Patent Docs: FDA releases further guidances for its biosimilar drug approval pathway

While provisional and still subject to revision, the trio of new guidances are beneficial in providing a starting point for the further development of the biosimilar pathway and lowering the cost of biologic drugs in the United States

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The FDA recently released three new “Guidances for Industry” related to its implementation of the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).
The first of these, released on December 29, 2016, and entitled Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, is directed to products for which “pharmacokinetic (PK) and pharmacodynamic (PD) data are needed to support a demonstration of biosimilarity” (presumably all biosimilar products). The rubrics set forth in this guidance are intended to be relevant for establishing that there are no “clinically meaningful differences” between the biosimilar and the reference biologic drug product.
In particular, the guidance is to be used to “address residual uncertainties” after comparative analytical data is acquired, and for providing direction and the need for additional clinical studies, as well as adding to the “totality of the evidence” in favor of biosimilarity and “extrapolation of data” regarding additional indications.
The guidance specifically reasserts the FDA’s fundamental policy decision to base approval of biosimilars vel non* on the totality of the circumstances, using “a risk-based approach” that includes all relevant data (enumerated as “data from the structural and functional characterizations, nonclinical evaluations, clinical PK and PD studies, clinical immunogenicity testing and an investigation of clinical safety, and, when appropriate, clinical effectiveness”).
The protocol FDA has adopted is to require such information in a “stepwise” approach, wherein at each step the agency reviews the amount of residual uncertainty that exists on the question of biosimilarity and fashions what is required to resolve such uncertainty.
The second guidance, released the week of Jan. 9 and entitled Nonproprietary Naming of Biological Products, sets forth the naming convention the agency has established for both reference biologic drug products and their biosimilar counterparts. The basis for this naming regime, and its extension to both types of biologic drugs, reflects the agency’s rationale for providing a naming convention in the first place and is based on FDA’s dual responsibilities to protect the public and at the same time facilitate availability of biosimilar drugs according to Congress’s intentions in passing the BPCIA.
In a nutshell, FDA sets forth a regime for a nonproprietary name that is the combination of a core name (equivalent to a generic name for small molecule drugs) combined with a four-letter suffix to designate its source. The suffix (both the requirement that each biologic drug have one and the “nonsense” [devoid of any meaning] nature of it) has been the source of much of the criticism of the naming scheme since the agency published a proposed rule in the Federal Register of August 28, 2015 (80 Fed. Reg. 52224) (“Designation of Official Names and Proper Names for Certain Biological Products”).
The guidance provides its rationale for the proposed rule, stating that the naming scheme, which is required “for each originator biological product, related biological product, and biosimilar product,” will “facilitate pharmacovigilance” (for all categories of biologic drugs), by permitting a specific biologic drug product to be tracked from its source, particularly in instances where other means of doing so are not readily available.
Also, these names would permit accurate source identification by patients, healthcare providers and payers (one of the features that biosimilar advocates fear might lead to discrimination). For the agency, using source suffixes also provides a means to “minimize inadvertent substitution” (especially when such biosimilar products, like all current biosimilar products have not been determined to be interchangeable; FDA will develop a naming convention based on the same principles for interchangeable biosimilar products but “is continuing to consider the appropriate format of the suffix for these products”). The benefits envisioned by FDA should be to “(1) encourage routine use of designated suffixes in ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices and (2) avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway” according to the guidance.
The latest guidance, released Jan. 17 and entitled Considerations in Demonstrating Interchangeability with a Reference Product, is long-awaited and addresses an important aspect of the biosimilar drug regime. Interchangeability, which is the standard for conventional, small-molecule generic drugs, is challenging for biologic drugs because of their size and complexity, and because the biosimilarity standard encompasses molecules that are not atom-for-atom identical to the reference biologic drug product. Accordingly, the ease with which conventional generic drugs are substituted for brand name versions is not appropriate for biosimilar drugs, and the statute sets out standards for FDA to award interchangeability status (Section 351(k)(4) of the PHS Act).
Interchangeability is important for a variety of reasons, particularly with regard to biosimilar drug acceptance and the ability for the interchangeable biosimilar to be substituted for a reference biologic drug product without intervention or approval of a health care provider. Accordingly, interchangeable biosimilar drugs are rewarded with additional layers of exclusivity (indeed, the only exclusivity for biosimilar drugs contained in the statute, as set forth in the PHSA under Section 351(k)(6)).
Perhaps reflecting this higher level of comparative stringency, unlike the guidances concerning the grounds for establishing biosimilarity, which permit comparative data with a non-U.S. licensed reference biologic drug products to be submitted, the guidance states that switching studies must be performed using a U.S. licensed reference biologic drug product. This is because in these studies the reference biologic drug product is not used just as a control but is also part of the study, administered in both the switching arm and the non-switching arm. This limitation appears to be based on concerns regarding unpredictable differences in immunogenicity or PK profiles, as well as the existence of several ex-U.S. versions of biosimilar drugs having slight but perhaps clinically relevant differences when used in a switching study that could negatively impact the reliability of study results.
As with earlier guidances these most recent efforts are provisional and subject to revision (indeed, the agency has taken the position that it is willing to consider each individual biosimilar applicant’s application on its own merits and is willing to adapt its interpretation of the statute as needed for a particular reference biologic drug product). These guidances are beneficial, however, as they provide a starting point for the further development of the biosimilar pathway in the U.S. intended to bring lower cost biologic drugs to patients.
* vel non—a term used by the courts in reference to the existence or nonexistence of an issue for determination
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,

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