Biosimilars
A Health Care
Professional’s Guide
Visit PfizerBiosimilars.com to
learn more about biosimilars.
Introduction
High-quality biosimilars may
have the potential to increase
access to biologic therapies and
provide savings and efficiencies
to health care systems.1
2
It is anticipated that health care spending in the United States will increase
from 17.4% in 2013 to 19.6% of gross domestic product (GDP) by 2024, and
the cost of prescription drug spending is projected at an average 6.3% annual
growth rate from 2015 through 2024.2 Health care spending is expected to
grow 5.8% on average from 2015 through 2024, 1.1% faster than GDP.2
Twenty-seven percent of pharmaceutical products approved in 2015 were
biologics.3 Figure 1 shows national health care spending as a percentage
of GDP.2,4
More than 30 years since the approval of the first biologic, biologic drugs have
revolutionized the treatment of patients with some of the most difficult-totreat diseases.5,6 They have had a meaningful impact on patient management
in multiple disease states.7,8 The growing demand for these biologics in health
care worldwide is demonstrated by the dramatic increase in their global share
of pharmaceutical sales. Global biologic sales are projected to exceed
$390 billion by 2020, accounting for up to 28% of the global market value
for pharmaceuticals.9 Biologics account for nearly half of approximately $85.5
billion spent on the top 15 drugs in 2015.10 Patents for a number of the most
commonly used biologic drugs have already expired, or are set to expire, in the
near future.11 These data suggest that there is a strong demand for increased
savings and efficiencies for health care systems.1,9,11 Biosimilars may have
the potential to provide value by addressing the high demand for biologics.1
They may also provide important treatment options, potentially facilitating
increased patient access to treatment.1
Figure 1. National Health Expenditure as a Percentage of GDP2,4
13.2%
17.4%
19.6%
2000
2013
2024
Health share of GDP
3
Biosimilars are different from
small molecule generics
Bioequivalent versions of small
molecule drugs are called generics.
Highly similar versions of biologics
are called biosimilars.12,13
4
Biologics, including biosimilars, are produced in living cells via a multistep
process.7 Unlike small molecules, which are chemically synthesized, biologics
are created by organic processes that require significant expertise and stateof-the-art technology.7 Table 1 shows the differences between small molecule
drugs and biologics.
Biosimilars are not identical to their reference biologics and are not generics.7
A generic drug is bioequivalent to the brand-name small molecule drug.12
A generic medication has to have the same active ingredients, dosage
form, safety profile, strength, route of administration, quality, performance
characteristics, and intended use as the brand-name drug.12 In contrast, a
biosimilar is a biologic that is highly similar, with no clinically meaningful
differences, to an already approved biologic in terms of the safety profile,
purity, and potency of the product.13 There are rigorous regulatory
requirements in place to demonstrate biosimilarity.13
Table 1. Differences Between Small Molecule Drugs and Biologics7,14,15
Small Molecule
(Chemical)
Biologic
(Protein)
Production
Chemical synthesis
Living systems (eg, cultured
bacterial, yeast, animal, or plant
cells)
Characterization
Can be characterized using
limited physicochemical methods
Necessary to perform
comprehensive structural and
functional assessment
Administration
Various routes, including oral,
topical, and parenteral (IM, IV, SC)
Parenteral (IM, IV, SC) delivery
Immunogenicity
Mostly nonimmunogenic
Potentially immunogenic
IM, intramuscular; IV, intravenous; SC, subcutaneous.
5
The complexity of biologics
Physically and chemically, biologics are more complex than small molecules.
