distinguished from a synthetic or naturally sourced protein) through the 505(b)(2) pathway without clinical trials (other than bioavailability or bioequivalence).” 



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