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FDA has issued three draft guidance documents on how to demonstrate that a biological product is biosimilar to an FDA-approved biological product using the abbreviated pathway established by the Public Health Service Act.

First Draft Guidance: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

FDA has outlined a risk-based totality-of-the-evidence approach, similar to that developed by the European Medicines Agency (EMA) . The extent of the analyses and testing that will be required to demonstrate biosimilarity of a protein product will be determined on a product-specific basis. The FDA expects the reference product to have been licensed by them; however, in contrast to the EMA, the FDA has left open the possibility of bridging to the U.S.-licensed product.

Similar to the EMA, the FDA recommends a step-wise approach, emphasising that the basis of every biosimilar development program is extensive structural and functional characterization comparing the biosimilar and the reference products. FDA proposes that data from each step — broadly categorized as structural analysis, functional analysis, animal data and clinical studies — should be evaluated to determine the extent to which “there is residual uncertainty” regarding a demonstration of biosimilarity between the biosimilar and reference products. At each stage the data is reviewed and used to identify next steps to address that uncertainty.

The extent to which it is necessary to perform animal toxicity studies is determined after a thorough review of data from structural and functional analyses. EMA has sought to limit the extent of animal toxicity testing and the FDA leaves plenty of room to justify why extensive testing is not warranted.

The extent of the clinical program depends on the accumulated data, in particular the structural and functional characterization. Nevertheless, it is reasonably clear that human PK and PD and immunogenicity studies will be fundamental to any biosimilar development and that evidence of comparable efficacy and safety will be required for complex protein products such as monoclonal antibodies. What is noteworthy is that FDA discusses circumstances where non-inferiority rather than equivalence study designs would be appropriate, stating that these would generally allow for a smaller sample size. They also provide guidance on the opportunity for extrapolation across indications.

In the summary, the FDA guidance provides general pointers but still leaves many questions unanswered for biosimilar developers. It is hoped that these open questions will eventually be addressed in product-specific guidance. The last sentence of the document is probably the main take-home message: “FDA anticipates that early discussions with FDA about product development plans and about the appropriate scientific justifications will facilitate biosimilar development.”

Second Draft Guidance: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

This provides an overview of analytical factors that may be relevant to evaluating the similarity of a biosimilar product and a reference product.

Similar to other biosimilar guidance, the importance of extensive structural (physicochemical) and functional (biological activity) characterization is emphasized. The guidance is broad, considering factors ranging from the expression system used to the stability of the final product. As with the previous guidance, it stresses a “totality of data” approach, noting that all data should be evaluated to assess the potential impact of any differences between the biosimilar and the reference products on efficacy and safety. It highlights the complexity of these types of drug product, the need for highly sophisticated analytical testing and interpretation, and the importance of the higher order structure and fine detail that may only be discernible with appropriate, clinically relevant, in vitro biological assays.

FDA recognizes scientific advances, noting that a “fingerprint”-like analysis of therapeutic protein products will continue to develop and that such advances may allow for a more selective and targeted approach to animal and/or clinical testing.

Finally, FDA states that it is still considering what type of information would be sufficient to show that a biological product is interchangeable with the reference product.

Third Draft Guidance: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

The final section provides answers to frequent asked questions (FAQs) regarding FDA’s interpretation of the BPCI Act. The draft guidance will be posted on FDA’s website and will be updated as appropriate.