Because biologics are frequently proteins, they must be produced in living
systems.7 The final form of a biologic is not a single entity, but a mix
of isoforms. This mixture of isoforms is frequently attributed to ‘‘posttranslational modifications” due to the fact that they occur after the gene
(nucleic acids sequence) has been translated into the corresponding protein
sequence (amino acid chain).16 In addition to the natural variability of
biologics within and between production batches, it is important to remember
that some additional variation can occur as a result of the manufacturing
process.17 Guidance from the US Food and Drug Administration (FDA) on
product comparability has been available since 1996.18 It explains the steps
manufacturers may perform to undergo FDA evaluation to allow them to make
manufacturing changes without conducting additional clinical comparability
studies to demonstrate safety and efficacy. Thus, manufacturers of biologics
perform a variety of comparability studies to help ensure that the new process
delivers a product with a comparable benefit/risk and efficacy profile for the
pre- and postprocess change biotherapeutic.18
Developing a biosimilar is far more complex than manufacturing process
changes and establishing comparability.18 Biosimilar developers establish
independent manufacturing processes and target quality attributes of
acceptable variability to establish biosimilarity based on a thorough
comparison with the reference product.18 Biosimilar manufacturers must
demonstrate a high degree of similarity in analytical and nonclinical studies,
and through clinical studies, demonstrate no clinically meaningful differences
between the proposed biosimilar and the reference biologic.13
6
The goal of biosimilar
development is to help
ensure that a consistent
product is manufactured
that will meet the highly
similar designation with
no clinically meaningful
differences from the
reference biologic in
terms of safety, purity,
and potency.18 To this end,
the regulatory process is
different for biosimilars
compared with small
molecule generics, with
far more rigorous testing
required to gain
regulatory approval.13
The potential of biosimilars
The introduction of biosimilars
into the US health system may
potentially broaden the availability
of effective biologics.1
8
Biosimilars may offer a number of potential benefits to patients, payers, and
health care providers. The potential of biosimilars for patients, payers, and
providers may include providing additional treatment choices at lower cost
to the health care system and increasing access to biologics, which may
lead to better health outcomes overall.1,19,20 Potentially offering a variety
of therapeutic options, biosimilars may also lead to possible savings and
efficiencies to the health care system.1,19,20
The rules for development of biosimilars may also foster innovation.21 The
Biologics Price Competition and Innovation Act (BPCIA) includes provisions
to assure 12 years of marketing exclusivity for reference biologics, as well
as including mechanisms for patent resolutions to mitigate any potential
violations.22 These steps may help to encourage development of new biologics
with unique or improved mechanisms of action.21
9
While biosimilars have the potential to provide additional treatment options
at lower cost, development of biosimilars requires substantial investment.
Development of a biosimilar may take 5 to 9 years at a cost of up to
$135 million, not including regulatory fees.1,21,23,24 A generic version of a
small molecule drug, on the other hand, costs $1 million to $4 million
to develop.25,26 Because the experience with biosimilars is relatively new,
estimates of cost savings may depend on clinical utilization and are quite
variable at this juncture (Table 2).9,27
Table 2. Potential Biosimilar Cost Savings Estimates Are Variable9,27
10
Source
Examples of Estimated Biosimilar Savings
Express Scripts
$250 billion savings possible during 2014-2024 if 11 likeliest
biosimilars enter the United States’ market
IMS
$54 billion to $108 billion in cumulative savings in the EU5
and United States combined over the next 5 years
“Patients and health care providers
will be able to rely upon the safety
and effectiveness of an FDA approved
biosimilar just as they would for the
reference product that the biosimilar
was compared to.”28
—FDA
A known product,
a tailored process
With new biologics being approved and
the expanding use of existing products,
global utilization of innovative biologics
will continue to grow.9
12
In 2015, the FDA acknowledged more than 100 therapeutic biologic products,
with approval dates ranging as far back as 1965 (collagenase) and covering
a range of indications from cosmetics to cancer.29 Biologics have become an
integral part of health care options in the United States and abroad; over
900 vaccines and biologics are currently in clinical development for more
than 100 diseases.30
In 2015, biologics accounted for more than 25% of all novel drug approvals by
