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FDA Takes Big Step Forward in Biosimilar Regulatory Pathway

Wednesday Feb 15, 2012

By Patti Seymour  (pseymouratbptcdotcom)   and Howard Levine  (hlevineatbptcdotcom)  

Nearly two years after the Biologics Price Competition and Innovation (BPCI) Act was passed, FDA has finally taken the big step towards defining a regulatory pathway for biosimilars in the US. On February 9, 2012 FDA issued three draft guidance documents, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, along with a Q&A summary of these documents, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, describing the Agency’s interpretation of the Act’s requirements for biosimilar product licensure.

These guidances reflect the broad framework that FDA officials have spent months outlining and are consistent with their August 2011 New England Journal of Medicine article, stating that FDA will take a “totality of evidence” approach to biosimilar approval and require extensive characterization of the biosimilar product using state of the art analytical techniques. Even with this detailed characterization, animal and human clinical studies will still be mandated for the foreseeable future. Consistent with EMA’s approach to biosimilar approval, the detailed and extensive analytical characterization will allow a reduction in the scope and extent of animal and/or human studies required.

While the guidances cover many issues important to the overall development of biosimilars, we are encouraged by several points that are especially relevant for the CMC development of biosimilars. The current draft guidances do allow for differences in the formulation of a biosimilar product compared to its reference product. For example, FDA indicates that it may be possible for a biosimilar product formulated without human serum albumin to be considered similar to a reference product formulated with human serum albumin. We applaud this rationale and sensible position of allowing biosimilar developers to move away from potentially dangerous raw materials used in the innovator products and implement technical advances in formulation development without losing the biosimilar status of the product. We also support allowing biosimilar products to use different delivery devices or container closure systems from that used in the reference product making it possible, for example, for a biosimilar product to be approved in a pre-filled syringe or auto-injector device while the reference product may be in a conventional vial presentation.

As you may recall from our previous post on this topic, we are in favor of allowing data generated using a non-US licensed reference products in support of a biosimilar application in the US. FDA agrees with this approach and will consider the use of a non-US licensed reference product in certain studies to support biosimilarity. Since most biologic products today are sourced from a single manufacturing location, but sold globally, FDA will require the relationship between the license holder for the non-US licensed product and BLA holder for the US licensed reference product to be disclosed, including whether the non-US licensed product is manufactured in the same facility(ies) as the US-licensed reference product and whether the facility(ies) are licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA. Even if non-US licensed reference product data can be used, analytical characterization and at least one clinical pharmacokinetic (PK) study and, if appropriate, at least one pharmacodynamic (PD) study must directly compare the biosimilar product with the US licensed reference product.

To help companies with the design of acceptable biosimilar development plans, FDA is encouraging them to meet with the Agency to discuss their detailed plans and share manufacturing information and preliminary comparative analytical data so that the Agency and the Sponsor can agree on the type and amount of animal and clinical data needed to support eventual licensure of the biosimilar product. According to Theresa Mullin, director of FDA’s Office of Planning and Informatics, FDA has received 31 requests for such meetings and had held 21 of these meetings as of December 2011.

These guidances are an important and meaningful first step toward full implementation of the BPCI Act. Overall, the guidances do not contain any surprises although we are pleased to find them more open to permissible deviations from the reference product than expected. The Agency is accepting public comment on the draft guidances for the next 60 days and will, hopefully issue its final guidances shortly thereafter. Now that these general guidances for biosimilar development have been published we hope FDA will turn its attention to product specific guidances as has already been done in Europe to ensure a clear and meaningful roadmap for the development and approval of biosimilar products in the US.

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