T1DF on FDA Draft Guidance for Industry: “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin”

For the full comment document with footnotes, see below. 

Proposed Draft Guidance

The comments below address the Draft Guidance for industry entitled “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin” FDA Docket ID: FDA-2017-D-5767-0002. This Draft Guidance is stated as intended to assist potential applicants in determining when an application for a synthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA ) origin (peptide of rDNA origin)  should be submitted as an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) rather than as a new drug application (NDA) under section 505(b) of the FD&C Act. Specifically, this guidance covers the following five peptide drug products: glucagon, liraglutide, nesiritide, teriparatide, and teduglutide. 

Introduction

The Type 1 Diabetes Defense Foundation (“T1DF”) welcomes the opportunity to submit comments on the Food and Drug Administration’s (“FDA’s”) Draft Guidance entitled “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin” issued on October 4, 2017 (“Draft Guidance”). Effective implementation of the Biologics Price Competition and Innovation Act (“BPCI Act”) is of importance to the individuals T1DF represents, and we greatly appreciate the FDA’s efforts to provide clarity on the interplay between the new drug approval pathways under the BPCI Act and the existing approval pathways under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”). 

As detailed below, we do have concerns about (1) the agency’s arbitrary reduction of the scope of “biological products,” as defined in the Public Health Service Act (“PHS Act”) and as amended by the BPCI Act, to a class solely based on the number of amino acids; (2) the resulting misclassification of glucagon as a molecule governed by the FD&C Act instead of the PHS Act; and (3) the bifurcation of approval pathways for analogous biological products, e.g. analog glucagon and analog insulin. 

To cure the above mentioned deficiencies, T1DF requests the following changes: 

  1. This Draft Guidance should be withdrawn in its entirety.
  2. The definition of a biological product under 42 U.S.C. 262(i)(1), as amended by section 351(i)(1) of the PHS Act, should be clarified to include smaller molecules (less than 40 amino acids) produced via biosynthesis.  
  3. The FDA should delete from its website and documents (see footnote 1) all references to analog glucagon and analog insulin as not being biological products. 
  4. The FDA should issue a Draft Guidance clarifying the classification of small biosynthesized molecules, including analog glucagon, as biological products analogous to protein under 42 U.S.C. 262(i)(1), as amended by section 351(i)(1) of the PHS Act.
  5. The FDA should re-issue a Draft Guidance addressing abbreviated new drug application pathways for small biosynthesized molecules under both the FD&C Act (legacy pathways until 2020) and PHS Act (biosimilar pathways). 
  6. The FDA should immediately investigate Eli Lilly’s delay to market of Locemia Solutions intranasal glucagon spray, should make the results of its investigation public, as this is a matter of public safety  and interest, and convene a new Patient Engagement Advisory Committee meeting where T1DF offers to articulate the public need for an intranasal glucagon product, particularly in the face of ongoing access barriers to injected emergency glucagon in K–12 school settings.

The Draft Guidance is presented as “assist[ing] potential applicants in determining when an application for a synthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA ) origin (peptide of rDNA origin)  should be submitted as an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).” But instead this Draft Guidance seems to assist potential applicants in understanding that the FDA reclassification of analog glucagon precludes the submission of an ANDA under section 505(j) of the FD&C Act, as is stated in the Draft Guidance’s footnote 12. 

Under this Draft Guidance, an intranasal analog glucagon spray, unless based on Eli Lilly’s or Novo Nordisk’s analog glucagon, would not qualify for an ANDA pathway under  the FD&C Act and would not, therefore, be eligible for fast-track designation and priority review under an ANDA as the FDA granted for nasal naloxone (approved within 6 months of the initial ANDA filing). Analog glucagon and the intranasal powder formulation relied upon by Locemia Solutions/Eli Lilly are now off-patent, and phase 3 trials were successfully completed in 2015. While Eli Lilly continues to delay sponsoring an ANDA for its nasal glucagon formulation (Lilly’s analog glucagon is not a “duplicate” subject to this Draft Guidance), this Draft Guidance closes the door on a submission and priority review under both section 505(j) of the FD&C Act and, in the alternative, under section 351(k) of the PSH Act—and thus prevents expedited approval and timely access to market for any competing intranasal glucagon product, a life-saving emergency product to treat severe hypoglycemia in individuals with diabetes who are using insulin, including insulin manufactured by Eli Lilly and Novo Nordisk. 

This Draft Guidance arbitrarily bifurcates the approval pathways for analog glucagon and analog insulin—two molecules produced using the same biosynthesis technology but differing in size (single chain, 29 amino acids for glucagon; dual chain, 51 amino acids for insulin).  This artificial bifurcation results from the legacy approval of biosimilars for analog glucagon (Novo Nordisk’s GlucaGen) and analog insulin (Novo Nordisk’s Novolog) under the ANDA pathway of the FD&C Act. While the misclassification of analog insulin has since been corrected, this Draft Guidance perpetuates the misclassification of analog glucagon. 

