690743

research-article2017
AOPXXX10.1177/1060028017690743Annals of PharmacotherapyStevenson et al

Review Article
Annals of Pharmacotherapy

Biosimilars: Practical Considerations

1­–13
© The Author(s) 2017
Reprints and permissions:
for Pharmacists sagepub.com/journalsPermissions.nav
DOI: 10.1177/1060028017690743
https://doi.org/10.1177/1060028017690743
journals.sagepub.com/home/aop

James G. Stevenson, PharmD1,2, Robert Popovian, PharmD3,

Ira Jacobs, MD4, Susan Hurst, RPh, PhD5, and Lesley G. Shane, PharmD6

Abstract
Objective: To review the scientific and regulatory aspects of biosimilar development and practical considerations for the
use of biosimilars that are relevant to pharmacists. Data Sources: Literature searches of PubMed and congress abstracts
for publications pertaining to biosimilars were conducted from January 2016 to January 2017. Individual drug company web
pages and governmental, regulatory, and other agency websites were also reviewed. Study Selection/Data Extraction:
Published articles, regulatory guidelines, and other sources covering biologic/biosimilar development and approval,
reporting results of biosimilar studies or survey research, and/or identifying biosimilars in development or approved for use
in Europe or the United States were reviewed and included. Data Synthesis: Biologic therapies have revolutionized the
treatment of serious diseases, including hematological or autoimmune disorders and cancers. A biosimilar is highly similar
to a licensed biologic (ie, reference or originator) and has no clinically meaningful differences in safety, purity, and potency.
Unlike small-molecule drugs, biologics are large, complex proteins that cannot be exactly replicated, so the concept
of a generic equivalent cannot be applied to biologics. Regulatory agencies have provided a framework for biosimilar
approval, but there are many practical considerations for pharmacists, including interchangeability, substitution, naming,
indication extrapolation, product labeling, therapeutic drug monitoring, manufacturer attributes, logistics of product use,
and reimbursement. Conclusions: Pharmacists will play a key role in managing the introduction of biosimilars into health
care systems. Understanding the principles of biosimilar development and evolving regulatory guidelines relevant to their
use will allow pharmacists to make informed decisions regarding formulary inclusion and educate patients and other health
care providers about biosimilars.

Keywords
biotechnology, legal/regulatory issues, formulary, clinical practice, postmarketing surveillance

Introduction evidence generated during biosimilar development and

Biologic therapies have revolutionized treatment of patients
with serious diseases, such as hematological (eg, anemia,
hemophilia) or autoimmune (eg, rheumatoid arthritis [RA],
Crohn’s disease) disorders and cancers. As patents or data
protection for many biologics expire,1 biosimilar agents
will become available that offer additional options and may
address the unmet need for broader access to biologic thera-
pies. A biosimilar is a biologic product that is highly similar
to and shows no clinically meaningful differences from a
licensed biologic (ie, reference or originator) in terms of
safety, purity, and potency.2-5 Unlike traditional pharmaceu-
tical or small-molecule agents, biologics have large, com-
plex, and heterogeneous structures that are difficult to fully
characterize and impossible to replicate exactly.6-10
Therefore, the concept of a generic equivalent cannot be
applied to biologics,2 and biosimilar approval pathways
must consider the degree of similarity between a proposed
biosimilar and reference product based on the totality of the
robustness in the biosimilar manufacturing process.2-5
The biosimilar market is expanding, and pharmacists will
help manage the introduction of biosimilars into health care
systems. Understanding the scientific principles of biosimi-
lar development and requirements for biosimilar approval
will allow pharmacists to make informed decisions about
1
College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
2
Hospital & Health Systems Services, Visante Inc, St. Paul, MN, USA
3
US Government Relations, Pfizer Inc, Washington, DC, USA
4
Oncology Biosimilars, Pfizer Inc, New York, NY, USA
5
Development Strategies Group in the Pharmacokinetics, Dynamics, and
Metabolism Department, Pfizer Inc, Groton, CT, USA
6
Outcomes and Evidence, Global Health and Value, Pfizer Inc, New
York, NY, USA
Corresponding Author:
James G. Stevenson, Department of Clinical Pharmacy, College of
Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109-
1065, USA.
Email: jimsteve@med.umich.edu
2 Annals of Pharmacotherapy 
Aspirin
180 Da
Small-molecule drugs
1000 Da
Figure 1.  Biologics are larger and more complex than small-molecule drugs.
Abbreviation: Da, Dalton.
product safety and efficacy during formulary review. It will
also help them educate patients and other health care provid-
ers about biosimilars. This review provides an overview of
biosimilars and discusses practical considerations for their
use that are relevant to pharmacists.
Data Sources and Selection
Searches of PubMed and congress abstracts for literature
pertaining to biosimilars were performed from January 2016
through January 2017 using terms that included biosimilar(s),
interchangeability, naming, substitution, labeling, extrapo-
lation, and reimbursement. Relevant English-language pub-
lications were selected and included. Additional information
about biologic/biosimilar development and approval was
obtained from drug regulatory, governmental, and other (eg,
World Health Organization [WHO]) agency websites.
Biosimilars in development and those authorized in Europe
or licensed in the United States were identified from drug
regulatory, drug company, and/or other authoritative (eg,
Generics and Biosimilars Initiative) websites.
Biologics Versus Traditional
Pharmaceutical Agents
Traditional pharmaceutical agents are small-molecule drugs
that are manufactured through standard chemical synthesis
Monoclonal Antibody
~150,000 Da
Biologics
and have simple, well-defined structures (Figure 1).6-10 In
contrast, biologics are large, complex proteins that are pro-
duced in living systems.6-10 Their primary structure is an
amino acid chain, which is folded into patterns that estab-
lish secondary structure and create a unique 3-dimensional
shape difficult to fully characterize.
