Perspectives on the Current State of the Biosimilar Regulatory Pathway in the United States

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The BPCI Act requires, among other considerations, that a biosimilar product have the same strength, route of administration, and dosage form as the reference product, and utilize the same mechanism of action (MOA) for the proposed conditions of use to the extent that the MOA of the reference product is known; the proposed conditions of use must have been previously approved for the reference product. A biosimilar product is licensed under section 351(k) of the Public Health Service (PHS) Act based on less than a full complement of product‐specific and clinical data that would be needed for licensure of a biologic product under section 351(a) of the PHS Act. The abbreviated licensure pathway is not a lower approval standard for biosimilar biologic products. Rather, the abbreviated pathway allows for reliance on the FDA's previous finding of safety and effectiveness for the reference product, promoting a potentially shorter, or abbreviated, and less costly development program. A biosimilar sponsor must provide an extensive data package that includes data from analytical studies, nonclinical studies, and clinical studies (Figure1); however, the types of data that are generated for a 351(k) product (e.g., comparative analytical data) are different than for a 351(a) product. How the data are considered is also different: the goal of the biosimilar development program is not to re‐establish the safety and efficacy of the product but rather to demonstrate that the biologic product is biosimilar to the reference product.
To support a demonstration of biosimilarity (Table1), the FDA recommends a stepwise development approach that should begin with extensive comparative analytical studies and proceed to animal and clinical studies.1 At each step in development a sponsor should identify any differences between the products and what residual uncertainty remains based on the potential impact of the observed difference, and then design subsequent studies to address the remaining residual uncertainty.
The foundation of a biosimilar development program is extensive comparative structural and functional characterization of the reference and proposed biosimilar products. Therapeutic protein products are characterized by a complex higher‐order structure and extensive heterogeneity resulting from, in part, manufacturing and storage conditions. Certain therapeutic protein products can be characterized by multiple MOAs. The similarity assessment includes state‐of‐the‐art analytical technologies that assess primary and higher‐order structure and posttranslational modifications. Relevant in vitro and, where appropriate, in vivo functional assays that assess the MOA(s) of the product are also included in the analytical similarity assessment. The extensive physicochemical and functional analyses of the products generate a robust analytical similarity package to support a demonstration of “highly similar.”2 Animal studies may be useful if uncertainties remain about the safety of the proposed biosimilar product prior to initiating clinical studies.1 The nature and scope of clinical studies needed depends on the extent of residual uncertainty that remains following comparative analytical and nonclinical studies. As a scientific matter, the FDA expects an adequate clinical pharmacokinetic (PK) and pharmacodynamic (PD) (if relevant) comparison between the products and at least one clinical study that includes a comparison of immunogenicity of the proposed biosimilar and reference product. While a clinical PK study is generally considered the most sensitive clinical study to detect differences between the products, a comparative clinical study is recommended when there are residual uncertainties about whether there are clinically meaningful differences between the products based on the analytical, animal, PK and PD data, and clinical immunogenicity assessments. The FDA may determine, at its discretion, that certain data elements are not necessary for licensure.
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