FDA Amends the Definition of “Biological Product” and Prepares for the Conclusion of a Decade-Long Transition Period

By Jennifer A. Davidson and Justine E. Lenehan

On February 21, 2020, FDA published a final rule that, effective March 23, 2020, amends the regulatory definition of “biological product” consistent with the statutory definition under the Biologics Price Competition and Innovation Act of 2009 (BPCIA), as amended by the Further Consolidated Appropriations Act, 2020 (FCAA), and added its interpretation of the statutory term “protein.”[1]  This regulatory action clarifies the statutory authority under which protein and peptide products are regulated, specifically whether such products will be regulated as drugs under section 505 of the federal Food, Drug, and Cosmetic Act (FDCA) or as biological products under section 351 of the Public Health Service Act (PHSA).

The BPCIA added “protein[s] (except any chemically synthesized polypeptide)” to the definition of biological product, with the parenthetical subsequently struck under the FCAA.[2]  In the final rule, FDA defined “protein” to mean:

any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size. When two or more amino acid chains in an amino acid polymer are associated with each other in a manner that occurs in nature, the size of the amino acid polymer for purposes of this paragraph (h)(6) will be based on the total number of amino acids in those chains, and will not be limited to the number of amino acids in a contiguous sequence.[3]

Notwithstanding certain public comments objecting to FDA’s proposal to define the term “protein” by setting a numerical hardline on the number of amino acids, FDA maintained this approach in the final rule, for the purpose of establishing a “scientifically reasonable, bright-line rule that provides regulatory clarity” for implementation of the BPCIA.[4] 

An amino acid polymer comprised of 40 or fewer amino acids (i.e., a “peptide”) does not qualify as a protein and will continue to be regulated as a drug under the FDCA, unless the peptide otherwise meets the statutory definition of a “biological product”.[5]  Further, a protein contained in a drug product as an inactive ingredient does not qualify as a protein triggering regulation under the PHSA.[6] 

In the case of products with multiple amino acid chains that are associated with each other in a manner that occurs in nature (that is to say, “in naturally occurring proteins”),[7] FDA instructs that the number of amino acids are to be added together to determine if the product qualifies as a protein.  For instance, insulin, an alpha amino acid polymer, consists of two amino acid chains with 21 amino acids and 30 amino acids, respectively.  Because the two chains are associated with each other in a manner that occurs in nature, insulin constitutes a protein (with 51 amino acids), and therefore a biological product, under FDA’s rule.[8]

To the extent amino acid chains in an amino acid polymer are not associated with each other in a manner that occurs in nature, FDA intends to assess a polymer’s status as a protein (and therefore as a biological product) on a case-by-case basis.  FDA suggests that its assessment will focus on whether the amino acid polymer “exhibit[s] characteristics generally associated with proteins.”[9]  Consequently, sponsors of proposed products are encouraged to connect with FDA early in the development process to address any issues related to product classification and pathway to market.[10]

This final rule was one of the last steps to implement the BPCIA’s 10-year transition period which ends on March 23, 2020.  Effective on that date, all marketing applications for products now defined as biological products initially approved under section 505 of the FDCA shall be deemed to be a license under section 351 of the PHSA. 

Although most biological products have been licensed under the PHSA, certain products have historically been approved as drug products under the FDCA and will therefore be subject to the transition as a result of the foregoing change in the definition of biological product.  Such products include, for instance, insulin and insulin analogs, human growth hormone, pancreatic enzymes, and reproductive hormones; FDA has made public a preliminary list (current as of December 31, 2019) of over 90 approved new drug applications (NDAs) for biological products that will be deemed to be biologics license applications (BLAs) on March 23, 2020.[11]

This transition will occur by operation of the statute; a holder of an approved NDA that is included on FDA’s preliminary list need not take any action in order for its NDA to be deemed a BLA.[12]  However, there are notable changes in the regulation of drug products versus biological products that sponsors must be aware of in the context of “deemed BLAs” (i.e., those products previously subject to regulation as a drug product under the FDCA).  For instance, such products must conform to the labeling requirements under section 351 of the PHSA.  FDA will exercise its enforcement discretion with respect to labeling of products under deemed BLAs until March 23, 2025, provided that the labeling otherwise complies with all other applicable labeling requirements.[13]  Similarly, such products must meet all Chemistry, Manufacturing, and Controls requirements under the PHSA.[14]

Following the transition, a product deemed to be licensed under section 351(a) of the PHSA may serve as a reference product for a BLA filed under section 351(k) of the PHSA seeking an FDA determination of biosimilarity or interchangeability with the transitioned product.  FDA has already taken steps to facilitate 351(k) applications for one important group of transitioned products – insulin – by issuing a draft guidance describing the data required to support a finding of biosimilarity or interchangeability.[15]  FDA predicts that the opportunity for approval of biosimilar and interchangeable products through the pathway established under section 351(k) of the PHSA will foster greater competition in the market for insulin and other transitioned products.[16] 

[1] Definition of the Term “Biological Product,” 85 Fed. Reg. 10,057 (Feb. 21, 2020) (amending 21 C.F.R. § 600.3(h)).

[2] Biologics Price Competition and Innovation Act of 2009 § 7002(b), 42 U.S.C. § 262(i) (2010), subsequently amended by Further Consolidated Appropriations Act, 2020, Pub. L. No. 116-94, § 605 (2019).

[3] 85 Fed. Reg. at 10,063.

[4] Id. at 10,059.

[5] FDA Guidance for Industry: The “Deemed To Be a License” Provision of the BPCI Act, Questions and Answers (March 2020), at 5 (“Deeming Guidance”).

[6] Id.

[7] 85 Fed. Reg. at 10,060.

[8] Id.

[9] Id.

[10] Id.

[11] See FDA, Preliminary List of Approved NDAs for Biological Products That Will Be Deemed to be BLAs on March 23, 2020 (current as of December 31, 2019), https://www.fda.gov/media/119229/download.

[12] Deeming Guidance at 5.

[13] Id. at 12-13.  See also Deeming Guidance at 13-16 (summarizing certain labeling and packaging requirements that may change as a result of the transition), 23-24 (stating its compliance policy for requirements related to labeling).

[14] Id. at 16-19.  The PHSA and FDCA address many of the same CMC requirements, so such obligations may not meaningfully change; however, this issue should be addressed for any deemed BLAs.

[15] FDA Draft Guidance for Industry: Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products (November 2019).  https://www.fda.gov/media/134778/download.

[16] Press Release, FDA, FDA Works to Ensure Smooth Regulatory Transition of Insulin and Other Biological Products (Feb. 20, 2020), https://www.fda.gov/news-events/press-announcements/fda-works-ensure-smooth-regulatory-transition-insulin-and-other-biological-products.