Order Code RL34045
FDA Regulation of Follow-On Biologics
Updated April 7, 2008
Judith A. Johnson
Specialist in Life Sciences
Domestic Social Policy Division

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FDA Regulation of Follow-On Biologics
Summary
Legislation introduced in the 110th Congress (H.R. 1038/S. 623, H.R. 1956, H.R.
5629, S. 1505, and S. 1695) would expand regulatory activities of the Food and Drug
Administration (FDA) by opening a pathway for the approval of follow-on biologics.
A biologic is a preparation, such as a drug or a vaccine, that is made from living
organisms. In contrast, most commonly used drugs are synthesized via a chemical
process. A follow-on biologic is similar to the brand-name, or innovator, product
made by the pharmaceutical or biotechnology industry.
The new regulatory pathway would be analogous to the FDA’s authority for
approving generic chemical drugs under the Drug Price Competition and Patent Term
Restoration Act of 1984 (P.L. 84-417), often referred to as the Hatch-Waxman Act.
The generic drug industry achieves cost savings by avoiding the expense of clinical
trials, as well as the initial drug research and development costs that were incurred
by the brand-name manufacturer. The cost of speciality drug products, such as
biologics, is often prohibitively high. For example, the rheumatoid arthritis and
psoriasis treatment Embrel costs $16,000 per year. It is thought that a pathway
enabling the FDA approval of follow-on biologics will allow for market competition
and reduction in prices, though perhaps not to the same extent as occurred with
generic chemical drugs under Hatch-Waxman.
In contrast to chemical drugs, which are relatively small molecules and for
which the equivalence of chemical composition between the generic drug and
innovator drug is relatively easy to determine, a biologic, such as a protein, is much
larger in size and much more complex in structure. Therefore, comparing a follow-
on protein with the brand-name product is more scientifically challenging than
comparing chemical drugs. In many cases, current technology will not allow
complete characterization of biological products. Additional clinical trials may be
necessary before the FDA would approve a follow-on biologic.
This report provides a brief introduction to the relevant law, the regulatory
framework at the FDA, the scientific challenges for the FDA in considering the
approval of follow-on biologics, and a description of the proposed legislation. It will
be updated as legislative events warrant.

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Contents
Relevant Laws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Regulatory Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Scientific Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

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FDA Regulation of Follow-On Biologics
The 110th Congress is considering legislation (H.R. 1038/S. 623, H.R. 1956,
H.R. 5629, S. 1505, and S. 1695) that would expand regulatory activities of the Food
and Drug Administration (FDA) by opening a pathway for the approval of follow-on
biologics.1 This pathway would be somewhat analogous to that which allowed for
the approval of generic
chemical drugs via passage of
the Drug Price Competition and
A biologic is a preparation, such as a drug or a
Patent Term Restoration Act of
vaccine, that is made from living organisms. In
1984 (P.L. 84-417), often
contrast, a chemical drug is synthesized via a
r e f e r r e d t o a s t h e
chemical process. A follow-on biologic is
Hatch-Waxman Act.2 By
similar but not identical to the brand-name, or
offering an alternative to brand-
innovator, product made by the pharmaceutical
name drug products, the Hatch-
or biotechnology industry.
Waxman Act is credited with
lowering the cost of drugs to
consumers, as well as allowing for the expansion of the generic drug industry in the
United States.
At the time that Hatch-Waxman was being debated by Congress and
implemented by the FDA, the biotechnology industry was just beginning to develop
its first human therapeutic agents. The first FDA approval of a biotechnology drug
for human use, human insulin, occurred in 1982, followed by human growth hormone
in 1985, alpha interferon in 1986, tissue plasminogen activator in 1987, and
erythropoietin in 1989. Biotechnology products are expected to become a larger and
larger share of the drugs sold by the pharmaceutical industry to U.S. consumers.
However, with no equivalent to the generic alternatives to chemical drugs, the cost
of therapeutic biologics is often prohibitively high for individual patients. For
example, the rheumatoid arthritis and psoriasis treatment Embrel costs $16,000 per
year, and biological drugs for multiple sclerosis range in price from $16,000 to
$25,000 per year.3 Spending by Medicare in 2006 on just one such drug, Epogen,
1 Sometimes referred to as biogenerics, biosimilars, or generic biologics. The FDA and
many others consider the use of the word generic to be inaccurate because the term has been
used, in the context of chemical drugs, to mean identical. The FDA often uses the term
follow-on protein product, because many biologics are proteins.
2 For further information, see CRS Report RL32377, The Hatch-Waxman Act: Legislative
Changes Affecting Pharmaceutical Patents, by Wendy Schacht and John R. Thomas, and
CRS Report RL30756, Patent Law and Its Application to the Pharmaceutical Industry: An
Examination of the Drug Price Competition and Patent Term Restoration Act of 1984 (“The
Hatch-Waxman Act”), by Wendy Schacht and John R. Thomas.
3 Bruce L. Downey, Chairman and CEO Barr Pharmaceuticals, Inc., testimony before the
(continued...)

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was $2 billion, more than the entire FY2006 budget for FDA, which was $1.863
billion ($1.494 billion in direct appropriations and $369 million in user fees).4
In 2006, U.S. spending on such speciality drugs was $54 billion, or about 20%
of total spending on pharmaceuticals.5 Speciality drugs are expected to comprise
26% of total pharmaceuticals purchased by 2010, almost doubling to $99 billion per
year, a rate of increase that is second highest among all the components of health care
spending, exceeded only by diagnostic imaging.6 From 2005 to 2006, the cost of
non-speciality (i.e., chemical) drugs rose 6%, whereas speciality (mostly biologic)
drugs rose 21%.7 Spending on all pharmaceuticals currently represents about 11%
of health care spending in the United States.
In the case of chemical pharmaceuticals, before a generic drug can be marketed,
the generic drug company must demonstrate to the FDA that the drug product is
identical to the original product. For chemical drugs, some experts argue that
“generic medications decrease prices 60% to 90% on branded oral-solid
medications.”8 The Congressional Budget Office estimated the savings generated by
generic drug use in 1994 was between $8 billion and $10 billion.9 The generic drug
industry achieves these cost savings by avoiding the expense of clinical trials, as well
as the initial drug research and development costs that were incurred by the brand-
name manufacturer.
Even though patents for several speciality biotechnology drug products have
expired, very few have had to face the same type of market competition that occurs
with chemical drugs. In contrast to the relatively simple structure and manufacture
of chemical drugs, follow-on biological products, with their more complex nature
and method of manufacture, will not be identical to the brand-name product, but may
instead be shown to be similar. The Generic Pharmaceutical Association (GPhA) has
advocated that the FDA establish a regulatory system for the approval of follow-on
3 (...continued)
House Energy and Commerce Subcommittee on Health, May 2, 2007, at
[http://energycommerce.house.gov/cmte_mtgs/110-he-hrg.050207.Downey-testimony.pdf].
4 CRS Report RL34334, The Food and Drug Administration: Budget and Statutory History,
FY1980-FY2007, by Judith A. Johnson, Donna V. Porter, Susan Thaul, and Erin D.
Williams; “Potential Federal Drug Savings Could Propel Biosimilars Bill,” FDA Legislative
Watch, April 1, 2008.
5 Speciality drugs consist of mostly high-priced biologic agents. Jonah Houts, Senior
Analyst, Express Scripts, Inc., testimony before the Committee on Oversight and
Government Reform, March 26, 2007, at [http://oversight.house.gov/documents/
20070326173059-55945.pdf].
6 Ibid., and Express Scripts, 2006 Drug Trend Report, April 2006, p. 38.
7 Express Scripts, 2006 Drug Trend Report, April 2006, p. 5.
8 Jonah Houts, testimony before the House Committee on Oversight and Government
Reform, March 26, 2007.
9 Congressional Budget Office, “How Increased Competition from Generic Drugs Has
Affected Prices and Returns in the Pharmaceutical Industry,” July 1998.

