Following The Guidance of The FDA
The FDA draft guidance related to “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product” was issued in February 2012. In the draft, the FDA considers the totality of the evidence provided to support a demonstration of biosimilarity. It also includes structural and functional characterization to assess whether a copy is highly similar to a reference product.
The biosimilar development process reflects a sequence of narrowing steps (Figure). The process of creating a biosimilar begins with extensive structural and functional characterization followed by increasingly targeted animal and clinical studies to validate that there are no differences. This stepwise approach can also include: general scientific principles in conducting comparative structural and functional analysis; animal testing; human PK and PD studies; clinical immunogenicity assessment; and clinical safety and efficacy.
Following these steps as well as performing structural and functional characterization to assess whether a copy is highly similar to the reference product is important in minimizing the burden of preclinical and clinical testing. However, we agree with the FDA on the statement that side-by-side clinical testing is essential when done between the copy and the original because variables such as structure and choices made during production can influence the nature of the biologic. Advancements in manufacturing and production methods have increased the likelihood that a biosimilar product can be deemed highly similar, but no matter how sophisticated and advanced analytical tools have become, it still may not be possible to detect relevant and functional differences between two proteins. These complexities make exact replication of the originator’s active molecule nearly impossible.
Within the draft guidance itself, the FDA states that data derived from analytical studies, animal studies, and a clinical study or studies are required to demonstrate biosimilarity unless FDA determines it unnecessary. However, in most cases, human PK and PD profiles of a protein product often cannot be adequately predicted from functional assays and/or animal studies alone.
Two of the most important and most difficult aspects of biosimilar clinical testing are bioequivalency (purity and potency) and immunogenicity (safety).