Industry stakeholders, including Pfizer and QuintilesIMS, have issued comments in response to the US Food and Drug Administration’s (FDA) draft guidance on biosimilar interchangeability, which the FDA released for public consultation in January 2017. The comment period for this document remains open and ends on May 19, 2017. The FDA has extended the comment period based on requests from several stakeholders.
The FDA’s draft guidance, Considerations in Demonstrating Interchangeability With a Reference Product, was issued to assist sponsors in demonstrating that a proposed therapeutic protein product is interchangeable with a reference product for the purposes of submitting a marketing application or supplement for biological products shown to be biosimilar or interchangeable with an FDA-licensed biological reference product under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)).
The Biologics Price Competition and Innovation Act of 2009 (BPCIA) amends the PHS Act and other statutes to create an abbreviated licensure pathway in Section 351(k) of the PHS Act for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological reference product. Although the 351(k) pathway applies generally to biological products, this draft guidance focuses on therapeutic protein products and gives an overview of scientific considerations in demonstrating interchangeability of a proposed therapeutic protein product with a reference product.
The draft guidance outlines the data and information for showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product. Key elements include: (1) the identification and analysis of the critical quality attributes; (2) the identification of analytical differences between the reference product and the proposed interchangeable product, and, in addition, an analysis of the potential clinical impact of the differences; (3) an analysis of mechanism(s) of action in each condition of use for which the reference product is licensed, which may include the following: the target receptor(s) for each relevant activity/function of the product; the binding, dose/concentration response, and pattern of molecular signaling upon engagement of target receptor(s); the relationship between product structure and target/receptor interactions; and the location and expression of target receptor(s); (4) the pharmacokinetics and biodistribution of the product in different patient populations (5) the immunogenicity risk of the product in different patient populations; (6) differences in expected toxicities in each condition of use and patient population (including whether the expected toxicities are related to the pharmacological activity of the product or to off-target activities); and (7) any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed.
In its comments on the draft guidance, Pfizer, which manufactures both innovator biologics and biosimilars, clarified to the FDA that biosimilars are not generics and that interchangeability is “a prerequisite only for substitution at the pharmacy, not for physician-mediated transition”. Pfizer requested that the FDA consider further educational initiatives for the implementation of the BPCIA and the uptake of biosimilars and interchangeable biological products.
Pfizer noted several key issues in its comments, including substitution scenarios at the prescriber-level and pharmacy-level; clarification of terminology and concepts in the guidance; analytical demonstrability; providing scientific justification for extrapolating data to support interchangeability; and labeling guidance.
On the issue of substitution, Pfizer pointed out that the draft guidance does not take into account a scenario where multiple interchangeable biological products may be available on the marketplace. In this scenario, the draft guidance does not explicitly state that non-interchangeable biosimilars should not be substituted without the intervention of the prescriber. The draft guidance currently only considers the situation where an interchangeable biological product may be substituted for the reference product without the intervention of the prescriber.
Pfizer also urges the FDA to directly address confusion in the concepts and terminology in the draft guidance between physician-mediated switching of interchangeable biological products and pharmacy-level substitution, which are often mistaken by stakeholders and not addressed in the guidance. Stakeholder education in the appropriate terminology and application of biosimilar and interchangeable biological products will be important to the implementation of the BPCIA, Pfizer said.
In terms of analytical demonstrability of interchangeability, Pfizer stated that the draft guidance should be clear that there is not an additional analytical standard for demonstration of interchangeability. The draft guidance uses the term “fingerprint-like” characterization, which lacks a clear definition, according to Pfizer. Statements in the draft guidance regarding fingerprint-like characterization reducing residual uncertainty “may lead to inaccurate perceptions of the quality, safety, and effectiveness of biological products based on their licensure pathway,” the company said.
Pfizer also suggested that the draft guidance be updated to clarify that a biosimilar sponsor should provide sufficient data or scientific justification for extrapolating data to support a determination that its product is interchangeable for each condition of use that the reference product is licensed for at the time of the sponsor’s designation request, regardless of whether the sponsor is seeking licensure of its product for fewer than all the conditions of use for which the reference product is licensed. Pfizer believes this would help mitigate practical implementation concerns in the event that an interchangeable biological product gets licensed for fewer than all the conditions of use for which the reference product is licensed.
Another key point that Pfizer emphasized is that no guidance is included for specific labeling of interchangeable biological products, and the company recommends that labeling for biosimilars and interchangeable biological products carry an “interchangeability statement” identifying whether or not interchangeability has been evaluated and explaining what interchangeability means.
QuintilesIMS noted concerns related to the control of post-approval changes for interchangeable biosimilars, pointing out that continued biosimilarity testing throughout the lifecycle of an interchangeable biosimilar product is not “feasible, or desirable”. The firm recommends applying the same approach to the evaluation of post-approval changes to the interchangeable product as for any other biologic products. QuintilesIMS’ position is that no additional considerations are required for the post-approval manufacturing changes of an interchangeable product other than meeting current requirements of comparability assessment.
QuintilesIMS also noted that the scientific justification for extrapolation of data for a determination of interchangeability should address multiple issues for the tested and extrapolated conditions. “A scientific justification should address these differences in the context of the totality of the evidence supporting a demonstration of interchangeability," the firm said.
QuintilesIMS holds the position that additional conditions of use for the reference product licensed, after the interchangeable product has been licensed, should be extrapolated to the interchangeable biosimilar with a scientific justification. “There is no reason to believe that for a condition of use approved for the reference product after an interchangeable designation was implemented, that interchangeability would not apply to the new condition of use should appropriate scientific justification be provided,” QuintilesIMS said.
Source: US eRulemaking Program