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biologics under its existing statutory authority.10 However, the Biotechnology
Industry Organization (BIO) has filed a citizen petition with the FDA requesting a
number of actions that would inhibit the approval of follow-on biologics.11
Proposed legislation (H.R. 1038/S. 623, H.R. 1956, H.R. 5629, S. 1505, and S.
1695) would provide a mechanism for FDA approval of biological products that are
similar to the brand-name product, thereby allowing for market competition and
reduction in prices, though perhaps not to the same extent as with generic chemical
drugs. An economic analysis released in February 2008 estimates savings in the
United States of $67.2 billion to $107.7 billion over the 10 years from 2010 to 2019,
and $235.7 billion to $377.7 billion over the 20 years from 2010 to 2029.12 Previous
economic studies on savings to the federal government over ten years due to the use
of follow-on biologics ranged “between nothing and $14 billion.”13 A study by
Avalere Health estimated “government savings at $3.6 billion in the first 10 years;”
another study by Express Scripts estimated “10-year consumer savings at $71 billion
and federal savings at $14 billion.”14
This report provides an overview of the FDA regulatory issues involved in the
approval of follow-on biologics.15
Relevant Laws
In general, biological products are regulated (licensed for marketing) under the
Public Health Service Act — originally by the National Institutes of Health (NIH)
and its precursors and later by the FDA — and chemical drugs are regulated
(approved for marketing) under the Federal Food Drug and Cosmetic Act (by the
FDA). This section provides a brief history of these two Acts and other relevant
laws, as well as some of the important amendments that have occurred during the
past 100 years.
10 Bill Nixon, President and CEO, Generic Pharmaceutical Association, letter to Daniel
Troy, Chief Counsel, FDA, January 18, 2002, at [http://www.fda.gov/cder/ogd/GPHA_jan_
21.htm].
11 BIO Citizen Petition, Follow-on Therapeutic Proteins, April 23, 2003, at
[http://www.fda.gov/OHRMS/DOCKETS/DOCKETS/03p0176/03p-0176-cp00001-01-
vol11.pdf].
12 Robert J. Shapiro, Karan Singh, and Megha Mukim, “The Potential American Market for
Generic Biological Treatments and the Associated Cost Savings,” February 2008, at
[http://www.insmed.com/PDF/Biogeneric_Savings.pdf].
13 “CBO Weighs 2 Studies That Show Little Savings From Biogenerics,” Inside Health
Policy, July 19, 2007.
14 Ibid.
15 For patent issues, see CRS Report RL33901, Follow-On Biologics: Intellectual Property
and Innovation Issues, by Wendy H. Schacht and John R. Thomas.

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The regulation of biologics by the federal government began with the Biologics
Control Act of 1902, “the first enduring scheme of national regulation for any
pharmaceutical product.”16 The act was groundbreaking, “the very first premarket
approval statute in history.”17 It set new precedents, “shifting from retrospective
post-market to prospective pre-market government review.”18 The Biologics Act was
passed in response to deaths (many in children) from tetanus contamination of
smallpox vaccine and diphtheria antitoxin. The act focused on the manufacturing
process of such biologic products and required an inspection of the manufacturing
facility before a federal license was issued to market the product.
The Biologics Act predates the regulation of drugs under the Pure Food and
Drugs Act, which was enacted in 1906. The 1906 Act “did not include any form of
premarket control over new drugs to ensure their safety ... [and] did not include any
controls over manufacturing establishments, unlike the pre-existing Biologics Act
and the later-enacted Federal Food Drug and Cosmetic Act (FDC Act).”19 The Pure
Food and Drugs Act was replaced by the FDC Act in 1938. The FDC Act required
that drug manufacturers submit a new drug application (NDA) prior to marketing that
demonstrated, among other things, that the product was safe.20
The Biologics Act was revised and re-codified (42 USC 262) when the Public
Health Service Act (PHS Act) was passed in 1944. The 1944 Act specified that a
biological product that has been licensed for marketing by the FDA under the PHS
Act is also subject to regulation (though not approval) under the FDC Act. A
biological product is defined under section 351(i) of the PHS Act, as
a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, or analogous product ... applicable to the
prevention, treatment or cure of a disease or condition of human beings.
Section 351(j) of the PHS Act states that “the FDC Act applies to a biological
product subject to regulation under this section, except that a product for which a
license has been approved under subsection (a) shall not be required to have an
approved application under section 505 of such Act.” Most biological products
regulated under the PHS Act also meet the definition of a drug under section 201(g)
of the FDC Act:
16 David M. Dudzinski, “Reflections on Historical, Scientific, and Legal Issues Relevant to
Designing Approval Pathways for Generic Versions of Recombinant Protein-Based
Therapeutics and Monoclonal Antibodies,” Food and Drug Law Journal, vol. 60, pp. 143-
260.
17 Ibid, p. 147.
18 Ibid.
19 Gary E. Gamerman, “Regulation of Biologics Manufacturing: Questioning the Premise,”
Food and Drug Law Journal, vol. 49, 1994, pp. 213-235.
20 For further information, see CRS Report RL32797, Drug Safety and Effectiveness: Issues
and Action Options After FDA Approval, by Susan Thaul.

