Recommendations for Biosimilar Development
Safety Assessment
Andrea Weir

Recommendations for Biosimilar Development

On February 9th, 2012, the FDA published recommendations for the development of biosimilars. For 60 days, these draft guidance documents will be open for comments and questions, many of which could ultimately affect the final guidance. There are three basic points to consider when developing biosimilars:

(1)    Biosimilarity can be demonstrated using an analytical, animal, or clinical study or studies–unless the FDA determines that one or more of these elements are unnecessary.

(2)    A stepwise approach should be used to develop biosimilars, with structural and functional comparisons acting as the foundation.

(3)    The FDA will use a totality of evidence approach to assess biosimilarity, including structural and functional characterization, preclinical evaluation and human studies.

Many companies have asked whether comparative data from a non-US-licensed reference product can be used to support licensure of a biosimilar in the US. The draft guidance states that a company must demonstrate similarity to a single reference product previously licensed by the FDA. However, it expands on this point by stating that companies may consider using data from animal or clinical studies which compare a proposed biosimilar to a non-US-licensed reference product to support, in part, US licensure. Companies will need to consult with the FDA and provide a scientific justification for such an approach.

The FDA has not yet provided details on how many batches of biosimilars and reference product must be tested during characterization studies. However, they stressed that batches of reference product should be identified with their expiry date as well as information on when they were used in a study–due to the potential for change with time. It was clearly stated that the requirements for biosimilarity are higher than those for comparability.

A number of companies have been relying on the European guidance documents to define their preclinical program. The new draft guidance addresses several preclinical topics, including animal toxicity, pharmacokinetics (PK) and pharmacodynamics (PD) as well as immunogenicity, and refers to ICH S6(R1), Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. Developers of biosimilars should rely on the draft US guidance when developing their preclinical programs.

Regarding toxicity study design, the FDA advises that dose, regimen, duration and test species should provide a meaningful toxicological comparison between the reference product and the biosimilar. They further advise that safety pharmacology, reproductive and developmental toxicity and carcinogenicity studies are not generally warranted when a biosimilar and reference product have been shown to be highly similar–further illustrating that the development of biosimilars is a stepwise approach. The potential role of preclinical PK/PD and immunogenicity testing is discussed as well. The circumstances under which the different studies discussed above are needed should be determined on a case-by-case basis.

For more information regarding the FDA’s recommendations for developing biosimilars, click here.