Compared with chemical synthesis, biological reactions are
inherently variable and yield heterogeneous products that are
also highly sensitive to their manufacturing and handling con-
ditions.6-10 Changes in the production process (eg, cell culture,
protein recovery and purification, formulation, storage, or
packaging) may lead to variations in primary amino acid
sequence or posttranslational modifications (eg, glycosylation)
that could disrupt higher-order structure and, therefore, the bio-
logical properties of the protein.6-14 For instance, glycosylation
can potentially influence biologic activity directly by altering
effector functions or indirectly by prolonging or shortening
half-life.7,11,15-19 Other chemical modifications (eg, oxidation
or deamidation) may occur that promote degradation or dena-
turation and the formation of protein aggregates that have little
or no drug activity and can contribute to the higher potential
for immunogenicity with biologics versus small-molecule
drugs.6,7,12,14,20 Although rare, the presence of antidrug antibod-
ies (ADAs) may cause allergy, anaphylaxis, and serum sick-
ness or loss of efficacy6,20; therefore, immunogenicity and
product safety must be assessed in clinical studies and moni-
tored through postmarketing pharmacovigilance.
Stevenson et al 3
The manufacturing process for a licensed biologic is
legally patented and protected by law; thus, biosimilar
manufacturers must independently develop their own pro-
duction processes to create biologic products that are
highly similar to reference products. Methodological dif-
ferences between the development of reference and bio-
similar products may result in structural and functional
differences. The potential impact of this heterogeneity on
drug safety and efficacy must be evaluated when seeking
biosimilar approval.
Overview of Regulatory Approval for
Biosimilars
Biosimilar approval is based on a demonstration of biosimi-
larity, which confirms that the biosimilar product is highly
similar to and has no clinically meaningful differences in
safety, purity, and potency from the reference product.2,3,5 A
determination of biosimilarity is based on the totality of the
evidence generated during biosimilar development, which
follows a stepwise approach and begins with extensive
structural and functional characterization.2,3,5 To be consid-
ered for clinical development, a proposed biosimilar must
have the same primary amino acid sequence as and be
highly similar to the reference product in terms of higher-
order structures, posttranslational modifications, isoform
profile, and product purity.2,3,5 The proposed biosimilar
should also demonstrate biologic activity that is highly sim-
ilar to and dependent on the same mechanism(s) of action as
the reference product.2,3,5
After demonstrating analytical and functional similarity
to the reference product, nonclinical pharmacokinetic and
pharmacodynamics studies are conducted to address
remaining uncertainties.2,3,5,21 Animal toxicity studies,
where applicable, should demonstrate high similarity
between the proposed biosimilar and reference product in
terms of drug exposure and response and may include
immunogenicity assessments to support the interpretation
of nonclinical results.2,3,21 Finally, comparative clinical
studies are conducted to demonstrate pharmacological
(pharmacokinetic/pharmacodynamics) and clinical (safety,
efficacy, and immunogenicity) similarity to the reference
product.2,3,5,21,23
Considerations for the evaluation of biosimilars (eg,
quality and manufacturing, nonclinical and clinical assess-
ments) are similar across European Medicines Agency
(EMA) and Food and Drug Administration (FDA) guide-
lines; however, there are some differences.2,3,5,13,21-23 For
instance, EMA outlines additional, product-specific require-
ments, based on biologic classification. In contrast, FDA
uses a risk-based approach to evaluate the totality of the
evidence from all stages of development and determines
product requirements for biosimilar approval on a case-by-
case basis.3
In the United States, small-molecule drugs are approved
under the Food, Drug, and Cosmetic Act (FDCA) either as
new drugs following section 505(b) or as generic drugs fol-
lowing section 505(j), which was added by the Hatch-
Waxman Act of 1984.24 In contrast, biologics are approved
under the Public Health Service Act (PHSA) either as new
biologics following section 351(a) or as biosimilar biolog-
ics following section 351(k), which was established by the
Biologics Price Competition and Innovation (BPCI) Act of
2009.4,25
Each pathway has different requirements for regulatory
approval. Compared with a new biologic license applica-
tion, the biosimilar drug application places greater empha-
sis on findings from analytical assessments.3,4 This approach
reduces unnecessary testing and provides the rationale for
abbreviated, comparative, nonclinical and clinical pharma-
cokinetics studies and confirmatory efficacy trials.2,3,5 In
contrast, regulatory approval for small-molecule generic
drugs is based on a demonstration of therapeutic equiva-
lence (ie, pharmaceutical equivalence and bioequivalence).
Once established, the safety and efficacy of a small-mole-
cule generic drug can be inferred from its brand-name coun-
terpart, thus eliminating a need for clinical testing.26
Some biologics approved as biosimilars by the EMA
have been approved by the FDA through alternate regula-
tory pathways, meaning they are not classified as biosimi-
lars in the United States.27 For instance, the FDA approved
nonoriginator low-molecular-weight heparin and insulin
products as well as human growth hormones either as
generic drugs under section 505(j) or as new drugs via sec-
tion 505(b) of the FDCA.28-30 A provision of the BPCI Act
requires all biologic products previously approved under
the FDCA to be regulated as biologics under the PHSA as of
March 2020.4,31 The FDA issued draft guidance on its
approach to implementing this provision and may reclassify
such biologics as biosimilars.31 Another example is the
granulocyte colony-stimulating factor (G-CSF) tbo-filgras-
tim, which was approved in the United States using a full
biologics license application, prior to the BPCI Act.32
However, this agent was approved by the EMA as a filgras-
tim biosimilar of Neupogen (Amgen) and marketed under
the trade name Tevagrastim in Europe.
