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Patent Docs: FDA releases draft guidances on biosimilars
September 2014
by Kevin Noonan  |  Email the author


The U.S. Food and Drug Administration (FDA) has been busy this spring, releasing two new guidances (in May and August) relating to its evolving standards for satisfying the biosimilarity requirements of the Biologics Price Competition and Innovation Act (BPCIA). Unlike the relatively generic tone of the three previous guidances, released in February 2012, the first of these recent guidances is more specific, being directed particularly to the type and amount of clinical pharmacology data the agency will require to demonstrate biosimilarity to a reference product, but is expressly “being distributed for comment purposes only,” and thus how the FDA will administer the BPCIA remains a work in progress.
This guidance establishes the relevance of clinical pharmacological data to the question of biosimilarity, stating that “[c]linical pharmacology studies are normally a critical part of demonstrating biosimilarity by supporting a demonstration that there are no clinically meaningful differences between the proposed biosimilar and the reference product.” These data are related to the “degree of similarity in drug exposure” between the reference drug product and the putative biosimilar, and notes that such data typically include pharmacodynamics endpoints and pharmacometric analyses that can reveal “clinically meaningful differences,” and thus “can add to the totality of the evidence, reduce residual uncertainty and thus guide the need for and design of subsequent clinical testing to successfully support a demonstration of no clinically meaningful differences in the overall demonstration of biosimilarity.”
The guidance sets forth “three key concepts” as being “especially relevant” to their assessment of the similarity of biosimilar products:
• Exposure and response assessment (Section III.A)
• Evaluation of residual uncertainty (Section III.B)
• Assumptions about analytical quality and similarity (Section III.C)
With regard to exposure and response assessment, the guidance defines “exposure” to be related to pharmacokinetic parameters, including dose, drug concentrations in blood, plasma and other biological fluids, and related variables including Cmax, Cmin , CtroughSS and area under the curve, or AUC. Response, on the other hand, is defined in the guidance as pharmacodynamics, “a direct measure of the pharmacological or toxicological effect of a drug,” the assessment of which includes single or multiple biomarkers (where using “broader” biomarker panels are preferred if they “capture multiple pharmacological effects of the [biosimilar] product”).
The portion of this guidance on evaluating residual uncertainty is less expansive, merely setting forth the FDA standard of assessing the “totality of the circumstances” on the evidence and suggesting that this evidence be collected and submitted “in a stepwise manner,” including the pharmacokinetic (PK) and pharmacodynamic (PD) data “obtained in conjunction with clinical pharmacology studies.”
Assumptions regarding analytical quality and similarity are defined in the context of such a “stepwise assessment of biosimilarity,” wherein “extensive and robust comparative structural and functional studies (e.g. bioassays, binding assays and studies of enzyme kinetics) should be performed to evaluate whether the proposed biosimilar product and the reference product are highly similar.” This, in turn, depends on the state of the art regarding analytical assays, including those related to measuring molecular weight, post-translational modifications, heterogeneity, impurity and degradation profiles and functional properties of the biosimilar.
The guidance also sets forth four different assessment decisions along a “developmental phase continuum,” as follows:
• Not similar, wherein there are sufficiently severe differences in the results of the analytical characterization between the reference product and the biosimilar that further development through the 351(k) regulatory pathway is not recommended.
• Similar, wherein there is sufficient evidence of biosimilarity that it is reasonable to develop further information to determine if the product is highly similar to the reference product, including additional analytical data or other studies.
• Highly similar, wherein the analytical evidence submitted by the biosimilar applicant demonstrated that the proposed biosimilar product meets the statutory standard for analytical similarity.
• Highly similar with fingerprint-like similarity, wherein the proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multiparameter approaches that are extremely sensitive in identifying analytical differences. 
As it has in earlier guidances, the FDA urges stakeholders to consult, especially with “critical study design issues,” including crossover and parallel designs, which are of “particular relevance” (Section IV.A). The “preferred design” for PK similarity assessments, according to the guidance, is a single-dose, randomized, crossover study, particularly with products having a “short” half-life (less than five days), “rapid” PD response (“onset, maximal effect and disappearance in conjunction with drug exposure”) and multiple dosing regimes where “the PD effect is delayed or otherwise not parallel to the single-dose drug PK profile.” Parallel study designs are recommended for biologic drugs having a long half-life and that elicit immunogenic responses.
Importantly, in view of the extensive experience some biosimilar companies have in Europe, the guidance states that “a sponsor may use a non-U.S. licensed comparator product in certain studies to support a demonstration that the proposed biological product is biosimilar to the U.S.-licensed reference product” but also should provide “adequate data or information to scientifically justify the relevance of these comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product.” 
The guidance concludes with a reminder that the FDA has decided that it will assess biosimilarity between a putative biosimilar product and a reference drug product based on the “totality of the evidence” (as set forth extensively in earlier guidances).
The second guidance relates to how the agency will establish the “date of first licensure” for reference biologic products, a date important because it determines the length of the market exclusivity of the reference product under the BPCIA (12 years; Sec. 351(k)(7), codified at 42 U.S.C. 55 262(k)), as well as the time (four years) that a biosimilar applicant must wait before filing an application for biosimilar approval. The guidance notes that “[n]ot every licensure of a biological product under 351(a) is considered a ‘first licensure’ that gives rise to its own exclusivity period,” where some changes in “previously licensed” reference products, from either the same or “related” reference product sponsors are expressly excluded from being considered as a date of first licensure. Because the FDA recognizes that it is the reference drug sponsor who will have “superior information” about such changes or such relationships between companies, the guidance sets forth “the types of information that reference product sponsors should provide to facilitate FDA’s determination of the date of first licensure for their products.”
The provisionality of these guidances is reflected most clearly in an express statement set forth at the beginning of the August guidance, stating:
“This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s or the Agency’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance.”
The tentativeness of the principles set forth are more akin to hints than rules and provide little other than further evidence that the FDA will act with utmost caution in examining evidence submitted with regard to biosimilarity.

Kevin Noonan is a partner with the law firm McDonnell Boehnen Hulbert & Berghoff LLP and represents biotechnology and pharmaceutical companies on a myriad of issues. A former molecular biologist, he is also the founding author of the Patent Docs weblog,
Although this Patent Docs column appeared in our Editorial/Commentary section in the September issue of DDNews, it usually runs every other month in the Business & Government Policy section of the magazine.
Code: E091407



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