It is largely up to the FDA.
In the U.S., what constitutes “highly similar” in the context of biosimilars is ultimately up to how the U.S. Food and Drug Admininstration applies the statutory language under the Biologics Price Competition and Innovation Act of 2009 (PDF). Demonstration that a biological product is “highly similar” to its reference product is a central tenet for biosimilarity under what is known as the 351(k) pathway, which establishes the abbreviated approval pathway for a biosimilar in the U.S. The statute reads, in part, as the initial step in demonstrating biosimilarity:
An application submitted under this subsection shall include information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies that demonstrate that the biological product is highly similar to the reference product nothwithstanding minor differences in clinically inactive components.
How the FDA interprets “highly similar” has far-reaching implications that may include:
- Products that are similar enough to use the abbreviated 351(k) pathway but different enough to avoid IP protections of the reference biologic;
- 12-year exclusivity for second generation biologic products;
- “Improved” versions of a previously approved product.
In crafting the biosimilars legislation, Congress ceded a lot of scientific discretion to the FDA. To their credit, the FDA has convened a number of opportunities for stakeholder input both leading up to and after passage of the BPCIA.
In this approach, FDA has followed in the footsteps of their European counterparts. Europe has been ahead of the U.S. in both the legal authorization and regulatory guidance for biosimilars. As part of their ongoing dialogue with stakeholders in the E.U., the European Medicines Agency convened a stakeholder meeting in July 2009 to discuss guidelines for biosimilar monoclonal antibodies because the next wave of biosimilar applications is likely to include these products. As indicated in an unofficial meeting summary, innovator and biosimilar stakeholders generally agreed that amino acid differences should not be allowed. While noting that the U.S. and E.U. biosimilar schemes are not the same, the principle invoked here for biosimilarity is that the products should be as structurally similar as possible. Many aspects of structure, such as glysosylation, may not be completely controlled by the developer and manufacturer, but amino acid sequence can be controlled. And where such control is possible, it should be applied. Thus from a scientific perspective, there is no reason to tolerate differences in amino acid sequence between the reference and biosimilar product. Identical amino acid sequences may not be sufficient to demonstrate the products are “highly similar” but they are likely necessary.
As FDA develops its biosimilar guidances, it will be interesting to see whether such principles are embraced and articulated. The result will have a large impact on biosimilar applications and the ever-evolving definition of “highly similar.”