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articles intended for use in the diagnosis, cure, mitigation, treatment, or
prevention of disease in man or animals; and articles (other than food) intended
to affect the structure or any function of the body of man or other animals.
The FDA Modernization Act of 1997 (FDAMA) amended the PHS Act to
require a single biological license application (BLA) for a biological product, rather
than the two licenses — Establishment License Application (ELA) and Product
License Application (PLA) — that had been required between 1944 and 1997. The
PHS Act provides authority to suspend a license immediately if there is a danger to
public health.
As stated previously, biological products are, in general, regulated — licensed
for marketing — under the PHS Act, and chemical drugs are regulated — approved
for marketing — under the FDC Act. However, through a historical quirk, the FDA
was given regulatory authority over certain natural source biological products; these
products have been regulated as drugs under the FDC Act rather than as biologics
under the PHS Act. Three years prior to the re-codification of the Biologics Act,
Congress gave the FDA authority over the marketing of insulin.21 Insulin is a peptide
hormone, a small protein that regulates carbohydrate metabolism.22 In the 1940s,
insulin “was obtained in the same manner as many biologics, namely extraction from
animals. Despite this similarity with biologics, insulin was regulated by FDA.”23 In
addition to insulin, the distinction of a biological product regulated as a drug under
the FDC Act rather than as a biologic under the PHS Act holds true for a small set
of products that are mostly hormones: glucagon, human growth hormone, hormones
to treat infertility, hormones used to manage menopause and osteoporosis, and certain
medical enzymes (hyaluronidase and urokinase).24
This distinction is important because the Hatch-Waxman Act provides a
mechanism for the approval of generic drugs under the FDC Act but not under the
PHS Act. Specifically, Hatch-Waxman added two abbreviated pathways to the FDC
Act for subsequent versions of already approved products: section 505(j) and section
505(b)(2).
Section 505(j) established an Abbreviated New Drug Application (ANDA)
process for a generic drug that contains the same active ingredient as the brand-name
innovator drug. In the ANDA, the generic company establishes that its drug product
21 Dudzinski, Food and Drug Law Journal, vol. 60, p. 153. The Insulin Amendments P.L.
77-366, codified at 21 USC 356, were repealed by P.L. 105-115, the Food and Drug
Administration Modernization Act (FDAMA).
22 A protein is a large organic molecule composed of a long chain or chains of amino acids
linked by chemical bonds. Insulin is a short chain of 51 amino acids. Examples of
carbohydrates include sugars and starch.
23 Dudzinski, Food and Drug Law Journal, vol. 60, p. 154.
24 Janet Woodcock, Deputy Commissioner, Chief Medical Officer, FDA, testimony before
the House Committee on Oversight and Government Reform, March 26, 2007, at
[http://oversight.house.gov/documents/20070326104056-22106.pdf]; BIO Citizen Petition,
Follow-on Therapeutic Proteins, April 23, 2003, at [http://www.fda.gov/OHRMS/
DOCKETS/DOCKETS/03p0176/03p-0176-cp00001-01- vol11.pdf].

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is chemically the same as the already approved innovator drug, and thereby relies on
the FDA’s previous finding of safety and effectiveness for the approved drug. The
505(j) pathway is used for the approval of most generic chemical drugs.
Under the second pathway, a drug that has a significant difference from an
innovator drug, but is still sufficiently similar to that drug, may be the subject of a
505(b)(2) application. The company filing the application must submit additional
non-clinical and clinical data to show that the proposed product is safe and
effective.25 However, the application may rely on published literature or on the
FDA’s finding of safety and effectiveness for the already approved product to support
the approval of the proposed product. The 505(b)(2) pathway has been used to
approve Omnitrope, a follow-on human growth hormone, and a few other follow-on
protein products.26 All have been members of the small set of biologic products that
were regulated as drugs.
Regulatory Framework
Following enactment of the 1902 Biologics Act, regulatory responsibility for
biologics was first delegated to the Hygienic Laboratory, a precursor of NIH.27 In
1972, regulatory authority for biologics was transferred from the NIH Division of
Biological Standards to the FDA Bureau of Biologics, which eventually became the
agency’s Center for Biologics Evaluation and Research (CBER).28
Because biotechnology products frequently cross the conventional boundaries
between biologics, drugs, and devices, determining the jurisdictional status of these
new products has been difficult for both the FDA and industry. Some products have
25 Janet Woodcock, testimony before the House Committee on Oversight and Government
Reform, March 26, 2007.
26 These products are GlucaGen (glucagon recombinant for injection), Hylenex
(hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical
(calcitonin salmon recombinant) Nasal Spray. Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Omnitrope (somatropin [rDNA origin]) Questions and
Answers, May 30, 2006, at [http://www.fda.gov/cder/drug/infopage/somatropin/qa.htm].
27 Ibid., p. 148, and The NIH Almanac — Historical Data: Chronology of Events, at
[http://www.nih.gov/about/almanac/historical/chronology_of_events.htm]. In 1937, the
biologics control program was assigned to the newly established Division of Biologics
Control. In 1955, the biologics control function was placed in the newly formed Division
of Biologics Standards.
28 The NIH Almanac; Donna Hamilton, “A Brief History of the Center for Drug Evaluation
and Research,” FDA History Office, November 1997, at [http://www.fda.gov/cder/about/
history/Histext.htm]. During the early 1980s, the Bureau of Drugs and the Bureau of
Biologics merged to form the National Center for Drugs and Biologics. In 1984, all of the
National Centers within FDA were redesignated simply as Centers. In 1987, the Center for
Drugs and Biologics was split into the Center for Drug Evaluation and Research (CDER)
and the Center for Biologics Evaluation and Research (CBER). CBER continues to use NIH
facilities and buildings until the expected move in 2012 to the new FDA headquarters in
White Oak, Maryland (see [http://www.fda.gov/oc/whiteoak/projectschedule.html]).

