FDA today issued its long-awaited draft guidance on developing and approving biosimilars, saying it intends to use a risk-based “totality-of-the-evidence” approach. The guidance to industry is contained in three documents, for which FDA will seek public comment.

The documents represent FDA’s interpretation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological reference product and was part of President Barack Obama’s Patient Protection and Affordable Care Act.

“[The draft guidances] should help biosimilar developers understand precisely how to move forward in such a way that they can understand the agency’s expectations, how to develop these products, how they need to interact with us,” Rachel Sherman, M.D., director of the Office of Medical Policy in FDA’s Center for Drug Evaluation and Research, said during a conference call with reporters.

The first document, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product,explains the evaluation approach, intended to help companies submitting new 351(k) applications for demonstrating biosimilarity. The first document includes FDA’s recommendation for a gradual or “stepwise” approach in the development of biosimilar products, which according to FDA “can include a comparison of the proposed product and the reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness.”

Asked whether most biosimilar applicants will be expected to carry out clinical trials, Dr. Sherman predictably said decisions will be made on a product by product basis: “it’s not one size fits all.” She added, “We do expect that virtually all applications will have immunogenicity studies required. But as to the extent of human testing, that will completely depend on the complexity of the product and what is known structurally about the product, perhaps safety signals we have with the reference product, and a host of other questions,” Dr. Sherman added.

Once a product is determined to be biosimilar, it will be eligible for a separate interchangeability determination. To meet the higher standard of “interchangeability,” an applicant must provide sufficient information to demonstrate biosimilarity and also to demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient; Interchangeable products may be substituted for the reference product without the intervention of the prescribing healthcare provider (see section 351(i)(3) of the PHS Act).

“But you may as a manufacturer decide that you’re probably not going to be interchangeable. You might decide that you are going to develop those data later on. That’s a decision that the manufacturer would make,” Dr. Sherman explained. “That requires additional study—in fact, clinical study—showing that going back and forth, switching, does not change either the efficacy or the safety profile.

“It’s going to be a pretty high bar—not an impossible bar to reach, necessarily. But we have to make sure, we have to know absolutely for certain, that going back and forth between products does not in any way diminish the efficacy or impact the safety profile of the product,” she added.

Another guidance document, “Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product,” provides an overview of analytical factors for drug developers to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product. Those factors include: the expression system, the manufacturing process, an assessment of physicochemical properties, functional activities, receptor binding and immunochemical properties, impurities, the reference product and reference standards, and stability.

“It is expected that the expression construct for a proposed biosimilar product will encode the same primary amino acid sequence as its reference product. However, minor modifications, such as N or C terminal truncations that will not have an effect on safety, purity, or potency, may be justified by the applicant,” the second draft guidance stated.

The third guidance document, “Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009,” is designed to answer common questions about biosimilar product development, in a question-and-answer format. Questions are intended to address concerns arising in the early stages of product development, including requesting meetings with the FDA, addressing differences in formulation from the reference product, and requesting exclusivity.

“These draft documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers,” Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research, said in FDA’s announcement of the draft guidances.

FDA received 35 requests for pre-IND meetings and held 21 such meetings with developers of biosimilar drugs since March 2010, when President Obama signed into law his healthcare overhaul. To date, not one drug developer has filed an application for approval of a biosimilar drug. Once applications are received, FDA has committed to reviewing them within 10 months, under the proposed fifth authorization of the Prescription Drug User Fee Act (PDUFA), which is pending before Congress.

FDA plans to continue the pathway program no matter the fate of the Patient Protection and Affordable Care Act, which has been challenged in the U.S. Supreme Court, Dr. Sherman said.

The BPCI Act also includes:

  • A 12-year exclusivity period from the date of first licensure of the reference product, during which approval of a 351(k) application referencing that product may not be made effective
  • A 4-year exclusivity period from the date of first licensure of the reference product, during which a 351(k) application referencing that product may not be submitted
  • An exclusivity period for the first biological product determined to be interchangeable with the reference product for any condition of use, during which a second or subsequent biological product may not be determined interchangeable with that reference product
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