Order Code RL34045
FDA Regulation of Follow-On Biologics
June 18, 2007
Judith A. Johnson
Specialist in Life Sciences
Domestic Social Policy Division

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FDA Regulation of Follow-On Biologics
Summary
The 110th Congress is currently considering legislation (S. 1082) to reauthorize
the Food and Drug Administration (FDA) user fee programs. Congress may decide
to include within the FDA legislation a measure that would expand the agency’s
regulatory activities by opening a pathway for the approval of follow-on biologics
(e.g., H.R. 1038/S. 623, H.R. 1956, or S. 1505). A biologic is a preparation, such as
a drug or a vaccine, that is made from living organisms. In contrast, a chemical drug
is 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 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

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FDA Regulation of Follow-On Biologics
The 110th Congress is considering legislation (S. 1082) that would reauthorize
provisions affecting Food and Drug Administration (FDA) regulation of
pharmaceutical and medical device marketing. Lawmakers may include within this
legislative package a measure (such as H.R. 1038/S. 623, H.R. 1956, or S. 1505) that
would open a pathway for FDA
approval of so-called “follow-
on” biologics.1 This pathway
A biologic is a preparation, such as a drug or a
would be somewhat analogous
vaccine, that is made from living organisms. In
to that which allowed for the
contrast, a chemical drug is synthesized via a
approval of generic chemical
chemical process. A follow-on biologic is
drugs via passage of the Drug
similar but not identical to the brand-name, or
Price Competition and Patent
innovator, product made by the pharmaceutical
Term Restoration Act of 1984
or biotechnology industry.
(P.L. 84-417), often referred to
as the Hatch-Waxman Act.2 By
offering an alternative to brand-name drug products, the Hatch-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
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 generic implies
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.

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year, and biological drugs for multiple sclerosis range in price from $16,000 to
$25,000 per year.3
In 2006, spending on such speciality drugs was $54 billion, or about 20% of
total spending on pharmaceuticals.4 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.5 From 2005 to 2006, the cost of
non-speciality (i.e., chemical) drugs rose 6%, whereas speciality (mostly biologic)
drugs rose 21%.6 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.”7 The Congressional Budget Office estimated the savings generated by
generic drug use in 1994 was between $8 billion and $10 billion.8 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
biologics under its existing statutory authority.9 However, the Biotechnology
Industry Organization (BIO) has filed a citizen petition with the FDA requesting a
3 Bruce L. Downey, Chairman and CEO Barr Pharmaceuticals, Inc., testimony before the
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 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].
5 Ibid., and Express Scripts, 2006 Drug Trend Report, April 2006, p. 38.
6 Express Scripts, 2006 Drug Trend Report, April 2006, p. 5.
7 Jonah Houts, testimony before the House Committee on Oversight and Government
Reform, March 26, 2007.
8 Congressional Budget Office, “How Increased Competition from Generic Drugs Has
Affected Prices and Returns in the Pharmaceutical Industry,” July 1998.
9 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].

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number of actions that would inhibit the approval of follow-on biologics.10 Proposed
legislation (H.R. 1038/S. 623, H.R. 1956, and S. 1505) 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.
This report provides an overview of the FDA regulatory issues involved in the
approval of follow-on biologics.11
Relevant Laws
In general, biological products are regulated under the Public Health Service Act
(first by precursors to the Public Health Service and later by the FDA), and chemical
drugs are regulated 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.
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.”12 The Act was groundbreaking, “the very first premarket
approval statute in history.”13 It set new precedents, “shifting from retrospective
post-market to prospective pre-market government review.”14 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 inspections 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
10 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].
11 For patent issues, see CRS Report RL33901, Follow-On Biologics: Intellectual Property
and Innovation Issues, by Wendy H. Schacht and John R. Thomas.
12 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.
13 Ibid, p. 147.
14 Ibid.

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and the later-enacted Federal Food Drug and Cosmetic Act (FDC Act).”15 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.16
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:
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 under the
PHS Act, and chemical drugs are regulated 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.17 Insulin is a peptide hormone, a small protein that regulates carbohydrate
15 Gary E. Gamerman, “Regulation of Biologics Manufacturing: Questioning the Premise,”
Food and Drug Law Journal, vol. 49, 1994, pp. 213-235.
16 For further information, see CRS Report RL32797, Drug Safety and Effectiveness: Issues
and Action Options After FDA Approval, by Susan Thaul.
17 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).

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metabolism.18 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.”19 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).20
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
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.21 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.22 All have been biologics that were regulated as drugs.
18 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.
19 Dudzinski, Food and Drug Law Journal, vol. 60, p. 154.
20 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].
21 Janet Woodcock, testimony before the House Committee on Oversight and Government
Reform, March 26, 2007.
22 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].

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Regulatory Framework
Following enactment of the 1902 Biologics Act, regulatory responsibility for
biologics was first delegated to the Hygienic Laboratory, a precursor of the National
Institutes of Health (NIH).23 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).24
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
had characteristics that met multiple statutory and scientific definitions.25 In 1991,
the FDA published an Intercenter Agreement between CBER and the Center for Drug
Evaluation and Research (CDER).26 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.27 On June 30, 2003, responsibility for most therapeutic
23 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.
24 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]).
25 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].
26 The Intercenter Agreement is available at [http://www.fda.gov/oc/ombudsman/drug-bio.
htm].
27 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].

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biologics was transferred from CBER to CDER.28 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.29 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-
Waxman, the FDA published in 1999 a draft guidance on applications covered by
section 505(b)(2); the guidance has never been finalized.30
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
28 Federal Register, vol. 68, no. 123, June 26, 2003, pp. 38067-38068.
29 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].
30 Guidance for Industry, Applications Covered by Section 505(b)(2), October 1999, at
[http://www.fda.gov/CDER/GUIDANCE/2853dft.pdf].

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proved safe, pure, potent, and effective.... There is no such thing as a “me-too”
biologic.31
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).”32 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 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 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
31 Federal Register, v. 39, no. 248, December 24, 1974, p. 44641.
32 Federal Register, v. 57, no. 82, April 28, 1992, p. 17951.

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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.”33 Pharmaceutical equivalents are products that contain the same active
ingredient in the same strength, dosage form, and route of administration.34
Bioequivalence means that the products are absorbed into the body at a similar rate
and extent.35 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
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.”36
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
33 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].
34 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].
35 Ibid.
36 Janet Woodcock, testimony before the Subcommittee on Health, Committee on Energy
and Commerce, May 2, 2007.

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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.37
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
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.”38
Legislation
Two different legislative approaches for the approval by the FDA of follow-on
biologics have been introduced in the 110th Congress. In general, H.R. 1038/S. 623
is the approach favored by the generic drug industry, whereas H.R. 1956 and S. 1505
37 Ibid.
38 Ibid.

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are favored by the companies that have developed the innovator or brand-name
products. Highlights of the bills are outlined below.
H.R. 1038 (Waxman), the Access to Life-Saving Medicine Act, was introduced
on February 14, 2007. A companion bill, S. 623 (Schumer), was introduced on
February 15, 2007. 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 bills 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. 1038 was referred to the Committee on Energy and Commerce
and to the Judiciary Committee.
H.R. 1956 (Inslee), the Patient Protection and Innovative Biologic Medicines
Act of 2007, was introduced on April 19, 2007. The bill 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 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

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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.
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. The bill would amend section 351 of the
PHS Act to provide for the approval of biosimilars. S. 1505 would allow any person
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 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

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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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