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had characteristics that met multiple statutory and scientific definitions.29 In 1991,
the FDA published an Intercenter Agreement between CBER and the Center for Drug
Evaluation and Research (CDER).30 In general, the agreement stated that traditional
biologics (vaccines, blood, blood products, antitoxins, allergenic products), as well
as most biotechnology products, would be regulated by CBER. The small set of
biologics mentioned earlier that are regulated as drugs under the FDC Act would
continue to be regulated by CDER, regardless of the method of manufacture.
In 2002, however, the FDA announced its intention to reorganize review
responsibilities, consolidating review of new pharmaceutical products under CDER,
thereby allowing CBER to concentrate on vaccines, blood safety, gene therapy, and
tissue transplantation.31 On June 30, 2003, responsibility for most therapeutic
biologics was transferred from CBER to CDER.32 Under the new structure,
biological products transferred to CDER will continue to be regulated as licensed
biologics under section 351 of the PHS Act. Examples of products transferred to
CDER include monoclonal antibodies; proteins intended for therapeutic use
(interferons, thrombolytic enzymes); immunomodulators (other than vaccines and
allergenic products); and, growth factors, cytokines, and monoclonal antibodies
intended to alter production of blood cells.33 Remaining at CBER are traditional
biologics such as vaccines, allergenic products, antitoxins, antivenins, venoms, and
blood and blood products, including recombinant versions of plasma derivatives
(clotting factors produced via biotechnology).
As stated previously, the Hatch-Waxman Act added two abbreviated pathways
under the FDC Act — 505(j) and 505(b)(2) — but not under the PHS Act, for the
approval of additional products subsequent to the innovator product. Because of the
complex nature of most biological products and their methods of manufacture, such
products will not be identical to the brand-name product; therefore, the 505(j)
pathway cannot be used for product approval. However, if a biological product is
sufficiently similar to the innovator product, the 505(b)(2) pathway may be used by
a company for the approval of its biologic. Following the enactment of Hatch-
29 See, for example, “Assignment of Agency Component for Review of Premarket
Applications,” Final Rule, Federal Register, vol. 56, no. 225, November 21, 1991, pp.
58754-58758, at [http://www.fda.gov/OHRMS/DOCKETS/98fr/91-27869.pdf].
30 The Intercenter Agreement is available at [http://www.fda.gov/oc/ombudsman/drug-bio.
htm].
31 FDA Press Release, “FDA to Consolidate Review Responsibilities for New
Pharmaceutical Products,” September 6, 2002, at [http://www.fda.gov/bbs/topics/NEWS/
2002/NEW00834.html].
32 Federal Register, vol. 68, no. 123, June 26, 2003, pp. 38067-38068.
33 Transfer of Therapeutic Products to the Center for Drug Evaluation and Research, at
[http://www.fda.gov/cber/transfer/transfer.htm]. Also of interest is Approved Products
Transferring to CDER, at [http://www.fda.gov/cber/transfer/transfprods.htm], and
Therapeutic Biological Products, at [http://www.fda.gov/cder/biologics/default.htm].

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Waxman, the FDA published in 1999 a draft guidance on applications covered by
section 505(b)(2); the guidance has never been finalized.34
As things currently stand, and as discussed above, the 505(b)(2) pathway has
been used only for those biologics that have been regulated as drugs under the FDC
Act. However, the vast majority of biologics have been regulated under the PHS Act.
The FDA’s position is that additional legislation is required to provide such a
pathway under the PHS Act. For traditional biologics regulated under the PHS Act,
the agency’s longstanding policy has been that a full BLA, including clinical testing,
would be required for the licensing of each such product. In a 1974 Federal Register
notice, the FDA stated that
[u]nlike the regulation of human and animal drugs, all biological products are
required to undergo clinical testing in order to demonstrate safety, purity,
potency and effectiveness prior to licensing, regardless whether other versions
of the same product are already marketed or standards for the product have been
adopted by rulemaking. Indeed, many of the existing standards require specific
clinical testing before approval will be granted. This is required because all
biological products are to some extent different and thus each must be separately
proved safe, pure, potent, and effective.... There is no such thing as a “me-too”
biologic.35
When publishing the final rule on the ANDA procedure that had been outlined
in Hatch-Waxman, the FDA stated in 1992 that “these procedures are inapplicable
to ... biological drug products licensed under 42 USC 262 (section 351 of the PHS
Act).”36 Most recently, during hearing testimony on May 2, 2007, before the
Subcommittee on Health of the House Energy and Commerce Committee, Janet
Woodcock, Deputy Commissioner and Chief Medical Officer of the FDA, stated in
response to questioning that there is no pathway under the PHS Act for the approval
or licensing of follow-on biologics that is similar to the 505(b)(2) pathway under the
FDC Act, and that the FDA would be willing to work with Congress in crafting a
legislative approach to creating such a pathway.
Scientific Challenges
In prepared testimony, Dr. Woodcock outlined the scientific challenges involved
in determining the safety and effectiveness of follow-on biologics. The FDA prefers
to call these products follow-on protein products. In contrast to chemical drugs,
which are relatively small molecules and for which the equivalence of chemical
composition between the generic drug and innovator drug is relatively easy to
determine, therapeutic proteins are much larger in size and much more complex in
structure. A protein is a large organic molecule composed of a long chain of
component parts, called amino acids, which are linked by chemical bonds. This
34 Guidance for Industry, Applications Covered by Section 505(b)(2), October 1999, at
[http://www.fda.gov/CDER/GUIDANCE/2853dft.pdf].
35 Federal Register, v. 39, no. 248, December 24, 1974, p. 44641.
36 Federal Register, v. 57, no. 82, April 28, 1992, p. 17951.

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amino acid chain folds into a complex three-dimensional structure. Slight changes
in the chain or three-dimensional shape can influence the protein’s biological
activity. Proteins can also be altered by the addition of other chemicals, such as
sugar groups (glycosylation), at various points along the amino acid chain.
Therefore, comparing a follow-on protein with the brand-name product is more
scientifically challenging than comparing chemical drugs. In many cases, current
technology will not allow complete characterization of biological products. Dr.
Woodcock describes these technical problems in her prepared testimony:
Current technologies, such as peptide mapping, protein sequencing, and mass
spectroscopy enable manufacturers to determine, with certainty, the amino acid
sequence of a recombinant protein. However, the amino acid sequence is the
most rudimentary characteristic of a protein. Conclusive analysis of other aspects
of a protein’s structure requires much more sophisticated technologies and is
fraught with uncertainties that are proportional to the size and complexity of the
protein itself. Such complexities include folding of the protein’s amino acid
chain into highly organized structures, post-translational modification of the
protein with a broad range of biochemical additions (e.g., glycosylation,
acetylation, phosphorylation, etc.), and association of multiple protein molecules
into aggregates. It is the combination of the protein’s amino acid sequence and
its structural modifications that give a protein its unique functional
characteristics. Therefore, the ability to predict the clinical comparability of two
products depends on our understanding of the relationship between the structural
characteristics of the protein and its function, as well as on our ability to
demonstrate structural similarity between the follow-on protein and the reference
product. Although this currently may be possible for some relatively simple
protein products, technology is not yet sufficiently advanced to allow this type
of comparison for more complex protein products.
Several terms are important in the discussion of the follow-on proteins and their
approval by the FDA. Products that are considered to be therapeutically equivalent
“are approved drug products, usually made by different manufacturers, that are
pharmaceutical equivalents and for which bioequivalence has been demonstrated.
Therapeutic equivalents can be expected to have the same clinical effect and safety
profile when administered to patients under the conditions specified in the
labeling.”37 Pharmaceutical equivalents are products that contain the same active
ingredient in the same strength, dosage form, and route of administration.38
Bioequivalence means that the products are absorbed into the body at a similar rate
and extent.39 Interchangeability “is not defined by FDA and could have a number of
different meanings. It could refer to products that are therapeutic equivalents, and
thus could, in some circumstances, be substituted at the pharmacy level without a
37 Janet Woodcock, Deputy Commissioner, Chief Medical Officer, FDA, testimony before
the Subcommittee on Health, Committee on Energy and Commerce, May 2, 2007, at
[http://energycommerce.house.gov/cmte_mtgs/110-he-hrg.050207.Woodcock-testimony.
pdf].
38 Janet Woodcock et al., “The FDA’s Assessment of Follow-on Protein Products: A
Historical Perspective,” Nature Reviews Drug Discovery, published online April 13, 2007,
at [http://www.nature.com/reviews/drugdisc].
39 Ibid.

