Contact:

Draft Guidance for Industry: ANDAs for

Charles Fournier
Director, Legal Advocacy & Certain Highly Purified Synthetic Peptide
Regulatory Affairs Drug Products That Refer to Listed Drugs of
(541) 257-8878
charles.fournier@t1df.org rDNA Origin (Docket ID: FDA-2017-
www.t1df.org D-5767-0002), October 4, 2017

P.O. Box 10841

Eugene, Oregon 97440 Proposed Draft Guidance
p/f: 541.257.8878
The comments below address the Draft Guidance for industry entitled
info@t1df.org
ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That
Refer to Listed Drugs of rDNA Origin FDA Docket ID: FDA-2017-
Docket ID: FDA-2017-
D-5767-0002. This Draft Guidance is stated as intended to assist
D-5767-0002 potential applicants in determining when an application for a synthetic
Agency: Food and Drug peptide drug product (synthetic peptide) that refers to a previously
Administration (FDA) approved peptide drug product of recombinant deoxyribonucleic acid
(rDNA ) origin (peptide of rDNA origin) should be submitted as an
Attachments: abbreviated new drug application (ANDA) under section 505(j) of the
n/a 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
Submission Date:
products: glucagon, liraglutide, nesiritide, teriparatide, and teduglutide.
December 3, 2017

Introduction

The Type 1 Diabetes Defense Foundation (T1DF) welcomes the opportunity to submit comments on
the Food and Drug Administrations (FDAs) Draft Guidance entitled ANDAs for Certain Highly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4, 2017 (Draft Guidance).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
FDAs 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).

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As detailed below, we do have concerns about (1) the agencys 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 Lillys 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 K12 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 Guidances footnote 12.

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Under this Draft Guidance, an intranasal analog glucagon spray,1 unless based on Eli Lillys or Novo
Nordisks analog glucagon,2 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).3 Analog glucagon
and the intranasal powder formulation4 relied upon by Locemia Solutions/Eli Lilly are now off-patent,
and phase 3 trials were successfully completed in 2015. 5 While Eli Lilly continues to delay sponsoring
an ANDA for its nasal glucagon formulation (Lillys 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 Actand 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
insulintwo 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 Nordisks GlucaGen) and
analog insulin (Novo Nordisks Novolog) under the ANDA pathway of the FD&C Act. While the

1 The same logic would apply to a transdermal glucagon patch such as Zosano Pharmas ZP-Glucagon patch
abandoned despite successful Phase 2 trials for lack of funding/interest from the only suppliers of analog
glucagon currently approved for therapeutic use in the U.S., Eli Lilly and Novo Nordisk (both companies
terminated their collaboration with Zosano at the same time its ZP-Glucagon patch demonstrated market
potential). See, e.g., http://insulinnation.com/research/glucagon-patch-performs-well-in-phase-ii-trial/

2This option does not currently exist, as neither Eli Lilly nor Novo Nordisk supplies its analog glucagon to third
parties for remarketing (therapeutic use).

3 Fast track is a process designed to facilitate development and expedite review of drugs intended to treat serious
conditions and that demonstrate the potential to address an unmet medical need. See: https://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm. Insulin-induced life-threatening severe
hypoglycemia is a serious condition with an unmet medical need; the design of current glucagon emergency
injection kits leads to a high failure rate, as has been extensively documented.

4 https://www.google.com/patents/WO1992016196A1?cl=en

5Novo Nordisk has had the capability to develop a nasal glucagon formulation since 1992 but has not done so.
The development of Locemia Solutions intranasal formulation began in 2012, immediately after Novo Nordisks
patent expired.

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misclassification of analog insulin has since been corrected, this Draft Guidance perpetuates the
misclassification of analog glucagon.6

It is T1DFs 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 technologyand related difference in impurity profiles and thus safety approval standards
and protocols.7

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 T1DFs 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.

6 Although the majority of therapeutic biological products have been licensed under section 351of the PHS Act,
some early protein products have historically been approved under section 505 of the 31 FD&C Act (See
Implementation of the Deemed to be a License Provision of the Biologics Price Competition and Innovation Act
of 2009 Guidance for Industry, Appendix, available at: https://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf). It is still lawful during the ten-year
transition period, until 2020, to sponsor a biological product under the prior FD&C pathway. This leads the FDAs
own website to conflate the legacy approval pathway for early biological products approved prior to 2010 with
statutory interpretation of the definition of biological products. For example, the FDAs Frequently Asked
Questions About Therapeutic Biological Products states that hormones such as insulin, glucagon, and human
growth hormone are regulated as drugs under the FDC Act, not biological products under the PHS Act. (https://
www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/
therapeuticbiologicapplications/ucm113522.htm).

7 S e e , e . g . , h t t p s : / / w w w . i b b r . u m d . e d u / s i t e s / d e f a u l t / fi l e s / p u b l i c _ p a g e / K o z l o w s k i % 2 0 -
%20Biomanufacturing%20Summit.pdf

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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
circumstancesthus 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 Agencys 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.

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It is thus T1DFs 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. 111148) (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 T1DFs 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 FDAs 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

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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.8

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.9 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.

8 Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and
Innovation Act of 2009, Guidance for Industry, page 15.

9 Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and
Innovation Act of 2009 Guidance for Industry, page 3.

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The exception to the definition of protein (except any chemically synthesized) and the FDAs 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 cellrelated impurities occur only in rDNA-origin drug
products produced in a living systemthus the need for a bifurcated pathway.

As shown in an FDA presentation on June 2013 (slide 8 copied above),10 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 T1DFs
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 Lillys 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

10Overview of Biological Products, FDA Basics Webinar, June 17, 2013, slide 8. Available at: https://www.fda.gov/
downloads/AboutFDA/Transparency/Basics/UCM356666.pdf

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 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 K12 school settings.

About T1DF. The Type 1 Diabetes Defense Foundation is a nonpartisan Oregon-based

nonprofit 501(c)(3) dedicated to advancing equal rights and opportunities for all people with
type 1 and other forms of insulin-dependent diabetes. We focus on the significant social impact of
living with a condition that requires patients to make constant dosing decisions with a drug that,
without careful management and constant monitoring, can kill them. T1DF strives to improve the
regulatory, legal and social ecosystem essential to development and adoption of new
technologies and therapies, with an explicit commitment to inclusive policies that will deliver for
all Americans with diabetes, insured and uninsured, equal access to standard-of-care
pharmaceuticals and equipment. T1DF accepts no funding from the pharmaceutical, pharmacy
benefit management, or insurance industries.

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