Summary of FDA Public Hearing Regarding Draft Guidances Relating to the Development of Biosimilar Products
May 17, 2012
On May 11, 2012, the U.S. Food and Drug Administration (“FDA”) held a public hearing entitled Draft Guidances Related to the Development of Biosimilar Products; Public Hearing; Request for Comments at its White Oak Campus. During the hearing, the FDA sought public comment regarding its February 2012 draft guidance relating to biosimilar products. The archived webcast of the hearing is available at http://www.fda.gov/Drugs/NewsEvents/ucm265628.htm, and a transcript of the hearing will eventually be available at this same site. The FDA indicated that additional written comments regarding the draft guidance may be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Electronic comments may be submitted to http://www.regulations.gov. Comments will be accepted until May 25, 2012.
The hearing consisted of thirty eight-minute presentations before FDA representatives from the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Office of the Chief Counsel. Patient advocacy groups, members of academia, insurance trade groups, pharmacist trade groups, pharmaceutical/biologics manufacturers, consulting companies, and pharmaceutical/biotechnology trade groups offered public comments during the hearing. Summaries of some of the major subject areas addressed by the presenters are provided below.
Presenters from Novo Nordisk and Pfizer questioned the definition of a “protein” in the draft guidance and advocated for a case-by-case analysis as to whether polymers of forty or fewer amino acids were “proteins” under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). The draft guidance define a protein as “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.” Any polymer of forty or fewer amino acids is classified as a peptide and is regulated under the Federal Food, Drug, and Cosmetic Act unless it “otherwise meets the statutory definition of a ‘biological product’ (e.g., a peptide vaccine).” The presenters acknowledged some benefit of a bright-line cutoff at forty amino acids, but criticized the cutoff as arbitrary, citing to a lack of scientific support for the distinction. The FDA representatives conceded that some amino acid polymers of forty amino acids or less were arguably closer to proteins in terms of characteristics like structural complexity, but countered that some polymers of forty-one or more amino acids were arguably more similar to peptides.
The issue of biosimilar and interchangeable naming conventions was raised by numerous presenters. Some presenters favored use of a common nonproprietary name for all related products. Other presenters advocated for unique names for reference products, related reference products (related products for which a full Biologics License Application (“BLA”) was filed), biosimilars, and interchangeables. Presenters advocating for unique naming conventions for biosimilars cited to safety, adverse incident tracking, and postmarketing pharmacovigilance concerns. Presenters advocating for common nonproprietary names for biosimilars argued that the combination of National Drug Codes, lot numbers, and other potential unique identifiers provided sufficient tracking capabilities to address safety concerns. A pharmacist industry trade group advocated that unique suffixes (appended to a common nonproprietary name) not be used to identify biosimilars due to concerns regarding database limitations and a human tendency to eliminate suffixes in abbreviations.
Numerous presenters addressed the issue of labeling requirements for biosimilar and interchangeable products. Several presenters advocated for more distinctive labeling for biosimilar and interchangeable products than is currently seen in labeling of generic small molecules pharmaceuticals. Some of the unique labeling requirements suggested were an indication of whether the product was interchangeable, a statement that biosimilar products should not be switched for the reference product, an identification of the studies conducted to support a finding of biosimilarity, and an identification of reference product approved indications for which the biosimilar had not received approval. There was also some discussion as to whether the concept of “drift” should be included in biosimilar labeling. This suggestion prompted the FDA representatives to ask whether language related to the potential for “drift” should also be included in reference product labels.
The draft guidance did not address factors the FDA would consider in assessing interchangeability; however, multiple presenters raised the issue of interchangeability during the hearing. Some presenters urged the FDA to issue guidance regarding interchangeability with an insurance trade group advocating that the cost benefits envisioned by the BPCIA would not be possible without interchangeable products. Presenters urging action on interchangeables cited to FDA experience in approving manufacturing changes for reference products as relevant experience for the FDA to draw upon. In contrast, other presenters, including patient advocacy groups, raised concerns regarding interchangeable products and advocated that product switching should not occur absent physician approval. Additionally, some presenters advocated for a single “highly similar” standard to be applied to both biosimilars and interchangeables, but the FDA representatives questioned whether a single “highly similar” standard would meet the requirements of the BPCIA. Some of these presenters also expressed concern that references to interchangeability being a “higher standard” than biosimilarity would create a public misconception that interchangeable products were “higher quality” than biosimilar products, presumably reducing patient acceptance of biosimilar products.
Some presenters, including patient advocacy groups, advocated that human clinical trials be mandated for all biosimilar applications. In contrast, other presenters advocated for flexibility and case-by-case determinations as to the extent of human clinical testing necessary to establish biosimilarity. Some of these presenters, including Momenta Pharmaceuticals, Inc., also stressed that any required biosimilar clinical testing should be analyzed as a confirmation of similarity to a reference product rather than independent proof of safety and efficacy.
Reliance on Non-US Approved Product Data/Extrapolation of Data Across Indications
There was a split in the presenters regarding the appropriateness of both the reliance on non-US approved product data and the extrapolation of clinical data across reference product approved indications. For example, Abbott advocated that reliance on non-US approved product data for a finding of biosimilarity violated the BPCIA’s requirement that each proposed biosimilar be compared to a single reference product. Abbott suggested that reliance on non-US approved product data, in addition to a US approved reference product, effectively and impermissibly created two reference products for a single biosimilar application. Regarding the extrapolation of data across indications, Teva Global Branded Products advocated that the ability to extrapolate should depend more on the similarity of indications rather than knowledge of the particular underlying mechanisms of action.
Several presenters advocated that certain types of products should be exempt from the BPCIA. First, the Immune Deficiency Foundation advocated that therapeutic immunoglobulins be exempt from the BPCIA biosimilar pathway because current testing methodologies cannot guarantee safety. Second, Novo Nordisk appeared to suggest that the biosimilar pathway should not be available for biosimilars of inadequately characterized reference products. Third, Janssen advocated that the biosimilar pathway was not appropriate for proposed products containing “avoidable differences” from the reference product, as those products would be more appropriately filed as a BLA. Janssen cited intentionally improved products as possessing avoidable differences, and inappropriate for the BPCIA biosimilar pathway.
Trade Secret Protections
Abbott Laboratories and BIO advocated that the FDA create reasonable safeguards to protect against unintentional disclosure of or unintentional reliance on a reference product sponsor’s trade secret information. Abbott proposed that FDA reviewers who were substantively involved in the review of a reference product BLA not be permitted to review biosimilar applications for that reference product as that might result in “subconscious bias” or “subconscious reliance” on reference product trade secret information.
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