the FDA. The number of new biologics being approved has more than doubled
between 2005 and 2015 (Figure 2).31 In 2015, biologics accounted for 7 of
the 15 highest-expenditure drugs.10,32-34
Figure 2. Growth in US new drug approvals: % biologics31
2005
= 10%
2015
>25%
13
According to the Centers for Medicare
& Medicaid Services, prescription
drug spending growth is projected to
average 6.3% annual growth from
2015 through 2024.2
As part of the Affordable Care Act, the BPCIA created the regulatory
framework for an abbreviated approval process for biosimilar products.22 The
act also provides for a 12-year exclusivity period from the date of licensing of
the reference product before approval of any biosimilar may occur. Potential
applications are not accepted or considered until 4 years after approval.22
It is estimated that approximately 100 biologics will lose patent or other
protections by 2021 (Table 3).11
Table 3. Many Biologic Patents Will Expire in the
Coming Years11
Patent Expiry Year
Number of Products
2012 and earlier
26
2013
5
2014
11
2015
14
2016
6
2017
8
2018
3
2019
21
2020
8
2021
9
2022 and later
17
15
Proving biosimilarity
The approval process for biosimilars in the United States is outlined in
Figure 3.13 The FDA has taken a “totality of evidence” approach to evaluating
biosimilar agents.13 All of the data are generated via a stepwise approach.13
Each step of comparative investigation is used to establish that the potential
biosimilar is “highly similar” to the reference product with no clinically
meaningful differences in safety, efficacy, or potency. Demonstration of
biosimilarity includes structural and functional characterization, nonclinical
evaluation, comparative clinical pharmacology PK and PD data, clinical
immunogenicity data, and may also typically include comparative clinical study
data.13 Using multiple state-of-the-art-methods, protein structures can be
extensively characterized so that the reference product and biosimilar can be
directly compared, helping to ensure comparability of both functional integrity
and performance in vivo.18
Figure 3. The Biosimilar Pathway Represents a Paradigm Shift in
Thinking From Standard Biologic and Generic Pathways7,35
Development Pathways7,35
Standard Biologics
Biosimilars
Clinical studies
Comparative
clinical studies
Clinical pharmacology
PK/PD
Bioequivalence
in healthy
volunteers
Comparative
clinical
pharmacology PK/PD
Nonclinical
Analytical
Analytical
Analytical
16
Small Molecule
Generics
Nonclinical
Analytical
Confirm safety profile
and efficacy in a
disease population
(dose ranging not
necessary)
In the development of a reference biologic, the greatest contribution to
clinical predictability resides at the top of the inverted pyramid (left;
Figure 3), where the biologic drug is evaluated in a large number of
patients with the aim of demonstrating superior efficacy versus placebo or
comparator products and an acceptable tolerability profile.36 In contrast
to the inverted pyramid for the reference biologic, the biosimilar development
pathway outlined by the FDA is focused at the bottom of the pyramid at right,
where comprehensive comparisons are made to the reference biologic with
respect to the structure and function of the molecule.13,37 For a biosimilar,
this molecular characterization will provide the foundation for development,
which builds on the clinical experience with the reference biologic.13,18 The
aim of biosimilar drug development is to establish similarity to the reference
product in terms of safety, purity, and potency, using a stepwise approach that
includes analytical, nonclinical, and clinical comparability studies.13
17
Common considerations
with biosimilars
Manufacturing consistency enables
the release of a biosimilar product
into the marketplace and clinic with
quality attributes similar to those
of the original reference product.38
18
HETEROGENEITY OF BIOLOGICS
Biologics are not typically a single molecule entity, but rather a complex mix
of the same protein molecule under various structurally close isoforms. This
results in heterogeneity.16 Potential sources and examples of heterogeneity
include glycosylation, methylation, conformation, substitution, and
oxidation caused by differences in cell type, culture conditions, and external
conditions such as temperature and pH.16 While there may be interbatch
variability due to the intrinsic nature of the biologic manufacturing process,
a product’s quality attributes must remain within an acceptable range.39 FDA
guidance on product comparability evaluates the potential significance of
changes to biologics, which has been available since 1996.18 Manufacturing
processes of biosimilars are designed, developed, and understood through
the science- and risk-based approaches of quality by design.40 Quality by
design uses the full understanding of how product attributes and processes
relate to performance.40 As a result, manufacturing processes can be
monitored and strategies can be implemented that help ensure a consistent
