On February 9, 2012, the US Food and Drug Administration (FDA) published the longawaited guidance documents on the criteria for development of biosimilars, for which an abbreviated approval pathway is envisioned under the Biologics Price Competition and Innovation Act of 2009. The Act establishes two categories of generic biologics: biosimilars and “interchangeable” biologic products. The draft guidance addresses only the criteria for approval of a biosimilar product (which is defined as one that is “highly similar” to the pioneer product notwithstanding minor differences in clinically inactive components). Here we provide a brief summary of the recent guidance from the FDA.

The guidance lays out a “stepwise” approach to demonstrating biosimilarity, starting with extensive structural and functional characterization of the proposed and referenced product. This characterization is the foundation of a biosimilar development program and informs the type and extent of additional studies that the FDA will require.

According to the guidance documents, the structural characterization should use state-of-the-art technology comparing primary structure, higher-order structure, enzymatic post-translational modifications, and other potential variants and modifications. This characterization should be performed on several lots to determine any variability in the manufacturing process. The functional characterization involves comparing the proposed and reference product with regard to biologic activity and potency, as well as the mechanism of action, to demonstrate that there are no clinically meaningful differences.

The FDA guidance also proposes that applicants conduct animal studies, including animal toxicity studies. Animal toxicity studies are useful when uncertainties remain about the safety of the proposed product after the structural and functional characterization that should be addressed before embarking on clinical studies. The animal studies envisioned by the FDA will likely include pharmacokinetic (PK) and pharmacodynamic (PD) studies, which can be incorporated into a single animal toxicity study if appropriate. Animal immunogenicity studies will generally not be required, unless there is a concern of immunogenic reactions from impurities or excipients.

According to the guidance documents, clinical studies will also likely be required. The scope will depend upon uncertainty regarding biosimilarity between the proposed and reference product after structural and functional characterization and animal studies. The FDA has emphasized that human PK and PD studies, as well as immunogenicity comparisons, will generally be required. Additional clinical studies may be required to demonstrate safety and effectiveness. The FDA envisions discussing the type and extent of clinical studies with the applicant, depending upon what residual uncertainties remain about biosimilarity based on the foundational and animal studies.