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physician’s intervention. Alternatively, the term could describe similar products that
are not ‘substitutable’ but which, under a physician’s supervision, could be used to
treat the same disease or condition in the same patient.”40
Most drugs approved under section 505(j) are therapeutically equivalent to the
already approved drug product. In her testimony, Dr. Woodcock explains the
importance of a determination of therapeutic equivalence for a generic drug and the
reasons why such a determination for a follow-on protein product may not be
possible, at least at the present time:
In many jurisdictions, therapeutically equivalent drugs may be substituted at the
pharmacy level, without a physician’s intervention.... Because of the variability
and complexity of protein molecules, current limitations of analytical methods,
and the difficulties in manufacturing a consistent product, it is unlikely that, for
most proteins, a manufacturer of a follow-on protein product could demonstrate
that its product is identical to an already approved product. Therefore, the section
505(j) generic drug approval pathway, which is predicated on a finding of the
same active ingredient, will not ordinarily be available for protein products.41
Immunogenicity, or the ability to elicit an immune response, is another
important term in the discussion of follow-on proteins. An immune response to a
therapeutic protein can range from detectable, but clinically insignificant, to one that
can cause safety problems for the patient or limit the effectiveness of the product.
For some biologics, such as vaccines, stimulating an immune response is the intended
outcome. However, for other types of therapeutic products, an immune response can
lower the clinical effect of a protein. Dr. Woodcock describes the implications at
length in the prepared testimony:
Adverse safety events from an immune response could include hypersensitivity
reactions such as anaphylaxis, rash, fever and kidney problems, to cross-reaction
with an endogenous (naturally occurring in the body) protein (e.g.,
erythropoietin). Immunogenicity may be influenced by patient-related,
disease-related, or product-related factors. Immune responses to administered
protein products can be extremely serious or life-threatening; therefore, this issue
requires significant attention. The ability to predict immunogenicity of a protein
product, particularly the more complex proteins, is extremely limited. Therefore,
some degree of clinical assessment of a new product’s immunogenic potential
will ordinarily be needed. The extent of independent testing needed will again
depend on a variety of scientific factors such as the indication, whether the
product is to be administered chronically, the overall assessment of the product’s
immunogenic potential, and whether there is the possibility of generating a
cross-reaction with an important endogenous molecule.
Even if a follow-on protein product is found to be safe and effective by the
FDA, this finding does not mean that the follow-on protein product would be
interchangeable with, or substitutable for, the originally approved brand-name
product. To establish that the follow-on protein product is substitutable for the
40 Janet Woodcock, testimony before the Subcommittee on Health, Committee on Energy
and Commerce, May 2, 2007.
41 Ibid.

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brand-name product, the manufacturer of the follow-on product must demonstrate
through additional clinical data that repeated switches from the follow-on product to
the brand-name product (and vice versa) would have no negative effect on the safety
and/or effectiveness of the products. In other words, there must be no problems with
immunogenicity. “For many follow-on protein products, and, in particular, the more
complex proteins, there is a significant potential for repeated switches between
products to have a negative impact on the safety and/or effectiveness. Therefore, the
ability to make determinations of substitutability for follow-on protein products may
be limited.”42
Legislation
Initially, there were two competing legislative approaches for the approval by
the FDA of follow-on biologics introduced in the 110th Congress: H.R. 1038/S. 623
vs. H.R. 1956 and S. 1505. The introduction of S. 1695 provided a third approach.
H.R. 5629 provides an approach that is similar in some respects to S. 1695 with some
important differences that are favored by companies that have developed the
reference product, also referred to as the innovator or brand-name product.
In general, H.R. 1038/S. 623 is favored by the generic drug industry, whereas
H.R. 1956 and S. 1505 are favored by the companies that have developed the
reference products. H.R. 1038/S. 623 would allow the FDA to make a determination
on interchangeability of a brand-name and follow-on biologic. H.R. 1956 and S.
1505 would not allow the FDA to designate a follow-on biologic as interchangeable
with (or therapeutically equivalent to) the brand-name product. In addition, H.R.
1956 and S. 1505 would require the publication of a final product class-specific
guidance document (H.R. 1956) or a final product class-specific rule (S. 1505) before
an application for a follow-on biologic could be submitted to the FDA. H.R. 1038/S.
623 make no such requirement on the publication by FDA of guidance documents or
final rules.
H.R. 1956 and S. 1505 would also set in place provisions governing the
nonproprietary naming of biotechnology-derived biologics.43 The bills would amend
the FDC Act to deem such a biologic to be misbranded if its labeling fails to meet
these new requirements. H.R. 1038/S. 623 do not contain such product naming
provisions. According to media reports, “the brand industry successfully pushed for
different names [for brand-name and follow-on products] in Europe. The brand
42 Ibid.
43 The nonproprietary name for a drug (also called a generic, common or established name)
is provided in this country by the United States Adopted Names (USAN) Council. The
USAN Council works with similar international groups to standardize drug nomenclature.
While a drug’s chemical name can be lengthy and difficult to pronounce and the brand or
trademark name is protected by intellectual property protections, the nonproprietary name
is in the public domain and is used for all legal and regulatory matters and in all official
correspondence. Dan Boring, “Names, Names, Names,” Modern Drug Discovery, v. 3,
September 2000, p. 31-32; and, Dan Boring, “More Names,” Modern Drug Discovery, v.
3, October 2000, p. 35-36.