Biosimilars must not be confused with noncomparable
biotherapeutic products (ie, intended copies). Intended cop-
ies have been introduced in some countries as biosimilars
but are not truly biosimilars because they have not met
EMA, FDA, or WHO requirements of biosimilarity.33-35
Because the quality and clinical profiles of intended copies
have not been characterized, there is an increased potential
risk to patient safety and drug efficacy. Finally, biologic
products that have been altered (structurally and/or function-
ally) to achieve improved efficacy and/or safety over the
originator biologic cannot be classified as biosimilars.36,37
An example may be the recombinant chimeric monoclonal
4 Annals of Pharmacotherapy 
antibody CMAB009 because there is evidence for an
improved safety profile for CMAB009 versus its reference
product, cetuximab.38
Practical Considerations for the Use
of Biosimilars That Are Relevant to
Pharmacists
Since publishing its first biosimilar guideline in 2005, the
EMA has granted marketing authorization approval for 26
biosimilar agents within the product classes of low-molecu-
lar-weight heparin, insulin, human growth hormone, G-CSF,
erythropoiesis-stimulating agents, follicle-stimulating hor-
mone, and tumor necrosis factor inhibitors (Table 1).39-42 Of
these, marketing authorization approval was voluntarily
withdrawn for 2 because of commercial reasons43,44; there-
fore, to date, 24 biosimilars are marketed in Europe.
Additional biosimilar applications are under evaluation by
the EMA, including applications for insulin glargine and
insulin lispro, pegfilgrastim, etanercept, adalimumab, ritux-
imab, and trastuzumab.45
Four biosimilars are currently approved in the United
States: Zarxio (filgrastim-sndz), a biosimilar of Neupogen
(filgrastim); Inflectra (infliximab-dyyb), a biosimilar of
Remicade (infliximab); Erelzi (etanercept-szzs), a biosimi-
lar of Enbrel (etanercept); and Amjevita (adalimumab-atto),
a biosimilar of Humira (adalimumab).46-49 Additional bio-
similars are under review by the FDA (Table 2),50-58 and
many more are in research and development (Table 3). As
more agents gain regulatory approval, the biosimilars mar-
ket will expand and pharmacists will play an important role
in their formulary evaluation, dispensing, and postmarket-
ing surveillance and monitoring. Regulatory agencies have
provided a framework for biosimilar approval. However,
the review process is evolving, and there are several practi-
cal considerations for pharmacists, including interchange-
ability, substitution, naming, indication extrapolation,
product labeling, therapeutic drug monitoring (TDM), man-
ufacturer attributes, and logistics of product use as well as
reimbursement.8,59-61
Interchangeability and Biosimilar Substitution
A provision of the BPCI Act created a second level of
approval that goes beyond biosimilarity, called interchange-
ability.4 Interchangeability is intended to mean that the bio-
similar product “can be expected to produce the same
clinical result as the reference product in any given patient”;
furthermore, the risk to efficacy or safety with alternating or
switching between the 2 products is not greater versus con-
sistent use of the reference product.4 Under the BPCI Act,
interchangeability status may be granted by the FDA; fur-
thermore, a 1-year exclusivity period will be granted to
the first biosimilar of a reference product that receives
interchangeable designation.4 In contrast, in Europe, indi-
vidual member states, not the EMA, determine interchange-
ability status.5,62
In January 2017, the FDA issued draft guidance for dem-
onstrating interchangeability.63 Similar to the overall pro-
cess for biosimilar approval, the agency will consider the
totality of the evidence when evaluating proposed inter-
changeable products and recommends a stepwise approach
for generating data to support a demonstration of inter-
changeability.63 The data and information that is required
may depend on and be influenced by product complexity,
the extent of comparative and functional characterization,
and product-specific immunogencity risk. For products that
demonstrate meaningful fingerprint-like analytical similar-
ity to the reference product, and have low structural and
functional complexity, and low immunogencity risk, data
from a switching study(ies) may be sufficient to support a
demonstration of interchangeability.63 In contrast, for prod-
ucts that are highly similar but do not demonstrate meaning-
ful fingerprint-like analytical similarity to the reference
product, and that have high structural and functional com-
plexity, and high immunogenicity risk postmarketing data
for the product as a licensed biosimilar may also be needed.63
In other cases, data from a switching study may not be
needed, i.e., for products that are intended to be adminis-
tered only once, but this decision should be justified.63
A switching study(ies) should include at least 2 alternat-
ing exposures (switch intervals) to the proposed inter-
changeable product and to the reference product.63 The
design and analysis of switching studies should also con-
sider how the proposed interchangeable product will be
used in clinical practice to guide selection of an appropriate
study population, calculate sample size, and determine the
number and duration of switches.63 Primary study endpoints
should include those which are most sensitive to detecting
changes in immunogenicity and/or exposure that may result
from alternating or switching, i.e., clinical pharmacokinet-
ics and pharmacodynamics (if available).63 Draft guidance
also recommends choosing an indication that would support
interchangeable approval for use in an indication(s) that
was not directly compared to the licensed biologic in a com-
parative clinical trial but for which the reference product is
approved (i.e., extrapolation).63
None of the biosimilars approved in the United States
has received interchangeable designation. However, clini-
cal trials have been conducted or are in progress to evaluate
the efficacy and safety of switching between a biosimilar
and reference product.64-67 A comparative clinical trial
(PIONEER; NCT01519700) in patients with breast cancer
treated with myelosuppressive chemotherapy showed no
increased risk to safety or loss of efficacy with switching
between filgrastim (Neupogen) and filgrastim-sndz (Zarxio)
versus consistent use of either product.64 Other comparative
clinical trials have adopted this crossover design to evaluate
Stevenson et al 5

Table 1.  Biosimilar Development in Europe.

