On May 22, 2019, FDA released a nonbinding draft Guidance for Industry titled, “Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations.” The draft guidance describes considerations and recommendations on the design and evaluation of comparative analytical studies that aim to demonstrate that a proposed therapeutic protein product is biosimilar to a reference product licensed under the Public Health Service Act (PHS Act). Additionally, the draft guidance makes recommendations to sponsors on the scientific and technical information for the chemistry, manufacturing, and controls (CMC) portion of a marketing application.

The draft guidance revises final guidance from 2015 titled, “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product,” providing additional discussion on factors to consider in developing comparative analytical assessment. It also provides further guidance on the use of data analysis methods as promised in 2018 when the FDA withdrew a 2017 draft guidance titled, “Statistical Approaches to Evaluate Analytical Similarity,” stating it would issue future draft guidance to address “appropriate methods to analyze analytical data to account for potential lot-to-lot variability in the reference product,” and “focus on providing appropriate flexibility for sponsors. . . without compromising the agency’s rigorous scientific standards for evaluating marketing applications for biosimilars.”

FDA states, “[c]omparative analytical data provide the foundation for the development of a proposed product for submission in an application under section 351(k) of the PHS Act and can influence decisions about the type and amount of animal and clinical data needed to support a demonstration of biosimilarity.” FDA encourages sponsors to submit comparative analytical data early in the development process so that it can provide input on the extent and scope of animal and additional clinical studies required for biosimilar development. Also, sponsors should develop and discuss with the FDA as early as practicable a comparative analytical assessment plan using a stepwise approach that first, determines the “quality attributes that characterize the reference product in terms of its structural/physiochemical and functional properties,” then ranks those attributes according to their “risk to potentially impact activity, PK/PD, safety, efficacy, and immunogenicity,” and finally evaluate the attributes “using quantitative analysis.” The guidance provides recommendations of factors to consider for risk assessment and quantitative and qualitative data analysis. A final comparative assessment report should be available when the 351(k) BLA is submitted.

The draft guidance identifies and discusses factors for consideration in performing comparative analytical assessment, including: (1) “Expression System”; (2) “Manufacturing Process”; (3) “Physiochemical Properties”; (4) “Functional Activities”; (5) “Target Binding”; (6) “Impurities”; (7) “Reference Product and Reference Standards”; (8) “Finished Drug Product”; and (9) “Stability.”

FDA notes that a “thorough understanding of the reference product is critical” for successful biosimilar development. FDA recommends that sponsors adequately characterize the lot-to-lot variability of the reference product and the proposed biosimilar. The draft guidance provides recommendations on the number and variety of lots of reference and proposed product that should be included in the comparative analytical assessment. Further, the draft guidance discusses the use of non-U.S.-licensed comparators and states that “combining data from the reference product and non-U.S.-licensed comparator product to determine the acceptance criteria or to perform the comparative analytical assessment to the proposed product would not be acceptable to support a demonstration that the proposed product is biosimilar to the reference product.”

Comments to this draft guidance will be due by July 22, 2019.