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industry argues having different names helps pinpoint which drugs are hurting
people, but the generic drug industry believes it is a ploy to thwart generic
substitution.”44 The brand name drug companies believe that “having different
names would make it easier for FDA to tell when a brand or a biosimilar is the cause
of side effects. However, FDA urged European regulators to not use this approach
when they were debating it last winter. FDA says it already has ‘many alternative
mechanisms’ to prevent inappropriate substitution.”45
The bipartisan Senate authors of S. 1695 claim to have negotiated a compromise
between the brand-name manufacturers and the generic drug industry. S. 1695 would
allow FDA to make a determination on interchangeability. S. 1695 does not require
the publication of guidance or rule prior to consideration of a follow-on biologic
application and does not require a different nonproprietary name for the follow-on
biologic than the brand-name drug. S. 1695 would provide, however, 12 years of
exclusive marketing for the brand-name product prior to the approval of a follow-on
biologic. H.R. 1956 and S. 1505 would provide at least 14 years of exclusive
marketing for the brand-name product; H.R. 1038/S. 623 would not provide an
exclusivity period.
Although the Bush Administration supports creating a pathway for the approval
by FDA of follow-on biologics, it is opposed to several aspects of S. 1695, such as
allowing FDA to make determinations on interchangeability, allowing the approval
of follow-on biologics without prior issuance of guidance, the creation of the
Biological Products Savings Fund, and the possible waiver by FDA of a requirement
for clinical trials prior to the approval of a follow-on biologic.46 The Bush
Administration also believes that a follow-on biologic should have a different
nonproprietary name than the brand name product. A June 26, 2007, letter from HHS
Secretary Michael Leavitt to the Chairman of the Senate HELP Committee outlines
the Bush Administration’s position on S. 1695.47
H.R. 5629 would require the publication of product-class specific guidance prior
to the approval of a biological product, as is the case with H.R. 1956 and S. 1505.
H.R. 5629 would allow FDA to make a determination on interchangeability, like
H.R. 1038/S. 623 and S. 1695. However, H.R. 5629 would require (1) the
publication of final guidance on interchangeability prior to determinations on
interchangeability, (2) the biological product must be biosimilar to the reference
product and any licensed product that is interchangeable with the reference product,
and (3) the biological product must produce the same clinical result for each
condition of use on the reference product label. H.R. 5629 would provide at least 12
years and possibly up to 14½ years of exclusive marketing for the brand-name
product. H.R. 5629 would require clinical studies of immunogenicity; these studies
44 John Wilkerson, “Senate Bill does not Require Biogenerics be ‘Same’ as Brands,” Inside
Health Policy, June 25, 2007.
45 John Wilkerson, “HHS Opposes Senate Plan for Biogenerics “Interchangeability” with
Brands,” Inside Health Policy, June 28, 2007.
46 Ibid.
47 Letter found at [http://insidehealthpolicy.com/secure/data_extra/dir_07/he2007_2375.pdf].

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may be waived only if final guidance on immunogenicity determinations has been
published. In contrast, S. 1695 would require that clinical studies submitted in
support of a biological product application must be designed to avoid needless
duplication or unethical clinical testing; the requirement for clinical and other studies
may be waived.
A summary of the key provisions in each of the bills is provided below.
H.R. 1038 (Waxman), the Access to Life-Saving Medicine Act, was
introduced on February 14, 2007. H.R. 1038 was referred to the Committee on
Energy and Commerce, and the Committee on the Judiciary. A companion bill, S.
623 (Schumer), was introduced on February 15, 2007. S. 623 was referred to the
Committee on Health, Education, Labor, and Pensions.
H.R. 1038 would amend section 351 of the PHS Act to establish a process for
the approval of an abbreviated biological product application for products that
contain the same or similar active ingredients as a previously licensed biological
product (the reference product). The bill would allow a person to file an abbreviated
biological product application with the FDA that includes (1) data demonstrating that
the product is comparable to or interchangeable with the reference product; (2)
information to show that the conditions or conditions of use prescribed,
recommended, or suggested in the labeling proposed for the biological product have
been previously approved for the reference product; and (3) information to show that
the route of administration, the dosage form, and the strength of the biological
product are the same as those of the reference product.
H.R. 1038 sets forth a number of conditions for approval of such an application
by the FDA. The bill allows an applicant to request that the FDA make a
determination as to the interchangeability of a comparable product and the reference
product, based on whether a product can be expected to produce the same clinical
result as the reference product in any given patient.
H.R. 1038 provides for a period of up to 36 months of market exclusivity for the
first approved interchangeable product, during which time the agency is precluded
from approving a second interchangeable product. H.R. 1038 requires the FDA to
establish requirements for the efficient review, approval, suspension, and revocation
of comparable biological product applications. The bill sets forth provisions
governing patent infringement claims against an applicant or prospective applicant
for a comparable biological product license.
H.R. 1956 (Inslee), the Patient Protection and Innovative Biologic
Medicines Act of 2007, was introduced on April 19, 2007. H.R. 1956 was referred
to the Committee on Energy and Commerce.
H.R. 1956 would amend section 351 of the PHS Act to provide for the approval
of similar biological products. The bill would allow any person to submit an
application to the FDA for approval of a biologics license for a biological product
that is to be similar to an already approved biological product (the reference product).
The application would be approved only if (1) the applicant demonstrates that the
similar biological product conforms to the applicable final product-class specific