Year of Market
Reference, Brand Name Authorization,
Product Class Biosimilar (Manufacturer) (INN) Status Withdrawal, or Refusal
low-molecular- Inhixa (Shenzhen Techdow Clexane (enoxaparin Authorized 2016
weight heparin Pharmaceutical Co, Ltd) sodium)
  Thorinane (Shenzhen Techdow Clexane (enoxaparin Authorized 2016
Pharmaceutical Co, Ltd) sodium)
Insulin Abasaglar (Lilly del Caribe, Inc; Eli Lantus (insulin glargine) Authorized 2014
Lily and Company)
Lusduna (Merck Sharp & Dohme Lantus (insulin glargine) Authorized 2017
Corp)
Solumarv (Marvel Lifesciences Humulin S (human insulin) Refuseda 2015
Ltd; BIOTON Sp)
Human growth Omnitrope (Sandoz GmbH) Genotropin (somatropin) Authorized 2006
hormone Valtropin (LG Life Sciences Ltd) Humatrope (somatropin) Withdrawnb 2012
G-CSF Accofil (Intas Pharmaceuticals Neupogen (filgrastim) Authorized 2014
Ltd)
Biograstim (SICOR Biotech UAB) Neupogen (filgrastim) Authorized 2008
Filgrastim Hexal (Sandoz GmbH) Neupogen (filgrastim) Authorized 2009
Filgrastim ratiopharm (SICOR Neupogen (filgrastim) Withdrawnb 2011
Biotech UAB)
Grastofil (Intas Pharmaceuticals Neupogen (filgrastim) Authorized 2013
Ltd)
Nivestim (Hospira Zagreb) Neupogen (filgrastim) Authorized 2010
Ratiograstim (SICOR Biotech Neupogen (filgrastim) Authorized 2008
UAB)
Tevagrastim (SICOR Biotech Neupogen (filgrastim) Authorized 2008
UAB)
Zarzio (Sandoz GmbH) Neupogen (filgrastim) Authorized 2009
Erythropoiesis- Abseamed (Rentschler Eprex/Erypo (epoetin alfa) Authorized 2007
stimulating Biotechnologie GmbH; Lek
agents Pharmaceuticals d.d.)
Binocrit (Rentschler Eprex/Erypo (epoetin alfa) Authorized 2007
Biotechnologie GmbH; Lek
Pharmaceuticals d.d.)
Epoetin Alfa Hexal (Rentschler Eprex/Erypo (epoetin alfa) Authorized 2007
Biotechnologie GmbH; Lek
Pharmaceuticals d.d.)
Retacrit (Norbitec GmbH) Eprex/Erypo (epoetin alfa) Authorized 2007
Silapo (Norbitec GmbH) Eprex/Erypo (epoetin alfa) Authorized 2007
Follicle- Bemfola (Polymun Scientific GONAL-f (follitropin alfa) Authorized 2014
stimulating Immunbiologische Forschung
hormone GmbH)
Ovaleap (Merckle Biotec GmbH) GONAL-f (follitropin alfa) Authorized 2013
TNF inhibitors Benepali (Biogen [Denmark] Enbrel (etanercept) Authorized 2016
Manufacturing ApS)
Flixabi (Biogen [Denmark] Remicade (infliximab) Authorized 2016
Manufacturing ApS)
Inflectra (Celltrion Inc) Remicade (infliximab) Authorized 2013
Remsima (Celltrion Inc) Remicade (infliximab) Authorized 2013
Interferon-α Alpheon (LG Life Sciences, Ltd) Roferon-A (interferon Refuseda 2006
alfa-2a)

Abbreviations: G-CSF, granulocyte colony-stimulating factor; INN, international nonproprietary name; TNF, tumor necrosis factor.
a
Market authorization was refused because of concerns related to product quality and manufacturing.41,42
b
Market authorization was voluntarily withdrawn for commercial reasons.43,44
6 Annals of Pharmacotherapy 
Table 2.  Biosimilar Biologics License Applications Submitted to the FDA.
Proposed Biosimilar
Product Class (Manufacturer)
G-CSF Grastofil (Apotex/Intas
Pharmaceuticals Ltd)50
Biosimilar pegfilgrastim (Apotex/
Intas Pharmaceuticals Ltd)51
CHS-1701 (Coherus
BioSciences)52
LA-EP2006 (Sandoz)53
Erythropoiesis- Retacrit (Hospira)55
stimulating agents
TNF inhibitors BI695501 (Boehringer
Ingelheim)56
  SB2 (Merck/Samsung Bioepis Co,
Ltd)57
HER2 inhibitors Myl-1401O (Mylan/Biocon)58
Abbreviations: FDA, Food and Drug Administration; G-CSF, granulocyte colony-stimulating factor; HER2, human epidermal growth factor receptor 2;
INN, international nonproprietary name; TNF, tumor necrosis factor.
a
Application rejected by the FDA, July 2016.54
switching from infliximab (Remicade) to CT-P13
(Remsima, Inflectra) in patients with autoimmune or
chronic inflammatory disorders.65-67 The PLANETRA
extension study (NCT01571219) in patients with RA and
PLANETAS extension study (NCT01571206) in patients
with ankylosing spondylitis demonstrated similar efficacy
and tolerability for switching from infliximab to CT-P13
versus continued treatment with CT-P13.66,67 Furthermore,
initial results from the ongoing NOR-SWITCH study
(NCT02148640) in patients with RA, spondyloarthritis,
psoriatic arthritis, ulcerative colitis, Crohn’s disease, and
chronic plaque psoriasis demonstrated noninferior efficacy
and similar safety and immunogenicity profiles for switch-
ing from infliximab to CT-P13 versus continued treatment
with infliximab.65
Interchangeable designation may permit substitution of
biosimilars for the originator without intervention of the
prescriber; however, both US and EU substitution policies
are determined by (member) state laws, not by the FDA or
EMA.5,62 To ensure efficacy and safety, each US state or
European country should evaluate the applicability of tradi-
tional pharmacy laws to interchangeable biosimilar substi-
tution, especially those pertaining to the recording of
substitutions. This is important because failure to record
interchangeable biosimilar substitutions could result in
misattribution of AEs to reference biologics.