It is T1DF’s opinion that the 5 peptides subject to this Draft Guidance, glucagon, liraglutide, nesiritide, teriparatide, and teduglutide should not be subject to regulation under the FD&C Act. Instead, they should be regulated under the Public Health Service Act (PHS Act), as they meet the statutory definition of analogous biological product. 

Section 351 of the PHS Act provides authority for the FDA to establish regulatory requirements for marketing biological products. The PHS Act gives precedence to consideration of production technology over molecule size when defining “biological products.” The FDA has similarly emphasized production technology—and related difference in impurity profiles and thus safety approval standards and protocols. 

Consistent with these interpretation standards, the 5 peptides covered by this Draft Guidance should be deemed analogous products to biosynthesized protein and should thus be defined as “biological products” within the meaning of  section 351(i)(1) of the PHS Act. 

It is thus T1DF’s opinion that an application for a biosynthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA) origin (peptide of rDNA origin) produce via biosynthesis should be submitted as a 351(k) application under the PSH Act rather than as an abbreviated new drug application (ANDA) under “section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act),” as suggested by this Draft Guidance. This Draft Guidance should be withdrawn.

Comment

The proposed Draft Guidance is intended to assist potential applicants in determining when an application for a synthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA) origin (peptide of rDNA origin) should be submitted as an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) rather than as a new drug application (NDA) under section 505(b) of the FD&C Act.

The proposed Draft Guidance attempts to define biosimilar peptides as a “duplicate” and “generic synthetic peptide drug product (proposed generic synthetic peptide)” on page 1, line 23-14.  This generic product is defined as being “the ‘same as the active ingredient in a previously approved peptide of rDNA origin.’” The key issue at hand is that biosimilar molecules are not identical, and the key difference between biosimilar products is generally not the API but the impurity profile as compared to the impurity profile for the peptide of rDNA origin as stated on line 28-30 in page 1. The Draft Guidance does not provide any statutory authority for the augmented definition of “generic” and “duplicate” it relies upon. 

The Draft Guidance itself acknowledges that the the potential for immunogenicity for glucagon, liraglutide, nesiritide, teriparatide, and teduglutide, would preclude the use of an ANDA under any circumstances—thus rendering the very purpose of this Draft Guidance moot.  See footnote 12: “Based on the types of data permitted to be submitted in an ANDA , FDA does not believe that an ANDA could include sufficient evidence for approval of a proposed peptide of rDNA origin at this time (see section 505(j)(2)(A) of the FD&C Act). This reflects the Agency’s view, based on currently available technologies, that clinical data would be needed to assess potential immunogenicity risks associated with a proposed generic peptide of rDNA origin. An applicant may file a 505(b)(2) application if it is seeking approval for a drug product that is ineligible for approval under section 505(j) of the FD&C Act (e.g., because clinical studies would be required to demonstrate the safety or effectiveness of the proposed drug product). An applicant seeking approval of a proposed peptide of rDNA origin may also consider a ‘stand-alone’ NDA submitted under section 505(b)(1) of the FD&C Act.“

These issues are, however, directly addressed in guidances dealing with biosimilarity for biological products, e.g. Guidance for Industry: “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product,” April 2015.  This guidance describes the factors to consider when demonstrating that a proposed therapeutic protein product (hereinafter proposed product or proposed biosimilar product) is highly similar to a reference product licensed under section 351(a) of the PHS Act for the purpose of submitting a marketing application under section 351(k) of the PHS Act.  If only for practical purposes, these peptides should be defined as biological products. 

It is thus T1DF’s opinion that the 5 peptides subject to this Draft Guidance, glucagon, liraglutide, nesiritide, teriparatide, and teduglutide should not be subject to regulation under the FD&C Act. Instead, they should be regulated under the PHS Act, as they meet the statutory definition of a biological product. 

The FDA considers any polymer composed of 40 or fewer amino acids to be a peptide regulated under the FD&C Act, rather than a protein regulated under the PHS Act, unless a peptide otherwise meets the statutory definition of a biological product. The Draft Guidance does not establish that the 5 mentioned peptides do not meet the statutory definition of a biological product. The Draft Guidance infers that the number of amino acids is a dispositive test for classifying these peptides. 

The BPCI Act amends the PHS Act and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (Pub. L. 111–148) (Affordable Care Act). 

The key difference between the molecules governed by the PHS Act and those governed by the FD&C Act, beyond the complex structure of biological products, involves the process by which such products are manufactured. Most biological products are produced in a living system such as a microorganism, or plant or animal cells, whereas small molecule drugs are typically manufactured through chemical synthesis. The 5 peptides subject to this proposed Draft Guidance are the exception: they are small molecule drugs and yet they are produced via biosynthesis. 

Section 351(i) of the PHS Act as amended by the BPCI Act defines biosimilarity to mean “that the biological product is highly similar to the reference product notwithstanding minor  differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” (see section 351(i)(2) of the PHS Act). This definition squarely applies, without modification, to the 5 peptides subject to this Draft Guidance. 

It is thus T1DF’s opinion that an application for a biosynthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide drug product of recombinant deoxyribonucleic acid (rDNA) origin (peptide of rDNA origin) produced via biosynthesis should be submitted as a 351(k) application under the PSH Act rather than as an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) as suggested by this Draft Guidance.

