The FDA’s recently published draft guidance titled Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and other Quality-Related Considerations (here) is a significant improvement over the withdrawn 2012 guidance (i.e., Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product) that it replaced. The increased level of detail and wider breadth of topics gives a significantly better view of the information that the Agency wishes to see in a BLA for a biosimilar product. Some significant changes, relative to the previous guidance, include:
In the section on “Functional Activities”, the new guidance limits the utility of functional activity assessment “to the extent that these activities are relevant to product performance”. This may seem odd to the reader, since one purpose of the functional activity comparison is to detect structural differences between the proposed product and the reference product that are undetected by physicochemical analyses. As such, this may be meaningful information even if the difference is not related to the mechanism of action of the product.
The section on “Reference Product and Reference Standards” has been expanded to include useful information regarding establishment and use of reference standards, including in-house reference standards and international reference standards.
There is a completely new section on “Comparative Analytical Assessment” which addresses the number of lots of reference product and proposed product that the FDA recommends be included in the analytical comparison studies (i.e., at least 10 reference product lots and 6-10 lots of the proposed product).
Perhaps the most significant addition in this new guidance is the section on “Accounting for Reference Product and Proposed Product Lots” which informs the reader of FDA’s expectation that the biosimilar BLA will include an accounting of every lot of reference product and proposed product that the applicant has acquired/manufactured and characterized (will this be an “or” rather than an “and”, in actual practice?). Naturally, the applicant will need to justify any lots of product that are excluded from the comparative analyses.
Another significant improvement in the new guidance document is the section on “Considerations for Data Analysis” which covers the need to evaluate and rank the quality attributes of the reference product with regard to risk to the mechanism of action and clinical function (e.g., PK/PD, safety, efficacy, and immunogenicity). Also provided in this section are details on performing quantitative and qualitative data analyses to compare the proposed product to the reference product.
All told, this guidance document is a very welcome addition to the set of guidelines the FDA has provided so far for the development of biosimilar products.