At the time of this publication, 25 US states and Puerto
Rico have enacted laws regarding interchangeable biosimi-
lar substitution.68 State legislation varies, but typically
requires FDA approval of a product as interchangeable. In
most states, pharmacists must notify prescribers and
patients and retain records of interchangeable biosimilar
Reference, Brand Name (INN) Filing Status With the FDA
Neupogen (filgrastim) Accepted for review, February
2015
Neulasta (pegfilgrastim) Accepted for review, December
2014
Neulasta (pegfilgrastim) Accepted for review, October
2016
Neulasta (pegfilgrastim) Accepted for review, last quarter
2015a
Epogen/Procrit (epoetin alfa) Submitted January 2015
Humira (adalimumab) Accepted for review, January
2017
Remicade (infliximab) Accepted for review, May 2016
Herceptin (trastuzumab) November 2016
substitutions. Entry of the specific product administered to
the patient into an electronic records system (eg, electronic
medical record, pharmacy benefit management system)
would be sufficient for meeting the prescriber notification
and records standards. In some cases, state law requires
patient consent prior to interchangeable biosimilar substi-
tution. Pharmacists may also be required to explain treat-
ment costs and, in some states (eg, Georgia, Illinois, North
Carolina, and Texas), must dispense the lowest retail priced
interchangeable biologic product that is in stock. Immunity
may be provided for pharmacists who perform substitu-
tions in compliance with state law on biologics. However,
prescribers may block substitution by indicating “dispense
as written” or “brand medically necessary.” Finally, indi-
vidual states may be required to maintain a public or web-
based list of permissible interchangeable products. The
Purple Book provides a listing of all originator, biosimilar,
and interchangeable biosimilar products approved by the
FDA.69 It also includes information regarding a biologic’s
licensure pathway and exclusivity status. This resource
will enable pharmacists to quickly identify interchangeable
biosimilars.
Naming
A consensus on whether a biosimilar should have an inter-
national nonproprietary name (INN) distinct from or shared
with its reference product is lacking. Distinct INNs for bio-
similar and reference products would facilitate pharmaco-
vigilance and product tracking and reduce the possibility of
inappropriate or inadvertent product switching that may
occur if products share a single INN. However, it may also
Stevenson et al 7

Table 3.  Proposed Biosimilar Products in Development With previously licensed.72 The first biosimilar approved in the
Registered Phase III Clinical Trials.a United States, Zarxio, was assigned an INN that included a
Active Substance Biosimilar Manufacturer suffix tied to the manufacturer name: filgrastim-sndz. While
this may have set a precedent for using a meaningful suffix,
Filgrastim MK-4214 Merck it should be noted that filgrastim-sndz was designated a
Epoetin alfa Apo-EPO Apotex “placeholder nonproprietary name” for Zarxio, and its
HX575 Sandoz approval preceded FDA guidance for nonproprietary nam-
Adalimumab BCD-057 Biocad ing of biological products.46 Nonproprietary naming of bio-
CHS-1420 Coherus similars subsequently approved in the United States
FKB327 Fujifilm/Kyowa Hakko
followed current FDA guidance in that all products contain
Kirin
a suffix devoid of meaning: Inflectra (infliximab-dyyb),
GP2017 Sandoz
M923 Momenta Pharmaceuticals/
Erelzi (etanercept-szzs), and Amjevita (adalimumab-atto).
Baxalta The naming convention for interchangeable biosimilar
MSB11022 Merck KGaA products (ie, suffix that is distinct from or shared with its
ONS-3010 Oncobiologics/Viropro reference product) is still under consideration.72
SB5 Samsung Bioepsis A naming convention that includes an INN and distin-
Infliximab BCD-055 Biocad guishing suffix, rather than prefix, would allow products to
NI-071 Nichi-Iko Pharmaceutical be grouped together by their INN in electronic databases to
Co, Ltd help identify them for ordering, prescribing, dispensing,
PF-06438179 Pfizer and pharmacovigilance.71,72 However, prescribers and/or
Rituximab ABP 798 Amgen pharmacists may have difficulty differentiating products by
BCD-020 Biocad a suffix devoid of meaning, and this may lead to inadvertent
BI 695500 Boehringer Ingelheim selection errors.73 One approach to reduce the likelihood of
CT-P10 Celltrion selection errors would be to include brand names as biolog-
GP2013 Sandoz ics are integrated into electronic systems.73 Consistent with
MabionCD20 Mabion this, a recent survey of US pharmacists indicated that
PF-05280586 Pfizer respondents who preferred the INN-plus-suffix naming
RTXM83 mAbxience
convention also favored the use of a suffix tied to the manu-
SAIT101 Archigen Biotech Ltd
facturer name over one devoid of meaning.70 Despite these
Trastuzumab ABP-980 Amgen
reported preferences, pharmacists were most confident with
BCD-022 Biocad
interchangeable biosimilar substitution when the biosimilar
CT-P6 Celltrion
PF-05280014 Pfizer
and reference products shared the same INN.70 Thus, phar-
SB3-G31-BC Samsung Bioepis macists’ perspectives on biosimilar naming conventions
Bevacizumab ABP 215 Amgen may also influence the likelihood to substitute interchange-
BCD-021 Biocad able biosimilars for licensed biologics, thereby affecting
BI 695502 Boehringer Ingelheim their uptake to market.
PF-06439535 Pfizer
a
Registered on ClinicalsTrials.gov, the International Clinical Trials Extrapolation
Registry Platform, or the European Union Clinical Trials Register.
Regulatory guidelines also permit extrapolation of clinical
data from one indication to support biosimilar approval for
cause confusion among prescribers or consumers and slow use in an indication that was not directly compared to the
the uptake of biosimilars to market.8,59,70 licensed biologic in a comparative clinical trial but for
The WHO guidelines propose a system in which a 4-let- which the reference product is approved.2,3,5 However,
ter biological qualifier (randomly generated consonants extrapolation must be scientifically justified and based on
devoid of meaning) is retrospectively or prospectively the totality of the evidence from all stages of biosimilar
assigned as a suffix to all biologic products, including bio- development.2,3,5 For example, the FDA approved Inflectra,
similars, that have or are eligible to have an INN.71 In the an infliximab biosimilar, across all indications of originator
European Union, biosimilar and originator biologics share infliximab based on data from comparative nonclinical
the same INN. For example, the originator G-CSF Neupogen assessments and comparative clinical efficacy and safety
and its biosimilar Zarzio both share the same INN of fil- studies in patients with RA or ankylosing spondylitis.47,66,67
grastim. Consistent with WHO recommendations, FDA Extrapolation reduces the need for duplicative clinical stud-
guidance also recommends the addition of a distinguishing ies in indications already approved for the reference prod-
suffix devoid of meaning to all biologics newly or uct.74 However, in certain circumstances, additional data
8 Annals of Pharmacotherapy 
may be required to justify extrapolation, such as when the
mechanism(s) of action or target receptors or safety and
immunogenicity profiles differ between indications.2,3,22
A formulary committee may authorize a biologic for
indications for which it has not received regulatory approval
based on evidence from clinical studies. Thus, pharmacists
could also consider whether available data support using a
biosimilar for nonlabeled indications of the originator.59
Authorization for nonlabeled uses of a biosimilar within a
formulary system is distinct from regulatory extrapolation;
however, it may be supported by the same scientific princi-
ples (eg, similar mechanisms and sites of action between
indications).
