Ever since the health care reform law was enacted almost two years ago, the biotechnology and pharmaceutical industries have been awaiting the FDA’s release of Guidance documents to describe the “biosimilars pathway,” i.e., the process for bringing to market alternative versions of biologic medicines a/k/a “biosimilars” or “follow-on biologics.” The health care reform law included the Biologics Price Competition and Innovation Act (BPCIA) which established the statutory framework for the biosimilars pathway but delegated the regulatory process to the FDA. The initial wait at least is now over as the FDA recently issued three draft Guidance documents titled, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, and, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, respectively.

In the Scientific Considerations Guidance, the FDA emphasized three key aspects of its approach to approving proposed biosimilars. First, the FDA stated that it will “consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity” (FDA’s emphasis). Second, the FDA “recommends that sponsors use a stepwise approach in their development of biosimilar products.” Finally, the FDA suggested that the applicant for approval of a biosimilar product meet with FDA at practically every step of the way to discuss the results of the prior step and requirements and goals for the next steps. Although the process for approval may vary on a product-by-product basis, the Scientific Considerations Guidance discusses the following steps in some detail:

• Structural analysis
• Functional analysis
• Animal studies (including toxicity, PK and PD, and immunogenicity)
• Human clinical studies (including pharmacology, immunogenicity, safety and effectiveness, and extrapolation of data across indications)

The Scientific Considerations Guidance states that post-marketing safety monitoring “is an important component in ensuring the safety and effectiveness of biological products.”

In the Quality Considerations Guidance, the FDA sets forth “recommendations to applicants on the scientific and technical information of the chemistry, manufacturing, and controls (CMC) section of a marketing application for a proposed biosimilar product….” In assessing whether a proposed biosimilar product and a reference product are “highly similar,” as required for approval, this Guidance discusses the following “factors for consideration:”

• Expression system
• Manufacturing process
• Assessment of physicochemical properties
• Functional activities
• Receptor binding and immunochemical properties
• Impurities
• Reference product and reference standards
• Finished drug product
• Stability

Finally, the Biosimilars: Q&A Guidance “provides answers to common questions from sponsors interested in developing proposed biosimilar products, biologics license application (BLA) holders, and other interested parties regarding FDA’s interpretation of the” BPCIA. It addresses such basic questions as who at FDA to contact with questions and when to ask for an initial meeting, to interpretive questions such as whether a biosimilar can be approved where it has a different formulation or delivery device than the reference product, or fewer routes of administration, fewer presentations, or fewer conditions of use than the reference product (yes to all), and several other questions as well.

The BPCIA recognized two levels of comparability between a proposed product and an existing reference product: “biosimilarity” and “interchangeability.” The determination that a follow-on biologic is “interchangeable” with a reference product means that a pharmacist can substitute one for the other without consulting the prescribing physician. The three Guidance documents do not address the process for obtaining a determination of interchangeability.

The initial reaction to the Guidance documents has been mixed. Some commentators have noted that the development process for biosimilars will be able to start “in the middle,” which is better than the beginning but not as close to the end as the starting point for generic drugs. The Guidance documents put patient safety in the forefront by acknowledging the increased complexity of biologic medicines and their method of manufacture as compared to generic drugs. The lack of guidance on interchangeability has been criticized, as has the lack of detail on clinical trials.