product is made, with its overall quality and attributes maintained
throughout its life cycle.40
MANUFACTURING CONSISTENCY
The manufacturing requirements for a biosimilar are equivalent to any
new biologic entity, ensuring the production of a consistent, high-quality
product.14,18 Biosimilar developers establish independent manufacturing
processes and target quality attributes of acceptable variability to establish
biosimilarity based on a thorough comparison with the reference product.38
The similarity of the biological activity, safety, and efficacy of a biosimilar
product to the reference product must be established based on the totality
of evidence gathered in analytical, nonclinical, and clinical studies.13
Demonstrating biosimilarity to a reference product requires more data
and information than establishing comparability between a post- and
premanufacturing change.18
19
EXTRAPOLATION
Extrapolation is a scientific and regulatory principle that refers to the
approval of a biosimilar for use in an indication held by the reference product
but not directly studied in a comparative clinical trial with a biosimilar.13,38
Once the biosimilar product has met the requirements for approval for a
specific indication, FDA guidance has indicated that the potential exists for
a biosimilar to be licensed for one or more additional conditions of use for
which the reference product is licensed.13 The rationale for extrapolation is
to avoid unnecessary studies in the target population for ethical reasons, for
efficiency, and to allow resources to be allocated to areas where studies may
be more valuable.41 Extrapolation to each additional indication will require
compelling evidence.13 Extrapolation is evaluated based on sufficient scientific
justification.13 Aspects that may be considered for extrapolation may include
mechanism of action in each condition, PK and biodistribution, expected
toxicities, and any other factor (such as comorbidities). Thus, extrapolation is
not automatic and is considered only after biosimilarity is established based
on the totality of evidence.13
Figure 4. Scientific Justification Is Required to Support Extrapolation
to Indications Not Clinically Studied13,42,43
Biosimilar Pathway
Clinical
studies
Clinical
pharmacology
PK/PD
Nonclinical
Extrapolation: extending conclusions from studies in one
patient population to make inferences in another population
Convincing scientific
justification to support
extrapolation to a
reference biologic’s
approved indications
Extrapolated
indications
Analytical
Image adapted from Sherman RE. Biosimilar biological products [biosimilar guidance webinar]. February 15, 2012.
20
IMMUNOGENICITY
A common consideration for all biologics, including biosimilars, is
immunogenicity. Immunogenicity is the ability of a molecule to elicit an
immune response from the host. When a foreign entity enters the body, the
immune system will trigger a response as a way of defending itself against
bacteria, viruses, or other harmful substances. Being proteins, most biologics
have the potential to induce antidrug antibodies (ADA), often resulting in
no clinically relevant consequences.13,44 However, there is the potential for
these antibodies to have clinical consequences.13,44 This reaction can result
in the production of ADA, including neutralizing antibodies, which can lead
to decreased efficacy13,44; ADA may also result in general immune effects,
including allergy, “serum sickness,” or anaphylaxis.13,44 Importantly, there may
be major clinical consequences if cross-neutralizing antibodies are generated
that affect both the biologic product and an endogenous protein with
essential activity.13,44
The potential for immunogenicity is evaluated through the rigorous testing
of the biosimilar during its development. Biosimilars need to demonstrate no
clinically meaningful differences in immunogenicity as compared with the
reference product.13
INTERCHANGEABILITY AND SUBSTITUTION
The FDA mandates that for a biosimilar to be considered interchangeable
with a reference product it must be able to produce the same clinical result
in any given patient and, if the product is administered more than once to an
individual, the risk in terms of safety or diminished efficacy of alternating or
switching between the biosimilar and reference product is not greater than
with continued treatment with the reference product alone.45 Even though
the FDA has indicated that interchangeability is possible, as of November
2016 it has not yet provided detailed guidance on approval requirements.
The designation of interchangeability will require a higher standard than
biosimilarity alone. Substitution is a practice by which an “interchangeable”
biologic is dispensed by a pharmacist to the patient without the prior
informed consent of the treating physician.46 In the United States, while
the FDA defines interchangeability, each state governs its regulation of
substitution; details regarding substitution legislation differ from state
to state.47
21
What’s in a name?