Product Labeling
Prescription drug labels (prescribing information or sum-
mary of product characteristics [SmPC]) are an important
source of information for health care practitioners at the
point of care because they are regularly updated to reflect
licensed indications and provide a summary of evidence
generated with a particular medicine.
In a recent survey of physicians in the European Union,
90.5% reported “frequently” or “occasionally” using the
SmPC when prescribing biologics, including biosimilars.75
Furthermore, nearly 70% of respondents reported using the
SmPC when prescribing a biologic for the first time, mak-
ing it the most frequently consulted information source in
this situation.75 SmPCs for biosimilars report data generated
with the reference product and include a statement that the
product is a biosimilar; however, they omit results from
comparability studies that supported biosimilar approval.76,77
Draft guidance issued by the FDA also recommends that
biosimilar product labeling incorporate relevant data from
the reference product labeling (along with a biosimilarity
statement) and advises against including comparative
data.78 Confirmatory comparative clinical studies are con-
ducted to demonstrate that there are no clinically meaning-
ful differences between a biosimilar and reference product,
using the most sensitive patient population and efficacy end
points.3,5,21,23 In some cases, study conditions may differ
from those used in pivotal trials that supported approval of
the reference product,3,5,21,23 which may cause confusion for
the prescriber.78 However, a product label that includes
results from comparative clinical trials and other data that
supported biosimilar approval (eg, analytical studies) would
increase transparency and build trust with health care prac-
titioners and patients. Indeed, in one recently conducted
survey of US physicians, approximately 83% of respon-
dents considered it important to include analytical and clini-
cal data in the biosimilar label.79
The prescription drug label is readily accessible to phar-
macists, and many rely on its contents to answer questions
about and help patients understand treatment options.
Omitting results from comparative clinical trials in the bio-
similar product label may affect the ability of pharmacists
to communicate with patients about the safety and efficacy
of biosimilars. For example, excluding clinical immunoge-
nicity data from biosimilar switch studies could make it dif-
ficult for pharmacists to address questions asked by patients
who switched from an originator to a biosimilar.
Therapeutic Drug Monitoring
Clinicians and pharmacists may use TDM to optimize dos-
ing when treating patients with biologic therapies. For
instance, infliximab demonstrates large, interpatient phar-
macokinetic variability, and infliximab serum trough con-
centrations are positively associated with clinical outcomes
in patients with inflammatory bowel disease.80,84 In this
case, TDM may help clinicians individualize dosage to
minimize or avoid secondary loss of response to infliximab
that may develop as a result of subtherapeutic drug concen-
trations or the formation of ADAs.85,86
As biosimilars become available and are added to a for-
mulary, it will be important to ensure that each biosimilar
whose reference product is part of a TDM program is appro-
priately incorporated into the bioanalytical assays for TDM
along with its ADA levels. In a recent study of originator
infliximab (Remicade) and 2 Remicade biosimilars
(Remsima and Inflectra), concentrations of all 3 infliximab
products were equally well quantified using a commercially
available ELISA developed for originator infliximab
(apDia, Belgium).87
A separate study showed good correlation of Remsima
serum trough concentrations quantification among 3 differ-
ent infliximab ELISAs: SHIKARI Q-Inflixi (Matriks Biotek,
Turkey), LISA-Tracker Duo Infliximab (Theradiag, France),
and RIDASCREEN IFX (R-Biopharm, Germany).88 Finally,
MA-IFX10F9, a neutralizing antibody against infliximab,
demonstrated equal reactivity toward Remicade, Remsima,
and Inflectra in anti-infliximab-bridging ELISAs, support-
ing its use as a universal calibrator.87 This would allow stan-
dardization and comparison of anti-infliximab titers against
different biosimilar products or of the same product evalu-
ated using multiple assays.87
Manufacturer Attributes and Logistics of Product
Use
It will also be important for pharmacists to consider manu-
facturer attributes and logistics of product use when evalu-
ating biosimilars for formulary inclusion. As a biologic, the
physicochemical and functional attributes of a biosimilar
are dependent on and sensitive to changes in its manufactur-
ing process.6-10 Thus, a manufacturer’s handling practices
and history of recalls associated with product quality should
be evaluated to ensure drug efficacy and patient safety.59
Stevenson et al 9
Patient care will depend on a reliable and consistent supply
of biosimilar medications, so drug availability should also
be assessed to determine whether a manufacturer can main-
tain adequate production and stock to meet product
demand.59 This includes a review of the manufacturer’s his-
tory of drug shortages and its processes and procedures for
mitigating such shortages (eg, multisite manufacturing
capabilities).59 Supply chain security should also be consid-
ered; antitheft and anticounterfeiting measures decrease the
risk of drug shortages and ensure product quality.59,89
Biologics are often administered to patients in hospital
and physician office settings; therefore, biosimilar formu-
lary review should also consider the logistics of product use
in these settings. Any differences in product packaging (eg,
vial size) and/or stability between biosimilar and reference
products should be evaluated to determine the potential
impact on product integrity and drug waste.59 Factors that
affect the ability to differentiate between products (eg,
product labeling, storage) and capabilities of information
technology systems for product tracking should be consid-
ered to minimize the potential for dispensing errors and
facilitate traceability of adverse events.59
Reimbursement
The US prescription drug coverage and reimbursement pol-
icies vary with distribution channel.61 Whereas pharmacy-
dispensed drugs are covered under pharmacy benefits (eg,
private insurance, Medicare part D, or Medicaid), those
administered by health care providers (eg, physician office
and hospital settings) are usually covered under medical
benefits (eg, private insurance, Medicare part A, Medicare
part B, or Medicaid).61 For Medicare part B, biosimilar
products and other physician-administered drugs are coded
using the US Healthcare Common Procedure Coding
System and reimbursed at rates determined by the Centers
for Medicare and Medicaid Services.90,91
Although typically administered to patients in physician
office and hospital outpatient settings, biologics may also
be considered specialty drugs, which are managed under
pharmacy benefits.61 Most private and public (eg, Medicare
part D) health plans use a formulary design, with tiered cost
sharing and access controls to manage drug costs.61 A recent
survey of health plans revealed that many are considering
placing biosimilars on a lower cost-sharing tier than origi-
nator biologics and may implement step-edits for the use of
biosimilars prior to originators.92 These reimbursement
policies could increase accessibility to and use of biosimi-
lars. The availability of manufacturer assistance programs
that subsidize treatment costs should also be considered.59
Under current Medicare part D reimbursement, biosimilars
are not subject to manufacturer discounts while patients are
in the coverage gap.93 This may discourage health systems
from switching to a biosimilar that is not eligible for the
same discount programs as its originator.59,94 However, it
could be addressed by requiring a biosimilar manufacturer
to provide patient assistance programs that are similar to or
better than those for the originator product.
