On December 14, 2017, the White House Office of Management and Budget (OMB), through the Office of Information and Regulatory Affairs (OIRA), released the Fall Update to the 2017 Unified Agenda of Federal Regulatory and Deregulatory Actions (Unified Agenda). The Unified Agenda is updated semiannually and provides the public with information about the regulatory actions that federal agencies plan to take in the upcoming year.
Among other FDA regulatory initiatives announced in the Unified Agenda for 2018, the FDA announced its plan to engage in a notice and comment rulemaking to amend its long-standing regulatory definition of “biological product” to conform to the statutory definition adopted in the Biologics Price Competition and Innovation Act of 2009 (BPCIA).1 This rulemaking initiative was slated to commence in February 2018. While the FDA had noted in other fora that it intended to revise this regulation at some point, it previously had declined to commit to any particular timeline for the rulemaking.2
Biological products are an increasingly important category of drugs that include a diverse range of medical products, such as blockbuster therapeutic antibodies (e.g., adalimumab, bevacizumab) and innovative cell-based gene therapies (e.g., chimeric antigen receptor T cell (CAR-T) therapy). These products are typically produced in biological systems using biotechnology methods (e.g., recombinant DNA technology) or isolated from natural sources (e.g., humans and animals). In contrast to conventional small-molecule drugs approved under the Federal Food, Drug, and Cosmetic Act (FDCA), the FDA licenses biological products under the Public Health Service Act (PHSA). Thus, the statutory definition of “biological product” has important regulatory and commercial consequences because it determines which pathway governs the approval/licensure of an innovator product and any follow-on competitor products that seek to rely on that product’s approval.
In 2010, the BPCIA amended the PHSA to create an abbreviated pathway for FDA licensure of a drug that is “biosimilar” to or “interchangeable” with a previously licensed biological product (reference product).3 The BPCIA also created a mechanism for resolving patent disputes between reference product sponsors and the manufacturers of biosimilars.4 Thus, the BPCIA’s purpose was at least conceptually similar to that of the Hatch-Waxman Act of 1984, which amended the FDCA to establish an abbreviated approval pathway for generic versions of FDA-approved small-molecule drugs.
Importantly, the BPCIA amended the definition of “biological product” in section 351(i) of the PHSA to include a “protein (except any chemically synthesized polypeptide).” Under the amended definition, a “protein” is licensed as a “biological product” under the PHSA and thus subject to the biosimilar pathway and the 12-year data exclusivity period created under the BPCIA.5 Notably, the BPCIA did not define the terms “protein” or “chemically synthesized polypeptide.” In the absence of a statutory definition, the FDA was accorded discretion to interpret these terms as part of its implementation of the BPCIA.
FDA’s Current Interpretation
To implement the amended definition of “biological product” in the BPCIA, the FDA interpreted the phrase “protein (except any chemically synthesized polypeptide)” in its Biosimilars Q&A Guidance.6 While the FDA’s guidance documents describe the agency’s current thinking on a topic, these agency documents are not binding.
In the Biosimilars Q&A Guidance, the FDA defines the term “protein” to mean “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.”7 The FDA considers an amino acid polymer composed of 40 or fewer amino acids to be a “peptide.”8 For purposes of these definitions, a molecule’s size is determined by its total number of amino acids and is not limited to the number of amino acids in a contiguous sequence.9 Data collected on therapeutic peptides entering clinical development since 2000 suggests that approximately 95 percent of therapeutic peptides are between two and 40 amino acids in length.10
The FDA defines the term “chemically synthesized polypeptide” to mean an alpha amino acid polymer that (1) is made entirely by chemical synthesis (“chemically synthesized”), and (2) is less than 100 amino acids in size (a “polypeptide”).11 In stating that a polypeptide must be made entirely by chemical synthesis—i.e., using a synthetic strategy that relies solely on methods such as solid phase peptide synthesis, solution phase peptide synthesis, or a hybrid approach—the FDA seems to be suggesting that polypeptides made using semi-synthetic strategies—i.e., those employing a combination of biosynthetic and chemical steps—will be licensed as biological products under the PHSA.
In support of its interpretation of the statute, the FDA lists several factors in the Biosimilars Q&A Guidance that informed its analysis. First, the FDA contends that the scientific literature generally excludes “peptides” from the category of “proteins.”12 The FDA acknowledges, however, that there is a lack of scientific consensus on the criteria for distinguishing proteins from peptides, including the size at which an amino acid polymer becomes a protein.13 Moreover, the FDA explains that its decision to distinguish proteins from peptides based solely on size was to “enhance regulatory clarity” and “minimize administrative complexity.”14
Last, a noteworthy aspect of the FDA’s current definitional scheme is that the regulatory status of amino acid polymers with 41 to 99 amino acids is dependent on how these molecules are manufactured. For example, a recombinant version of an amino acid polymer containing 53 amino acids would be licensed as a “biological product” under the PHSA; however, an entirely synthetic version of the same molecule—to the extent it was feasible to produce—would be approved as a “drug” under the FDCA. By comparison, an amino acid polymer with less than 40 amino acids (a “drug”) or greater than 99 amino acids (a “biological product”) would have a fixed regulatory status, regardless of how the molecule is manufactured.
Comments from Regulated Industry: Three Competing Approaches to the Definition
Numerous stakeholders from regulated industry have submitted comments to the FDA on the amended definition of “biological product” in the BPCIA. Broadly speaking, these comments have requested that the FDA adopt either (1) a bright-line approach based on a product’s primary method of manufacture, not its size; or (2) a flexible, case-by-case approach that takes into consideration the factors that influence a product’s complexity.15 In general, both approaches seek to expand the types of therapeutic amino acid polymers that are licensed as biological products under the PHSA. And each has a distinct potential for market impact.