A biosimilar obviously cannot carry the same proprietary brand
name as the reference product. However, the FDA has indicated that
it also is not appropriate for biosimilar and reference products to
share the same nonproprietary name.48 Rather, biosimilars should
include an FDA-designated suffix.48 There is a need to clearly identify
and distinguish biological products that have not been determined
to be interchangeable, for the purposes of safe use and to improve
pharmacovigilance.48 Approved biosimilars, therefore, should have both
names and labels that are readily distinguishable from the reference
product and reflect their unique manufacturing processes
and origins.48,49
The FDA recommends use of a brand name in the label, where feasible
and appropriate, in order to make distinctions between products as clear
as possible.49 In addition to this, a clearly distinguishable nonproprietary
name is necessary to track adverse events related to the specific
biosimilar or reference product, to help ensure appropriate prescribing
and dispensing, and to allow prescriber choice in health care systems
where the nonproprietary name is typically used.48,49
23
Introducing biosimilars
into clinical practice
24
Approved biosimilars should be a potential consideration for all patients
who receive treatment with biologic medications for eligible indications.41
Acceptance by physicians that all qualifying patients can be treated with
biosimilars may potentially facilitate increased access to biologic therapies for
all patients.41
AT THE PHARMACY LEVEL
In the United States, while the FDA defines interchangeability, the states
regulate substitution.47 Many states have considered legislation governing
the substitution of biosimilars. While details vary from state to state, laws
generally have a number of things in common47:
•Substitution is permitted only if the biosimilar has been designated
as interchangeable
•Substitution may be prohibited if the prescribing physician has indicated a
preference for the reference product
•The prescriber must be notified of any substitution made by the pharmacy
Where do we go from here?
Since their introduction more than 30 years ago, biologics have had a
meaningful impact on patient management in multiple disease states.5-8
As demonstrated by their growth in share of total pharmaceutical sales,
there is a strong demand for patient access to innovative biologic therapies.9
Biosimilars are highly similar versions of existing biologic drugs.13 The
introduction of these agents into a variety of markets around the world may
fulfill the promise of providing effective biologics to previously underserved
and undertreated patients, leading to better overall health outcomes.1
With a heritage of bringing innovation to health care, Pfizer is positioned
to help integrate biosimilar medicines into clinical practice. Leveraging
developmental and clinical expertise, Pfizer Biosimilars has 3 marketed
biosimilars outside the United States,50-52 4 monoclonal antibodies in latestage clinical development, and 1 approved biosimilar in the United States.
Pfizer strives to extend its legacy of quality treatment options to patients
in need.53-55
25
Glossary
Biologics: Biologics include a wide range of biological products such as
vaccines, blood and blood components, allergenics, somatic cells, gene
therapy, tissues, and genetically engineered therapeutic proteins. In this
guide, “biologics” refers to genetically engineered proteins produced by
living cells.12
Biologics License Application (BLA): Biological products are approved
for marketing under the provisions of the Public Health Service (PHS)
Act. It requires a firm that manufactures a biologic for sale in interstate
commerce to hold a license for the product. A BLA is a submission that
contains specific information on the manufacturing processes, chemistry,
pharmacology, clinical pharmacology, and the medical effects of the
biologic product. If the information provided meets FDA requirements, the
application is approved and a license is issued allowing the firm to market
the product.12
Biosimilar: Biosimilars are similar to the original biologics. Although it
is impossible to produce an identical copy of any biologic medicine, a
biosimilar must be proven to show no clinically meaningful differences from
an originator medicine.13
Extrapolation: If a product meets FDA requirements for licensure as a
biosimilar based on, among other things, data derived from a clinical study
or studies that demonstrate safety, purity, and potency in one condition of
use, additional conditions of use for which the reference product is licensed
can be considered if the manufacturer provides sufficient scientific evidence