Summary and Conclusions
Biosimilars have the potential to increase accessibility to
and expand the use of biologic therapies worldwide.
Biosimilar approval is granted through regulatory pathways
that are distinct from small-molecule generics and novel
therapeutics. Pharmacists will play an important role in
managing the introduction of biosimilars into health care
systems. As pharmacists consider biosimilar products for
formulary inclusion, they should evaluate the totality of the
evidence for biosimilarity, including analytical, nonclinical,
and clinical data that demonstrate product quality, safety,
and efficacy; economic factors, such as reimbursement and
treatment costs; postmarketing pharmacovigilance data, if
available; manufacturer attributes; and logistics of product
use.59 Pharmacists will also rely on data from both analytical
assessments and comparative clinical trials of the biosimilar
and reference products to make informed decisions regard-
ing product use. Finally, evolving regulatory guidelines for
interchangeability, naming, and product labeling may influ-
ence substitution practices, product tracking, and postmar-
keting pharmacovigilance as well as the type and extent of
information pharmacists can communicate to patients and
other health care providers about biosimilar products.
Acknowledgments
Medical writing support was provided by Elyse Smith, PhD, of
Engage Scientific Solutions and funded by Pfizer Inc.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: James G. Stevenson is an employee of Visante and reports
providing compensated consulting for Amgen, receiving fees from
Pfizer Inc for serving on an advisory board, and fees from AbbVie
for his participation in an educational program. Robert Popovian,
Ira Jacobs, Susan Hurst, and Lesley G. Shane are full-time employ-
ees of and declare stock holdings and/or stock options from Pfizer
Inc.
Funding
The authors disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
review was supported by Pfizer Inc.
References
1. Philippidis A. Biosimilars: 11 drugs to watch. http://www.
genengnews.com/insight-and-intelligence/biosimilars-
11-drugs-to-watch/77900135. Accessed January 16, 2017.
10 Annals of Pharmacotherapy 
2. World Health Organization. Expert Committee on Biological
Standardization. Guidelines on evaluation of similar bio-
therapeutic products (SBPs). http://www.who.int/biologicals/
areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_
WEB_22APRIL2010.pdf. Accessed January 16, 2017.
3. US Food and Drug Administration. Scientific considerations
in demonstrating biosimilarity to a reference product: guid-
ance for industry. http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
UCM291128.pdf. Accessed January 16, 2017.
4. Public law number is 111-148, 124 Stat. 119. An act entitled
the Patient Protection and Affordable Care Act. 2009.
5. Committee for Medicinal Products for Human Use (CHMP).
Guideline on similar biological medicinal products. http://
www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2014/10/WC500176768.pdf. Accessed
January 16, 2017.
6. Crommelin D, Bermejo T, Bissig M, et al. Pharmaceutical
evaluation of biosimilars: important differences from generic
low-molecular-weight pharmaceuticals. Eur J Hosp Pharm
Sci. 2005;11:11-17.
7. Kuhlmann M, Covic A. The protein science of biosimi-
lars. Nephrol Dial Transplant. 2006;21(suppl 5):v4-v8.
doi:10.1093/ndt/gfl474.
8. Daller J. Biosimilars: a consideration of the regulations in the
United States and European Union. Regul Toxicol Pharmacol.
2016;76:199-208. doi:10.1016/j.yrtph.2015.12.013.
9. Dombrowski SR. A health-system pharmacist’s guide to bio-
similars: regulatory, scientific, and practical considerations.
http://ashpadvantagemedia.com/downloads/biosimcentral_
guidelines.pdf. Accessed January 16, 2017.
10. Schellekens H. Biosimilar therapeutics-what do we need to
consider? NDT Plus. 2009;2(suppl 1):i27-i36. doi:10.1093/
ndtplus/sfn177.
11. Kawasaki N, Itoh S, Hashii N, et al. The significance of gly-
cosylation analysis in development of biopharmaceuticals.
Biol Pharm Bull. 2009;32:796-800.
12. Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggre-
gation: pathways, induction factors and analysis. J Pharm Sci.
2009;98:2909-2934. doi:10.1002/jps.21566.
13. US Food and Drug Administration. Quality considerations in
demonstrating biosimilarity of a therapeutic protein product
to a reference product: guidance for industry. http://www.
fda.gov/downloads/drugs/guidancecomplianceregulatoryin-
formation/guidances/ucm291134.pdf. Accessed January 16,
2017.
14. Berkowitz SA, Engen JR, Mazzeo JR, Jones GB. Analytical
tools for characterizing biopharmaceuticals and the implica-
tions for biosimilars. Nat Rev Drug Discov. 2012;11:527-540.
doi:10.1038/nrd3746.
