The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “Draft Guidance for Industry on Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product”(the Draft Guidance).
BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.
PART 1: General Comments:
BIO commends FDA for the issuance of this science-based draft guidance on quality considerations for demonstrating biosimilarity to a reference product. The document addresses many relevant issues associated with the topic and we believe it will assist manufacturers that are developing biosimilar products and help ensure that patients will receive high quality biosimilar products.
Manufacturing and quality aspects are critical components of a biosimilarity assessment. Each of these aspects needs to be assessed in relation to what knowledge lies in the public domain concerning the reference product, such as the formulation excipients, manufacturing equipment, raw materials used in the manufacturing process for the active ingredient, manufacturing process, the container closure system and the cold chain distribution system. A difference from the innovator product with respect to any one of these can potentially have a significant impact upon safety or efficacy of the biosimilar product.
It is neither expected nor required that a biosimilar applicant be able to demonstrate that all quality or physico-chemical attributes of the proposed biosimilar are identical to those of the reference product. The quality attributes of the products (both the active ingredients and the finished products) must be highly similar, however, and the biosimilar manufacturer must demonstrate that any differences between the products do not result in clinically meaningful differences. The results of the analytical comparison form the basis for determining the extent and nature of non-clinical and clinical testing needed to support a biosimilarity determination.
Comparability vs. Biosimilarity:
We appreciate FDA’s comments made in the Draft Guidance regarding the difference between conducting a comparability assessment of an innovator product before and after a manufacturing change versus assessments required to establish biosimilarity. We agree that the two may share some common scientific principles regarding the approach to conducting the assessments, but there are significant differences in the knowledge of the innovator regarding the initial development and subsequent commercial manufacture of the innovator product and that available to a biosimilar manufacturer.
Quality Attributes that Shift over Time:
We also note that the Draft Guidance fails to address how quality comparisons between reference and biosimilar products should be conducted when quality attributes are unstable or may change over time (e.g., size or charge variant purity). We encourage FDA to address this issue since it would be the responsibility of the biosimilar manufacturer to assess reference material of different dating periods to determine whether the biosimilar and the reference product have a highly similar degradation profile. BIO recommends that FDA publish guidance on the appropriate nature and extent of reference product sampling over time, and address whether quality comparisons need to be normalized for differences in product age to ensure valid assessments of biosimilarity.
Differences between a proposed biosimilar’s host cell type, primary structure, formulation, or immediate package and those of the reference product may significantly affect the proposed biosimilar’s safety, effectiveness, and immunogenicity profiles. These differences increase the risk of undetected, clinically significant differences between a proposed biosimilar and the reference product. They should not be permitted if they are reasonably avoidable. Further, a biosimilar applicant should always be required to demonstrate that any such difference (that is not reasonably avoidable) is not clinically meaningful. This demonstration may often necessitate substantial additional testing. If the possibility of clinically meaningful differences cannot be reasonably excluded, the proposed product should be submitted for approval under section 351(a) on the basis of a full application.
Clinical Trial Material:
The biosimilar material used in the principal clinical trial should be the same as the proposed to-be-marketed material. At a minimum, a clinical immunogenicity study evaluating the to-be-marketed biosimilar should always be required.
“Meaningful Finger-Print-Like Analysis”:
The Agency discusses the use of a “meaningful fingerprint-like analysis algorithm” (lines 312-315) to gain additional insight into the similarity between a biosimilar product and the reference biological product. However, it is not clear what this term means. We request that the Agency provide greater clarity or explanation regarding whether these “additional product attributes” and their relationship to each other must correlate with clinical safety and efficacy, consistency in manufacture, or some other meaningful feature for establishing biosimilarity between the biosimilar product and the reference.
We note that ‘fingerprinting’ has been used in other contexts to connote a strategy to derive an exact match or ‘sameness.’ It is critical to note that development of such a ‘fingerprint’ for recombinant DNA products presupposes that an applicant recognizes the necessary attributes to evaluate, designs the appropriate methods to fully interrogate the product and identifies compensatory measures for the limitations or ‘test error’ of its analytical methodology. Please clarify what is meant by “a meaningful fingerprint-like analysis algorithm” and what would be required to develop such an algorithm. We suggest that reference be made to the Kozlowski et al 2011 New England Journal article where this approach is mentioned in greater detail.
Scientific and Technical Expectations Should Be Clearly Conveyed:
We have a fundamental concern related to the use of the word “should” in the Draft Guidance. We appreciate that the word “should” is used in guidance documents to mean that something is suggested or recommended, but not required. This allows for flexibility with respect to the necessity of certain requirements and is appropriate for making case-by-case decisions. However, the use of the word “should” where certain requirements are fundamental and expected to be performed may not convey the necessary criticality of the data. In other parts of the draft guidances, the Agency uses phrases such as “is expected to”, “will need to”, “FDA recommends”, or “are fundamental components” to convey clearer expectations for certain data and information. To give just one example, in line 321 the Agency states: “The type, nature, and extent of any differences between the proposed biosimilar product and the reference product, introduced by design or observed from comprehensive analytical characterization of multiple manufacturing lots, should be clearly described and discussed.” We think this is a fundamental requirement for all biosimilar products, and that in this case the use of the phrase “is expected” instead of “should” is more appropriate, just as it is used in line 368 where the Agency states, “It is expected that the expression construct for a proposed biosimilar product will encode the same primary amino acid sequence as its reference product.” In the chart in Part 3 of these comments, we provide other examples of the use of the word “should” for fundamental requirements that must be expected to be performed.
FDA is regarded as one of the leading regulatory agencies in the world, and other countries developing their own biosimilar guidance will consider the content and wording of FDA guidance documents for their own policies. Therefore, it is of global importance for the Agency to be clear about what are fundamental requirements, and what might be discussed on a case-by-case basis.
BIO appreciates this opportunity to comment on the “Draft Guidance for Industry on Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product.” Specific, detailed comments are included in the following charts. We would be pleased to provide further input or clarification of our comments, as needed.