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By Ping Ji

Ji Ping-finalBiosimilars are a category of biologic products that are licensed in the United States through a pathway created under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). Since the act passed, there has been tremendous interest from industry, scientists, and health care providers about the scientific and regulatory considerations for biosimilar development. A biological product may be demonstrated to be “biosimilar” if data shows that, among other things, the product is “highly similar” to an already licensed biological product (the reference product) and has no clinically meaningful differences in terms of safety, purity, and potency from the reference product (also referred to as an originator product). But how are these products developed to support a demonstration of biosimilarity, and how does the U.S. Food and Drug Administration (FDA) review them?

The objective of a biosimilar development program is to demonstrate biosimilarity; a biosimilar sponsor does not need to independently establish the safety and effectiveness of their product. FDA recommends (PDF) a stepwise approach in developing evidence to support a demonstration of biosimilarity. The stepwise approach ensures that at each stage of development, sponsors evaluate the extent to which there is residual uncertainty regarding a demonstration of biosimilarity between the proposed product and the reference product, and identify next steps to address that uncertainty. The demonstration of biosimilarity should consider the totality of the data and information, including structural and functional characterization, nonclinical evaluation, human PK/PD data, and clinical data, including immunogenicity data.

The extensive comparative structural and functional characterization of the proposed biosimilar product and the reference product serves as the foundation of a biosimilar development program. If any differences are identified, the impact that the differences could have on safety, purity, and potency should be adequately addressed with additional data. In some cases, animal studies can provide additional support with regard to the safety of the proposed biosimilar product and for similarity between the reference product and the proposed biosimilar product. Often times, however, human PK/PD profiles and immunogenicity of a biological product cannot be adequately predicted from functional assays and/or animal studies alone. Therefore, as a scientific matter, an adequate comparative human PK study and an evaluation of PD, if there is a relevant PD measure, between the proposed biosimilar product and the reference product should be conducted. The objective of a well-designed clinical PK and/or PD study in a biosimilar development program is to provide the data that describe the degree of similarity in drug exposure between the proposed biosimilar product and the reference product.

Clinical immunogenicity should be evaluated in an appropriate study population in at least one comparative clinical study to evaluate potential differences between the proposed biosimilar product and the reference product in the incidence and severity of human immune responses. If additional clinical data are needed, a comparative clinical study for a biosimilar development program should be designed to investigate whether there are clinically meaningful differences between the proposed biosimilar product and the reference product. FDA uses a risk-based, totality-of-the-evidence approach to evaluate all available data and information submitted in support of a determination of biosimilarity of the proposed product. Therefore, the type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis and sponsors should discuss their development plans with FDA.

Ping Ji, Ph.D., is pharmacologist in Office of Clinical Pharmacology, U.S. Food and Drug Administration (FDA). Prior to joining FDA in 2008, she was a senior research investigator in the pharmaceutical industry conducting clinical trials.