for extrapolating clinical data to support the biosimilarity determination for
each additional condition where licensure is sought.13
Generic drug: A generic drug is the same as a brand-name drug in dosage,
safety, strength, route of administration, quality, performance, and intended
use. Before approving a generic drug product, the FDA requires many rigorous
tests and procedures to assure that the generic drug can be substituted
for the brand-name drug. The FDA bases evaluations of substitutability, or
26
“therapeutic equivalence,” of generic drugs on scientific evaluations. By law,
a generic drug product must contain the identical amounts of the same
active ingredient(s) as the brand-name product. Drug products evaluated as
“therapeutically equivalent” can be expected to have equal effect and no
difference when substituted for the brand-name product.12
Immunogenicity: The ability of a substance to trigger an immune response
or reaction (eg, development of specific antibodies, T-cell response, or
allergic or anaphylactic reaction).56
Interchangeability: To meet the additional standard of interchangeability,
biosimilarity needs to be established first. An “interchangeable” biologic
product must demonstrate that it can be expected to produce the same
clinical result as the reference product in any given patient. In addition,
if the biologic product is administered more than once to an individual,
the risk in terms of safety profile or diminished efficacy of alternating
or switching between the use of the biologic product and the reference
product is not greater than the risk of using the reference product without
such alternation or switch.45
Pharmacovigilance: The science and activities relating to the detection,
assessment, understanding, and prevention of adverse effects or any other
drug-related problems.56
Reference product: Reference product means the single biological product
licensed under section 351(a) of the PHS Act against which a biological
product is evaluated in a 351(k) application.13
Small molecule drugs: Small molecule drugs are usually chemically
synthesized with a fixed, known structure having a molecular weight of
less than 1000 daltons, and typically between 300 and 700 daltons. For
reference, aspirin is 180 daltons and paclitaxel is 854 daltons.57
27
References
1. Henry D, Taylor C. Pharmacoeconomics of cancer therapies: considerations with the introduction
of biosimilars. Semin Oncol. 2014;41(suppl 3):S13-S20.
2. Centers for Medicare & Medicaid Services. National Health Expenditure Projections 2014-2024.
https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and Reports/
NationalHealthExpendData/NationalHealthAccountsProjected.html. Last updated: July 30, 2015.
Accessed April 21, 2016.
3. US Food and Drug Administration. Novel Drugs 2015. January 2016 Summary. http://www.fda.
gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm. Accessed November 10,
2016.
4. Stanton MW, Rutherford MK. Reducing costs in the health care system: learning from what
has been done. Rockville, MD: Agency for Healthcare Research and Quality. Research in Action.
2002;9. AHRQ Pub. No. 02-0046. http://archive.ahrq.gov/research/findings/factsheets/costs/
costria/costsria.pdf. Accessed April 21, 2016.
5. Junod SW. Celebrating a milestone: FDA’s approval of first genetically-engineered
product. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/
SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm081964.htm. Last updated: April 10, 2009.
Accessed April 11, 2016.
6. Kinch MS. An overview of FDA-approved biologics medicines. Drug Discov Today. 2015;20(4):393398.
7. Ryan AM. Frontiers in nonclinical drug development: biosimilars. Vet Pathol. 2015;52(2):419-426.
8. Kozlowski S, Woodcock J, Midthun K, Behrman Sherman R. Developing the nation’s biosimilars
program. N Engl J Med. 2011;365(5):385-388.
9. Delivering on the Potential of Biosimilar Medicines: The Role of Functioning Competitive Markets.
Parsippany, NJ: IMS Institute for Healthcare Informatics; March 2016. https://www.imshealth.
com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_
Brief_March_2016.pdf. Accessed April 11, 2016.
10.IMS Institute for Healthcare Informatics. Medicines Use and Spending in the US: A Review of 2015
and Outlook to 2020. April 2016. Parsippany, NJ: IMS Health Incorporated; 2016.
11. Thayer AM. The new copycats. Chem Eng News. 2013;91(40):15-23. http://cen.acs.org/content/
dam/cen/91/40/09140-cover.pdf. Accessed May 3, 2016.
12.US Food and Drug Administration. Drugs@FDA Glossary of Terms. http://www.fda.gov/drugs/
informationondrugs/ucm079436.htm. Last updated: February 2, 2012. Accessed April 14, 2016.