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guidance and, on the basis of the data submitted in conformance with such guidance,
the FDA concludes the product is safe, pure, and potent; (2) the facility in which the
similar biological product is manufactured, processed, packed, or held meets
standards designed to ensure that the biological product continues to be safe, pure,
and potent; and (3) the applicant consents to the inspection of the manufacturing
facility.
H.R. 1956 would allow FDA approval of an application submitted for a similar
biological product (1) only for indications for which the reference product is
approved and (2) only if, with respect to each such indication, the application
conforms to the applicable final product-class specific guidance, and on the basis of
non-clinical and clinical data submitted regarding such indication, the FDA
concludes the product is safe, pure, and potent.
H.R. 1956 would not allow the FDA to designate a similar biological product
as therapeutically equivalent to the reference product. Two years after enactment,
and every two years thereafter, the bill would require that a report be submitted to
Congress making recommendations on (1) whether it is feasible, in the current state
of scientific and technical knowledge, to make therapeutic equivalence
determinations for similar biological products, and (2) if so, the statutory criteria that
should govern such determinations.
H.R. 1956 would not allow an application for a similar biological product to be
submitted to the FDA unless (1) the FDA has published final product-class specific
guidance applicable to the reference product and (2) not less than 12 years have
elapsed from the date on which the reference product was approved or licensed.
Under the bill, approval of an application would not be effective until at least 14
years after the date the reference product was approved or licensed. Approval would
not be effective until 15 years after the reference product was approved or licensed
if (1) during the 12-year period following the approval or licensing of the reference
product, the FDA approves a supplement to the new drug or biologics license
application for the reference product that seeks approval to market the reference
product for a new indication and (2) the new indication provides a significant clinical
benefit in comparison with existing therapies. The bill would allow any person to
submit a request to the FDA for the issuance of product-class specific guidance, and
the bill provides specific requirements on the issuance of such guidance documents.
H.R. 1956 includes provisions governing the naming of biotechnology-derived
therapeutic protein products and other biological products. The bill would amend the
FDC Act to deem a biotechnology-derived therapeutic protein to be misbranded if
its labeling fails to meet these requirements.
S. 1505 (Gregg), the Affordable Biologics for Consumers Act of 2007, was
introduced on May 24, 2007. S. 1505 was referred to the Senate Committee on
Health, Education, Labor, and Pensions.
S. 1505 would amend section 351 of the PHS Act to provide for the approval
of biosimilars. The bill would allow anyone to submit an application to the FDA for
approval of a biologics license for a biosimilar that is to be similar to an already
approved biotechnology-derived therapeutic biological product (the reference

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product). The application would be approved only if (1) the applicant demonstrates
that the biosimilar conforms to the applicable final product class-specific rule and,
on the basis of the data submitted in conformance with such rule, the FDA concludes
the product is safe, pure, and potent; (2) the applicant demonstrates that the
biosimilar is as similar to the reference product as may be achieved given the state
of scientific knowledge and technology capabilities at the time of submission of the
application; (3) the applicant demonstrates that the biosimilar has the same route of
administration, dosage form, mechanism of action, and strength as the reference
product; (4) the facility in which the biosimilar is manufactured, processed, packed,
or held meets standards designed to ensure that the biological product continues to
be safe, pure, and potent; and (5) the applicant consents to the inspection of the
manufacturing facility.
S. 1505 would allow FDA approval of an application submitted for a biosimilar
(1) only for indications for which the reference product is approved; (2) only if, with
respect to each such indication, the application conforms to the applicable final
product class-specific rule, and on the basis of non-clinical and clinical data
submitted regarding such indication, the FDA concludes the product is safe, pure, and
potent; and (3) only if the applicant agrees to provide to the FDA, on an ongoing
basis, all written documents it prepares for any purpose (including any patent
litigation) that characterizes the difference between the biosimilar and the reference
product.
S. 1505 would not allow the FDA to designate a biosimilar as interchangeable
with (or therapeutically equivalent to) the applicable reference product. Two years
after enactment, and every two years thereafter, the bill would require an assessment
of the state of scientific and technical knowledge regarding the ability of the FDA to
make a determination that a biosimilar is interchangeable with (or therapeutically
equivalent to) a reference product on a product class basis. If the assessment finds
that the state of scientific and technical knowledge enables the FDA to make a
determination of interchangeability (or therapeutic equivalence) with respect to one
or more product classes, a report would be submitted to Congress that describes such
findings and recommendations for statutory criteria that should govern such a
determination.
S. 1505 would not allow an application for a biosimilar to be submitted to the
FDA unless (1) the FDA has published a final product class-specific rule applicable
to the reference product and (2) not less than 12 years have elapsed from the date on
which the reference product was approved or licensed. Approval would not be
effective until at least 14 years after the date on which the reference product was
approved or licensed. Approval would not be made effective until at least 16 years
after the reference product was approved or licensed if (1) during the 12-year period
following the approval or licensing of the reference product, the FDA approves a
supplement to the new drug or biologics license application for the reference product
that seeks approval to market the reference product for a new indication and (2) the
new indication provides a significant clinical benefit. The bill would allow any
person to submit a request to the FDA for the issuance of a product class-specific
rule, and the bill provides specific requirements on the issuance of such a rule.

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S. 1505 includes provisions governing the naming of biotechnology-derived
therapeutic protein products and other biological products. The bill would amend the
FDC Act to deem a biotechnology-derived therapeutic protein to be misbranded if
its labeling fails to meet the requirements.
S. 1695 (Kennedy), the Biologics Price Competition and Innovation Act of
2007, was introduced on June 26, 2007. S. 1695 was referred to the Senate
Committee on Health, Education, Labor, and Pensions. On June 27, 2007, the bill
was ordered to be reported with an amendment in the nature of a substitute.
S. 1695 would amend section 351 of the Public Health Service Act to establish
a pathway for the licensure of biosimilar biological products. Under the bill, such an
application would be required to include, unless the Secretary determines that it is
unnecessary, information demonstrating that the biological product is similar to the
reference (brand-name) product based on data derived from (1) analytical studies
that show the two products are highly similar, notwithstanding minor differences in
clinically inactive components; (2) animal studies, including a toxicity assessment;
and (3) a clinical study or studies, including an assessment of immunogenicity and
other factors. S. 1695 would require that the application include information
demonstrating that (1) the biological product and reference product have the same
mechanism of action; (2) the condition of use in the proposed labeling for the
biological product has been previously approved for the reference product; (3) the
route of administration, the dosage form, and the strength of the biological product
are the same as those of the reference product; and (4) any facility in which the
biological product is manufactured or held meets standards that ensure the product
is safe, pure, and potent. The application may also include information
demonstrating interchangeability of the biological product with the reference product.
S. 1695 would allow the Secretary to license the biological product if the
information submitted in the application is sufficient to show that the biological
product is either (1) biosimilar to the reference product or (2) interchangeable with
the reference product. The biological product would be interchangeable with the
reference product if (1) it can be expected to produce the same clinical result as the
reference product in any given patient and (2) the risk, in terms of safety or
diminished efficacy, of alternating or switching between use of the biological product
and the reference product is not greater than the risk of using the reference product
without such alternation or switch.
S. 1695 would allow for a one-year period of exclusive marketing for the first
interchangable biosimilar biological product to be approved as interchangable for a
particular reference product. The bill would not allow for the approval of any
biosimilar application until 12 years after the reference product was first licensed.
S. 1695 would allow the Secretary, after the opportunity for public comment,
to issue general or specific guidance on the application process for licensure of a
biosimilar biological product. The issuance (or non-issuance) of guidance would not
preclude the review of, or action on, a submitted application.
S. 1695 would establish a new process for identifying patents that might be
disputed between the brand-name company and the company submitting a biosimilar

