FDA took an important step toward developing a regulatory pathway for biosimilars in the United States with the issuance of a draft guidance, Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, which describes the clinical pharmacology studies and related analytical testing needed to support a decision that a proposed therapeutic biological product is biosimilar to its reference product. In its final form, this guidance will be one in a series that FDA is developing to implement the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The BPCI Act, which was enacted as part of the Patient Protection and Affordable Care Act, established an abbreviated pathway for FDA licensure of biological products that are demonstrated to be biosimilar to or interchangeable with an FDA-licensed reference product. The draft guidance outlines four possible assessments of biosimilarity (not similar, similar, highly similar, and highly similar with fingerprint-like similarity) that would inform the next steps needed to show biosimilarity.
The draft guidance pertains to therapeutic biological products for which pharmacokinetic (PK) and pharmacodynamic (PD) data are required as part of a stepwise approach to developing the data and information necessary to support a demonstration of biosimilarity. Specifically, the draft guidance discusses some of the overarching concepts related to clinical pharmacology testing for biosimilar products, approaches for developing the appropriate clinical pharmacology database, and the utility of modeling and simulation for designing clinical trials. The guidance describes three key concepts, exposure and response assessment, evaluation of residual uncertainty, and assumptions about analytical quality and similarity, which are especially relevant to development of proposed biosimilar products. The draft guidance also examines the bioanalytical methodology and clinical pharmacology studies needed to gain safety and immunogenicity information.
In the draft guidance, FDA says it will use a risk-based approach to evaluate biosimilarity by considering the totality of the data and information submitted, including, for example, data from structural and functional characterization, nonclinical evaluations, human PK and PD studies, clinical immunogenicity testing, and studies for clinical safety and, when necessary, clinical effectiveness. These data should be collected in a stepwise manner. The need for additional studies at each step will be determined by the degree of "residual uncertainty" that remains at each step regarding the similarity of the products and whether or not the study can address these uncertainties.
In a stepwise assessment of biosimilarity, the draft guidance says that comparative structural and functional studies (e.g. bioassays, binding assays, and studies of enzyme kinetics) should be performed to evaluate whether the proposed biosimilar product and the reference product are highly similar. A meaningful assessment depends on, among other things, the capabilities of available analytical assays to assess, for example, the molecular weight of the protein, its higher order structure and post-translational modifications, heterogeneity, functional properties, impurity profiles, and degradation profiles denoting stability. The comparative analytical characterization may lead to one of four assessments within a development-phase continuum:
• Not similar: Certain differences in the results of the analytical characterization may lead to an assessment of "not similar" and further development through the 351(k) regulatory pathway (i.e., regulatory pathway for biosimilars) is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that is likely to lead to a highly similar biological product.
• Similar: Further information is needed to determine if the product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product. As an example, glycosylation plays an important role in the PK of certain protein products. Manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product help resolve that some differences in glycosylation identified in the analytical studies would be within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.
• Highly similar: The proposed biosimilar product meets the statutory standard for analytical similarity. The results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.
• Highly similar with fingerprint-like similarity: The proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. The results of these fingerprint-like analyses permit a very high level of confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.
The outcome of the comparative analytical characterization would inform the next steps in the demonstration of biosimilarity.
Written comment on the draft guidance may be submitted to FDA by August 12, 2014.