The key issue relates to the FDA’s interpretation of the category of “protein (except any chemically synthesized polypeptide)” in the amended definition of “biological product” in section 351(i)(1) of the PHS Act. The BPCI Act amends the definition of “biological product” in section 351(i) of the PHS Act to include a “protein (except any chemically synthesized polypeptide)” and provides that an application for a biological product must be submitted under section 351 of the PHS Act, subject to certain exceptions. 

Chemically synthesized polypeptides, when made entirely by chemical synthesis, are not a “biological product” and are regulated as a drug under the FD&C Act. The issue at hand involves small polypeptides that are entirely made by biosynthesis. In the absence of clear scientific consensus on the criteria that distinguish proteins from peptides, including the exact size at which a chain(s) of amino acids become(s) a protein, FDA  uses a threshold of 40 amino acids as appropriate for defining the upper size boundary of a peptide. Accordingly, FDA considers any polymer composed of 40 or fewer amino acids to be a peptide and not a protein. Therefore, unless a peptide otherwise meets the statutory definition of a “biological product,” it is regulated as a drug under the FD&C Act.

Under 42 U.S.C. 262(i)(1), as amended by section 351(i)(1) of the PHS Act, a "biological product" is defined as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” 

The FDA Draft Guidance did not address whether a peptide produced via biosynthesis is an analogous product to a “protein (except any chemically synthesized polypeptide).” Whether a product is analogous could either be based on the structure of biological products or on the production process by which such products are manufactured. Most biological products are produced in a living system such as a microorganism, or plant or animal cells, whereas small molecule drugs are typically manufactured through chemical synthesis. The issue at hand is whether a small molecule drug produced in a living system, like a biological product, should be considered a biological product under 42 U.S.C. 262(i)(1), as amended by section 351(i)(1) of the PHS Act. 

FDA presentation on June 2013 (slide 8

FDA presentation on June 2013 (slide 8

The exception to the definition of protein (“except any chemically synthesized”) and the FDA’s own interpretation in prior guidance documents support the conclusion that production methodology, rather than the number of amino acids, is the controlling characteristic. Regardless of whether a peptide drug product is produced by a  recombinant or synthetic process, it may contain impurities. As acknowledged in the Draft Guidance, host cell–related impurities occur only in rDNA-origin drug products produced in a living system—thus the need for a bifurcated pathway. 

As shown in an FDA presentation on June 2013 (slide 8 copied above), the differentiation between small molecules and biological products relies on several factors. Glucagon is made with live organisms (factor No. 2). This process uses almost as many critical steps as insulin production (Factor No. 3) and requires complex filtration and purification processes (Factor No. 6). It is therefore T1DF’s interpretation that glucagon is an analogous product to biosynthesized protein and thus a “biological product” within the meaning of section 351(i)(1) of the PHS Act. 

Requested Changes

  1. This Draft Guidance should be withdrawn in its entirety.
  2. The definition of a biological product under 42 U.S.C. 262(i)(1), as amended by section 351(i)(1) of the PHS Act, should be clarified to include smaller molecules (less than 40 amino acids) produced via biosynthesis.  
  3. The FDA should delete from its website and documents (see footnote 1) all references to analog glucagon and analog insulin as not being biological products. 
  4. The FDA should issue a Draft Guidance clarifying the classification of small biosynthesized molecules, including analog glucagon, as biological products analogous to protein under 42 U.S.C. 262(i)(1), as amended by section 351(i)(1) of the PHS Act.
  5. The FDA should re-issue a Draft Guidance addressing abbreviated new drug application pathways for small biosynthesized molecules under both the FD&C Act (legacy pathways until 2020) and PHS Act (biosimilar pathways). 
  6. The FDA should immediately investigate Eli Lilly’s delay to market of Locemia Solutions intranasal glucagon spray, should make the results of its investigation public, as this is a matter of public safety  and interest, and convene a new Patient Engagement Advisory Committee meeting where T1DF offers to articulate the public need for an intranasal glucagon product, particularly in the face of ongoing access barriers to injected emergency glucagon in K–12 school settings.

About T1DF

The Type 1 Diabetes Defense Foundation is a nonpartisan Oregon-based 501(c)(3) nonprofit dedicated to advancing equal rights and opportunities for Americans with type 1 and other forms of insulin dependent diabetes. T1DF accepts no funding from the pharmaceutical, medical device, pharmacy benefit management, or insurance industries or from any organization they fund. We support regulatory frameworks in which manufacturers compete directly on innovation and price to consumers and where drug channel actors can engage in open and efficient price arbitraging, without price discrimination and asymmetries of information.

T1DF is currently a plaintiff in two cases that name Eli Lilly and Novo Nordisk as a defendants: Boss, et al. v. CVS Health Corporation, et al. (United States District Court, District of New Jersey, No. 3:17-cv-01823-BRM-LHG — insulin pricing), and Bewley, et al. v. CVS Health Corporation, et al. (United States District Court, Western District of Washington, No. 2:17-cv-00802-RAJ — glucagon pricing). 

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