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application. The bill would provide a multistep, but according to the bill’s sponsors,
expedited, patent resolution process.
S. 1695 would require all applications for the approval of a biological product
to be submitted under section 351 of the PHS Act rather than section 505 of the FDC
Act. The bill would provide an exception for the class of biological products that
have traditionally been approved under section 505 of the FDC Act; the exception
would terminate 10 years after enactment of S. 1695. All approved applications
under section 505 of the FDC Act would then be deemed to be a license for the
biological product under section 351 of the PHS Act.
S. 1695 would make preliminary provisions for the collection of user fees for
the review of biosimilar biological products.
S. 1695 would direct the Secretary of the Treasury to determine the amount of
savings to the federal government as a result of enactment of S. 1695 and would
transfer the amount to a special reserve fund, the Biological Product Savings Fund,
to be expended by the Secretary of HHS on activities authorized under the Public
Health Service Act.
S. 1695 would require the Government Accountability Office to conduct a study
and report to Congress, not later than three years after enactment, on the extent to
which pediatric studies of biological products are being required under the FDC Act
and any pediatric needs not being met under existing authority.
Lastly, S. 1695 would specify that biosimilars to orphan drug products (i.e.,
reference products that have been designated under section 526 of the FDC Act for
a rare disease) would be licensed only after the expiration for such reference product,
the later of either (1) the seven-year period specified in section 527(a) of the FDC
Act or (2) the 12-year period described in S. 1695.
H.R. 5629 (Eshoo), the Pathway for Biosimilars Act, was introduced on
March 13, 2008. H.R. 5629 was referred to the Committee on Energy and
Commerce, and the Committee on the Judiciary.
H.R. 5629 would require the biological product license application to include
information demonstrating that the biological product is biosimilar to the reference
product based on data from (1) analytical studies, (2) animal studies, and (3) a
clinical study or studies (of immunogenicity) for each condition of use for which the
reference product is approved. The requirement for analytical studies and animal
studies may be waived. Immunogenicity assessment may be waived only if draft and
final guidance has been published. The bill would not allow such an application to
be submitted until the later of (1) the start of a proceeding for issuing applicable
product class guidance for that product or (2) four years after the reference product
was licensed. The bill would not allow the Secretary to accept an application until
the Secretary has initiated a proceeding for issuance of applicable product class
guidance for that biological product.
H.R. 5629 would require that a license application for such biological products
would be reviewed by the division that reviewed and approved the reference product.

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Risk evaluation and mitigation strategies under the FFDCA would apply. The bill
would allow the approval of an application only if the biological product is biosimilar
to the reference product with respect to each condition of use for which the reference
product is approved, and the applicant consents to the inspection of the
manufacturing facility. If the biological product is, bears, or contains a select agent
or toxin, the application would not be approved. An application may not be approved
until the Secretary has completed the proceeding for issuance of guidance with
respect to the product class within which the biological product falls.
H.R. 5629 would not allow the approval of an application for a follow-on
product to become effective until at least 12 years after licensing of the reference
product. For pediatric applications, application approval would not become effective
until 12 years and 6 months after approval of the reference product. Pediatric
exclusivity must be determined by the FDA no later than nine months prior to the
expiration of the marketing exclusivity period or no additional pediatric exclusivity
will be awarded.
H.R. 5629 would not allow the approval of an application for a follow-on
product to become effective until 14 years after the reference product was first
licensed if, during the 8-year period following licensure of the reference product,
approval of a new indication for the reference product would provide a significant
improvement (compared to current marketed products) in the treatment, diagnosis,
or prevention of disease. For pediatric applications in this situation, approval of a
follow-on product application would not become effective until 14 years and 6
months after approval of the reference product. Pediatric exclusivity must be
determined by the FDA no later than nine months prior to the expiration of the
marketing exclusivity period or no additional pediatric exclusivity will be awarded.
H.R. 5629 would require a determination on interchangeability if the application
shows that the biological product (1) is biosimilar to the reference product and any
licensed biological product that has been determined to be interchangeable with the
reference product, (2) can be expected to produce the same clinical result in any
given patient for each condition of use on the reference product label, and (3) can be
alternated or switched between use of the reference product without risk to the patient
in terms of safety or diminished efficacy compared with use of the reference product
alone. The bill would require that determinations on interchangeability would not
be made prior to publication of draft and final guidance advising that it is feasible to
make interchangeability determinations on products in that product class, and
explaining the data that will be required to support such a determination.
H.R. 5629 would require the Secretary to publish proposed guidance for public
comment prior to publication of final guidance with respect to licensure of a
biological product or product class. The Secretary must establish a process to allow
public input regarding priorities for issuing guidance. For a reference product that
was licensed more than seven years prior to enactment, a person may petition the
Secretary to commence the process for issuing final guidance for the reference
product’s product class. The petition must include a description of the scientific
feasibility and rationale for the request. The Secretary must issue final product class
guidance within two years of such petition. A guidance may state that the Secretary
will not license a product or product class (not including any recombinant protein)

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because the science and experience, as of the date of the guidance, does not allow
licensure. The bill would require the product class-specific guidance to include a
description of (1) the criteria that will be used to determine whether a biological
product is biosimilar to a reference product in such product class; (2) the criteria, if
available, that will be used to determine whether a biological product meets the
standards for interchangeability; and (3) the criteria, if available, that will be used to
assess immunogenicity. The bill would allow the Secretary to issue subsequent
guidance to modify or reverse previous guidance.
H.R. 5629 would require the Secretary to ensure that the labeling and packaging
of each biological product bears a unique name that distinguishes it from the
reference product and any other biological products that are evaluated against such
reference product.
H.R. 5629 would allow a period of market exclusivity for the applicant that is
the first to establish that its product is interchangeable with the reference product for
one or more conditions of use. This period of market exclusivity would be 24
months after the later of either the date of the first commercial marketing of the
product that is interchangeable with the reference product, or if marketed before
interchangeability is determined, the date the product is determined to be
interchangeable.
H.R. 5629 would establish a process for identifying patents that might be
disputed between the brand-name company and the company submitting a biosimilar
application. The bill would provide a multistep patent resolution process.
H.R. 5629 would require all applications for the approval of a biological product
to be submitted under section 351 of the PHS Act rather than section 505 of the FDC
Act. The bill would provide an exception for the class of biological products that
have traditionally been approved under section 505 of the FDC Act; the exception
would terminate 10 years after enactment of H.R. 5629. All approved applications
under section 505 of the FDC Act would then be deemed to be a license for the
biological product under section 351 of the PHS Act.
H.R. 5629 would allow for the collection of user fees for the approval of a
biological product licensed under this newly created section of the PHS Act, section
351(k).
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