For those under cloudy skies for two years, even a small break in the clouds would seem like a bright sunshiny day. The U.S. Food and Drug Administration's (FDA) newest draft guidance on demonstrating biosimilarity largely reiterates FDA's past guidance on the subject, but offers more insight on its current thinking. Prudent companies looking to file a biosimilar application, however, will likely continue to engage in early and frequent discussions with FDA regarding their planned clinical studies in order to position themselves for approval.
The 2009 Biologics Price Competition and Innovation Act established a pathway for approval of biosimilar products if the sponsor of a biosimilar application could show that its proposed product is "highly similar" to a reference biologic product. [Section 351(i)(2) of the Public Health Services Act (42 U.S.C. § 262(i)).] A proposed product is "highly similar" if there is "no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product." (Id.) The industry waited with bated breath for FDA to provide further guidance as to the quantum of testing needed to meet the statutory standard for biosimilarity. In February 2012, FDA issued a guidance titled Scientific Considerations in Demonstrating Biosimilarity to a Reference Product ("the 2012 Guidance"), which was appreciated by the industry but left many wanting for more substantive direction from FDA. After another two-year wait, on May 13, 2014, FDA issued a guidance titled Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product ("the 2014 Guidance"). While the 2014 Guidance focuses more on the clinical showing needed to demonstrate biosimilarity, the substantive information it provides is largely found in the 2012 Guidance. In addition, the 2014 Guidance provides scant information on demonstrating structural similarity between a proposed biosimilar product and the reference product. In a few areas, the 2014 Guidance provides further detail regarding the clinical testing needed to either demonstrate biosimilarity or to provide direction on the additional clinical testing needed.
Similarities Between the 2012 Guidance and the 2014 Guidance
Many of the substantive positions articulated by FDA in the 2012 Guidance are echoed and reiterated in the 2014 Guidance, including:
Applicants should take a stepwise approach to developing the data necessary to demonstrate biosimilarity, and functional and clinical data can guide whether additional testing is needed and the design of that additional testing.
FDA will take a "totality-of-the-evidence" view of the data submitted in support of a biosimilar application.
The use of animal and human immunogenicity, pharmacokinetic (PK) and pharmacodynamic (PD) data, including an emphasis on any clinically relevant PD measures and endpoints, as part of the totality of the evidence.
A preference for crossover human clinical studies where the product has a short half-life (e.g., shorter than five days) and low incidence of immunogenicity, and a recommendation to use a parallel study design where the products have a longer half-life.
The use of in vivo and in vitro functional assays to demonstrate bioequivalence, including bioassays, biological assays, binding assays, and assays to elucidate the mechanism of action of the product.
The potential availability of using data from a foreign reference product, provided that the sponsor gives adequate data or information to justify the relevance of such data and to establish a bridge to the U.S.-licensed reference product.
The utility of comparing quality attributes of the proposed biosimilar product and the reference product using a "fingerprint-like analysis" that evaluates a large number of such attributes with high sensitivity using orthogonal methods.
The totality-of-the-evidence approach and the significance of evaluating many attributes using sensitive measures to provide a "fingerprint-like analysis" were not even a new concept to FDA's 2012 Guidance. An August 2011 article in the New England Journal of Medicine by FDA's Dr. Kozlowski and Dr. Woodcock, stated:
Such a 'totality of the evidence' approach can also be applied to assessing biosimilars, since it seems possible to exceed a current state-of-the-art analytic characterization by evaluating more attributes and combinations of attributes at greater sensitivity with multiple complementary methods. There may be strategies that allow a 'fingerprint'-like identification of very similar patterns in two different products. … Although additional animal and clinical studies will generally be needed for protein biosimilars for the foreseeable future, the scope and extent of such studies may be reduced further if more extensive fingerprint-like characterization is used.
S. Kozlowski et al. (2011) Developing the Nation's Biosimilars Program, N. ENGL. J. MED.; 365, 385–388, 386.
Thus, the general blueprint for demonstrating biosimilarity has been in place since 2012 and appears to have germinated from seeds planted back in 2011 or earlier.
Additional Information from the 2014 Guidance
Four areas where FDA provided additional information that is likely to be of value for companies looking to file a 351(k) biosimilar application are discussed below.
First, FDA maintained that three key concepts—exposure and response assessment, evaluation of residual uncertainty and assumptions about analytical quality and similarity—are particularly relevant to its review. (2014 Guidance at 3.) With respect to exposure (well-known PK variables, such as Cmax, Cmin and AUC) and response (PD, or the direct measure of the pharmacological or toxicological effect of a drug), FDA provides some detail regarding the clinical studies that will allow the applicant to determine the extent and design of additional clinical studies that may be needed. (Id. at 3–4.) The 2014 Guidance provides additional detail on how to determine the appropriate PD markers to be measured. (Id.) The Guidance also states that the degree of uncertainty at each clinical step will dictate the need for further studies. (Id.) Finally, in discussing the quality attributes analysis, the 2014 Guidance again encourages the use of a fingerprint-like algorithm to compare the proposed and reference products. (Id. at 5.) The 2014 Guidance states that the comparative characterization data will be used to assess the proposed product as either (1) not similar, (2) similar, (3) highly similar or (4) highly similar with fingerprint-like similarity. (Id. at 5–6.) While FDA provides a description of these categories, there is less clarity on what information or data will ensure a proposed product falls in the third or fourth categories.
Second, FDA discusses three specific assays that it describes as "particularly important": ligand binding assays, concentration and activity assays and PD assays. (2014 Guidance at 7–8.) The Guidance suggests multiple assays may be necessary to provide meaningful information on the PK activity and PD effect of the proposed product. (Id.) Sponsors may want to be prepared to provide supporting data for choice of assay and for any markers chosen for evaluation. (Id.)
Third, with respect to the use of foreign reference products and the need for a bridge study, the 2014 Guidance states that the type of bridging data needed "will always include data from analytical studies (e.g., structural and functional data) that directly compares all three products (i.e., the proposed biosimilar product, the U.S.-licensed reference product, and the non-U.S.-licensed product) and is likely to also include PK and, if appropriate, PD study data for all three products." (2014 Guidance at 10.) This general criteria for bridging data is not surprising, though it is likely to be viewed as reassuring to have FDA expressly articulate a criteria.
Fourth, the 2014 Guidance states that modeling and simulation tools can be useful for designing PK and/or PD studies. (2014 Guidance at 13–14.) Several creative companies were already investigating the use of modeling or simulation tools, and many have probably already submitted plans to use such data from these tools in pre-filing meetings with FDA as part of FDA's Biological Product Development Program (BPDP)—the program that allows for pre-application meetings with FDA to optimize product development and facilitate submission of biosimilar applications.
Uses of the 2014 Guidance
The 2014 Guidance reinforces the main teachings from the 2012 Guidance, but provides some additional detail regarding the clinical data and information needed to demonstrate that a proposed product is "highly similar." The added teachings in the 2014 Guidance may be helpful in formulating a clinical study plan of action. Open and early communication with FDA is likely to be key for preparing biosimilar applications, along with enrolling and participating in FDA's BPDP to discuss and improve any clinical study plan of action.