13.US Food and Drug Administration. Guidance for Industry: Scientific Considerations in
Demonstrating Biosimilarity to a Reference Product. Silver Spring, MD: FDA; 2015.
14.Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19(3):411419.
15.Nowicki M. Basic facts about biosimilars. Kidney Blood Press Res. 2007;30(5):267-272.
16.Ho K, Trouvin JH. Biologicals’ characteristics. In: Prugnaud JL, Trouvin JH, eds. Biosimilars: A New
Generation of Biologics. Paris: Springer-Verlag Paris; 2013:1-22.
28
17.Pavlovic M, Prugnaud JL. From the biosimilar concept to the marketing authorisation. In:
Prugnaud JL, Trouvin JH, eds. Biosimilars: A New Generation of Biologics. Paris: Springer-Verlag
Paris; 2013:23-36.
18.US Food and Drug Administration. Guidance for Industry: Quality Considerations in Demonstrating
Biosimilarity of a Therapeutic Protein Product to a Reference Product. Silver Spring, MD: FDA; 2015.
19.Strober BE, Armour K, Romiti R, et al. Biopharmaceuticals and biosimilars in psoriasis: what the
dermatologist needs to know. J Am Acad Dermatol. 2012;66(2):317-322.
20.Scheinberg MA, Kay J. The advent of biosimilar therapies in rheumatology—“O brave new world.”
Nat Rev Rheumatol. 2012;8(7):430-436.
21.Blackstone EA, Fuhr JP. The economics of biosimilars. Am Health Drug Benefits. 2013;6(8):469-478.
22.US Congress. Biologics Price Competition and Innovation Act of 2009, Title VII, Subtitle A, § 70017003 of the Patient Protection and Affordable Care Act, Public Law 111-148, 124 Stat.119, 804-21
(2010).
23.Pharmaceutical Research and Manufacturers of America. Drug Discovery and Development:
Understanding the R&D Process. Washington, DC: PhRMA; 2007.
24.Generics and Biosimilars Initiative. GaBI Online. Development of biosimilars. http://www.
gabionline.net/Biosimilars/Research/Development-of-biosimilars. Posted: July 1, 2011. Accessed
January 3, 2016.
25.Grabowski H, Cockburn I, Long G. The market for follow-on biologics: how will it evolve? Health
Aff (Millwood). 2006;25(5):1291-1301.
26.IMS Health. Shaping the Biosimilars Opportunity: A Global Perspective on the Evolving Biosimilars
Landscape. London, UK: IMS Health Incorporated; December 2011.
27.Miller S. The $250 billion potential of biosimilars. St. Louis, MO: Express Scripts; April 23, 2013.
http://lab.express-scripts.com/insights/industry-updates/the-$250-billion-potential-ofbiosimilars.
Accessed December 30, 2015.
28.US Food and Drug Administration. Information for Consumers (Biosimilars). http://www.fda.gov/
drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/
therapeuticbiologicapplications/biosimilars/ucm241718.htm. Updated: August 27, 2015. Accessed
October 15, 2016.
29.US Food and Drug Administration. CDER Therapeutic Biologic Products: CDER Billable Biologic
Product List. http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/
UCM164641.pdf. Last updated: September 2015. Accessed April 12, 2016.
30.Pharmaceutical Research and Manufacturers of America. 2013 Report: Medicines in Development—
Biologics. Washington, DC: Pharmaceutical Research and Manufacturers of America; 2013. http://
phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf. Accessed April 12, 2016.
31.Serebrov M. Biologics’ share of medicine chest grows, and so do pricing concerns. BioWorld.
January 8, 2016. www.bioworld.com/content/biologics-share-medicine-chest-grows-and-sodopricing-concerns. Accessed May 17, 2016.
32.Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the
Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25.
29
References (cont)
33.Hwang HG, Kim KJ, Lee SH, et al. Recombinant glargine insulin production process using
Escherichia coli. J Microbiol Biotechnol. 2016;26(10):1781-1789.
34.Ghidini M, Hahne JC, Trevisani F, et al. New developments in the treatment of chemotherapyinduced neutropenia: focus on balugrastim. Ther Clin Risk Manag. 2016;12:1009-1015.