Under the “bright-line” approach, the FDA would define both the terms “protein” and “chemically synthesized polypeptide” by reference to the product’s primary method of manufacture.16 Thus, any alpha amino acid polymer—regardless of its size—would be licensed as a biological product under the PHSA if manufactured by a process that utilizes a biological system.17 Similarly, any alpha amino acid polymer made entirely by chemical synthesis would be approved as a drug under the FDCA.
While potentially administratively convenient, and arguably a more appropriate interpretation of the statutory language, this approach has been criticized in other comments submitted to the FDA. These comments raise concerns about whether such a policy could create an incentive for a manufacturer to select a suboptimal manufacturing process for the sole purpose of having its product regulated under a particular statute.18 For example, a manufacturer seeking the additional exclusivity period provided under the PHSA might choose to produce a molecule by recombinant methods, despite the fact that it could be made more quickly and less expensively by chemical synthesis.19
Under the flexible case-by-case approach, the FDA would take into consideration not just the manufacturing method, but also other factors influencing the complexity of the product.20 A key factor would be the extent to which the molecule’s function depended on its higher order (i.e., secondary, tertiary, quaternary) structure. Accordingly, under this approach, a “chemically synthesized polypeptide” would be approved as a drug under the FDCA only where the molecule’s function does not depend on its higher order structure.21
Last, the FDA could adopt a third approach that was suggested in a citizen petition submitted by a manufacturer of an FDA-approved therapeutic peptide. In its petition, the manufacturer noted that the amended definition of “biological product” encompasses both a “protein” as well as any “analogous product [to a protein].”22 Thus, the petitioner contended that, even if the FDA were to retain its current interpretation, the plain language of the statute indicates that the definition of “biological product” includes products analogous to proteins, such as recombinantly derived “peptides.”23
The comments submitted by regulated industry signal the possibility that the FDA’s current interpretation of the phrase “protein (except any chemically synthesized polypeptide)” could be challenged at some point as arbitrary and capricious in violation of section 706 of the Administrative Procedure Act. Having said that, the FDA’s decision to proceed with a rulemaking to amend its regulatory definition of “biological product” offers an opportunity to address many of these concerns.
In sum, stakeholders are encouraged to monitor and actively participate in the FDA’s forthcoming rulemaking process. Robust engagement in the process will help to ensure that the FDA fully understands and considers the potential ramifications of whichever approach the agency ultimately decides to adopt at the conclusion of the rulemaking process. u
1. View Rule: Definition of the Term “Biological Product,” OIRA, https://www.reginfo.gov/public/do/eAgendaViewRule?pubId=201710&RIN=0910-AH57 (last visited Mar. 14, 2018).
2. FDA Petition Denial Letter, Doc. No. FDA-2016-P-2515-0027, at 2 (Jan. 17, 2017).
3. See generally Daniel L. Flint & Deborah M. Shelton, FDA Issues Much-Anticipated Draft Guidance on Interchangeable Biologics: Are the First Approvals on the Horizon?, 13 ABA Health eSource, no. 7, Mar. 2017.
4. See 42 U.S.C. § 262(l).
5. In contrast, a “chemically synthesized polypeptide” is regulated as a “drug” under the FDCA and thus subject to the section 505(b)(2) abbreviated approval pathways and the five-year (new chemical entity) and three-year (new clinical investigation) exclusivity periods awarded under the FDCA.
6. FDA, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009: Guidance for Industry (2015) [hereinafter Biosimilars Q&A Guidance].
7. Id. at 14.
8. Id. at 15.
9. Id. at 14.
10. Jolene L. Lau & Michael K. Dunn, Therapeutic Peptides: Historical Perspectives, Current Development Trends, and Future Directions, Bioorganic & Medicinal Chemistry (2017).
11. Biosimilars Q&A Guidance, supra note 6, at 14.
13. Id. at 15.
14. Id. at 14–15.
15. While less numerous, the FDA also has received comments that generally support its current interpretation. See, e.g., Amgen Inc., Comment Letter on Draft Guidance for Industry on Biosimilars, Doc. No. FDA-2011-D-0611-0033, at 41 (Apr. 16, 2012) (“At this early stage of BPCIA implementation, Amgen concurs with FDA’s proposed focus on polymer size to define ‘protein.’ That said, Amgen also recognizes the potential need for flexibility as FDA continues to evaluate whether other considerations may be appropriate.”).
16. See Novo Nordisk Inc., Comment Letter on Draft Guidance for Industry on Biosimilars, Doc. No. FDA-2011-D-0611-0004, at 5 (Apr. 5, 2012).
17. See Eli Lilly & Co., Comment Letter on Draft Guidance for Industry on Biosimilars, Doc. No. FDA-2011-D-0611-0052, at 2 (Oct. 9, 2014).
18. See Janssen Research & Development, LLC, Comment Letter on Draft Guidance for Industry on Biosimilars, Doc. No. FDA-2011-D-0611-0030, at 14 (Apr. 16, 2012).
19. See Pfizer Inc., Comment Letter on Draft Guidance for Industry on Biosimilars, Doc. No. FDA-2011-D-0618-0054, at 3 (May 25, 2012) (acknowledging the concerns of other stakeholders).
20. See, e.g., Pharmaceutical Research & Manufacturers of America (PhRMA), Comment Letter on Draft Guidance for Industry on Biosimilars, Doc. No. FDA-2011-D-0611-0039, at 5 (Apr. 16, 2012).
21. Id. at 6.
22. See Eli Lilly & Co., Citizen Petition, Doc. No. FDA-2016-P-2515-0001, at 32 (Aug. 18, 2016).
23. Id. at 35–36.