35.US Food and Drug Administration. Abbreviated New Drug Applications (ANDA): Generics.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/
ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/. Updated August 4, 2016.
Accessed October 17, 2016.
36.Kingham R, Klasa G, Carver KH. Key regulatory guidelines for the development of biologics in the
United States and Europe. In: Wang W, Singh M, eds. Biological Drug Products: Development and
Strategies. 1st ed. Hoboken, NJ: John Wiley & Sons, Inc. 2014:75-109.
37.Schneider CK, Vleminckx C, Gravanis I, et al. Setting the stage for biosimilar monoclonal
antibodies. Nat Biotechnol. 2012;30(12):1179-1185.
38.Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of
extrapolation. Blood. 2014;124(22):3191-3196.
39.Schiestl M, Stangler T, Torella CM, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality
attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310-312.
40.Winkle HN. Implementing quality by design. Presented at: PDA/FDA Joint Regulatory Conference.
Evolution of the Global Regulatory Environment: A Practical Approach to Change; September 24,
2007. http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103453.pdf. Accessed
January 18, 2016.
41.Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians should know. Blood. 2012;
120(26):5111-5117.
42.European Medicines Agency. Concept Paper on Extrapolation of Efficacy and Safety Profile in
Medicine Development [final]. London, UK: EMA; 2013. EMA/129698/2012.
43.Sherman RE. Biosimilar biological products [biosimilar guidance webinar]. February
15, 2012. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/
Biosimilars/ucm292463.pdf. Accessed January 4, 2016.
44.Kessler M, Goldsmith D, Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial
Transplant. 2006;21(suppl 5):v9-v12.
45.US Food and Drug Administration (FDA). Guidance for Industry: Biosimilars: Questions and Answers
Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. Silver
Spring, MD: FDA; 2015.
30
46.US Food and Drug Administration (FDA). Information on Biosimilars. http://www.fda.gov/Drugs/
DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/
TherapeuticBiologicApplications/Biosimilars/. Updated May 10, 2016. Accessed October 17, 2016.
47.National Conference of State Legislatures. State Laws and Legislation Related to Biologic
Medications and Substitution of Biosimilars. http://www.ncsl.org/research/health/state-lawsandlegislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed
July 14, 2016.
48.US Food and Drug Administration. Guidance for Industry: Nonproprietary Naming of Biological
Products. Silver Spring, MD: FDA; 2015.
49.US Food and Drug Administration. Guidance for Industry: Labeling for Biosimilar Products. Silver
Spring, MD: FDA; 2016.
50.European Medicines Agency. European public assessment report. London: ©European
Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/
medicines/000872/human_med_001031.jsp&mid=WC0b01ac058001d124. Updated July 8, 2016.
Accessed November 11, 2016.
51.European Medicines Agency. European public assessment report. London: ©European
Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/
medicines/001142/human_med_001344.jsp&mid=WC0b01ac058001d124. Updated October 26,
2016. Accessed November 11, 2016.
52.European Medicines Agency. European public assessment report. London: ©European
Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/
medicines/002778/human_med_001677.jsp&mid=WC0b01ac058001d124. Updated September 21,
2016. Accessed November 11, 2016.
53.Data on file. Pfizer Inc, New York, NY.
54.Pfizer 2015 Annual Review. Manufacturing and Supply Chain. https://www.pfizer.com/files/
investors/financial_reports/annual_reports/2015/manufacturing-and-supply-chain.htm. Accessed
July 20, 2016.
55.Pfizer Inc. Pfizer Pipeline. August 2, 2016. http://www.pfizer.com/sites/default/files/
productpipeline/Product_Pipeline_Update_.pdf. Accessed October 24, 2016.
56.World Health Organization. Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs).
Geneva, Switzerland: WHO; October 2009. http://www.who.int/biologicals/areas/biological_
therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf?ua=1. Accessed April 14, 2016.
57.Dranitsaris G, Dorward K, Hatzimichael E, et al. Clinical trial design in biosimilar drug
development. Invest New Drugs. 2013;31(2):479-487.
31
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