15. Egrie JC, Dwyer E, Browne JK, Hitz A, Lykos MA.
Darbepoetin alfa has a longer circulating half-life and greater
in vivo potency than recombinant human erythropoietin. Exp
Hematol. 2003;31:290-299.
16. Higuchi M, Oh-eda M, Kuboniwa H, Tomonoh K, Shimonaka
Y, Ochi N. Role of sugar chains in the expression of the
biological activity of human erythropoietin. J Biol Chem.
1992;267:7703-7709.
17. Misaizu T, Matsuki S, Strickland TW, Takeuchi M, Kobata
A, Takasaki S. Role of antennary structure of N-linked sugar
chains in renal handling of recombinant human erythropoi-
etin. Blood. 1995;86:4097-4104.
18. Kanda Y, Yamada T, Mori K, et al. Comparison of biologi-
cal activity among nonfucosylated therapeutic IgG1 antibod-
ies with three different N-linked Fc oligosaccharides: the
high-mannose, hybrid, and complex types. Glycobiology.
2007;17:104-118. doi:10.1093/glycob/cwl057.
19. Shinkawa T, Nakamura K, Yamane N, et al. The absence
of fucose but not the presence of galactose or bisecting
N-acetylglucosamine of human IgG1 complex-type oligosac-
charides shows the critical role of enhancing antibody-depen-
dent cellular cytotoxicity. J Biol Chem. 2003;278:3466-3473.
doi:10.1074/jbc.M210665200.
20. Schellekens H. Factors influencing the immunogenicity of
therapeutic proteins. Nephrol Dial Transplant. 2005;20(suppl
6):vi3-vi9. doi:10.1093/ndt/gfh1092.
21. Committee for Medicinal Products for Human Use (CHMP).
Guideline on similar biological medicinal products contain-
ing biotechnology-derived proteins as active substance: non-
clinical and clinical issues. http://www.ema.europa.eu/docs/
en_GB/document_library/Scientific_guideline/2015/01/
WC500180219.pdf. Accessed January 16, 2017.
22. Committee for Medicinal Products for Human Use (CHMP).
Guideline on similar biological medicinal products contain-
ing biotechnology-derived proteins as active substance:
quality issues (revision 1). http://www.ema.europa.eu/docs/
en_GB/document_library/Scientific_guideline/2014/06/
WC500167838.pdf. Accessed January 16, 2017.
23. US Food and Drug Administration. Clinical pharmacology data
to support a demonstration of biosimilarity to a reference product:
guidance for industry: draft guidance. http://www.fda.gov/down-
loads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM397017.pdf. Accessed January 16, 2017.
24. Public law number is 98-417, 98 Stat. 1585. An act to amend
the Federal Food, Drug, and Cosmetic Act to revise the pro-
cedures for new drug applications, to amend title 35, United
States code, to authorize the extension of the patents for cer-
tain regulated products, and for other purposes. 1984.
25. US Congress. The Public Health Service Act. Washington,
DC: The Office of the Law Revision Counsel, US Government
Printing Office; 1944.
26. US Food and Drug Administration.Bioavailability and bio-
equivalence studies for orally administered drug products—
general considerations: guidance for industry. http://www.
fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-
BioAvail-BioEquiv.pdf. Accessed January 16, 2017.
27. Stevenson JG. Clinical data and regulatory issues of biosimilar
products. Am J Manag Care. 2015;21(suppl 16):s320-s330.
28. US Food and Drug Administration. Drug approval package: omni-
trope (somatropia [rDNA origin]) injection. http://www.access-
data.fda.gov/drugsatfda_docs/nda/2006/021426s000TOC.cfm.
Accessed January 16, 2017.
29. US Food and Drug Administration. FDA approves Basaglar, the
first “follow-on” insulin glargine product to treat diabetes. http://
www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm477734.htm. Accessed January 16, 2017.
Stevenson et al 11
30. US Food and Drug Administration. FDA approves first
generic enoxaparin sodium injection. http://www.fda.
gov/NewsEvents/Newsroom/PressAnnouncements/2010/
ucm220092.htm. Accessed January 16, 2017.
31. US Food and Drug Administration. Implementation of the
“deemed to be a license” provision of the Biologics Price
Competition and Innovation Act of 2009: guidance for indus-
try: draft guidance. http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
UCM490264.pdf. Accessed January 16, 2017.
32. US Food and Drug Administration. FDA approves new treat-
ment for severe neutropenia in certain cancer patients. http://
www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm317392.htm. Accessed January 16, 2017.
33. Álvarez AA, Mysler E, Ruiz de Castilla EM, Flores-Murrieta
FJ, Hughes J, Azevedo VF. Recommendations for the regula-
tion of biosimilars and their implementation in Latin America.
GaBI J. 2014;3:143-148. doi:10.5639/gabij.2014.0303.032.
34. IFMPA. Policy statement: non-comparable biotherapeutic
products. http://www.ifpma.org/wp-content/uploads/2016/02/
Non-comparable_Biotherapeutic_Products__English__02.
pdf. Accessed January 16, 2017.
35. Azevedo VF. Biosimilars require scientifically reliable com-
parative clinical data. Rev Bras Reumatol. 2013;53:129-131.
36. Anour R. Biosimilars versus “biobetters”—a regula-
tor’s perspective. GaBi J. 2014;3:166-167. doi:10.5639/
gabij.2014.0304.039.
37. Weise M, Bielsky MC, De Smet K, et al. Biosimilars: why
terminology matters. Nat Biotechnol. 2011;29:690-693.
doi:10.1038/nbt.1936.
38. Wang C, He X, Zhou B, et al. Phase 1 study of anti-epidermal
growth factor receptor monoclonal antibody in patients with
solid tumors. MAbs. 2011;3:67-75.
39. European Medicines Agency. European public assessment
reports. http://www.ema.europa.eu/ema/index.jsp?curl=page
s%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=WC0
b01ac058001d124&searchTab=searchByAuthType&already
Loaded=true&isNewQuery=true&status=Authorised&status
=Withdrawn&keyword=Enter+keywords&searchType=nam
e&taxonomyPath=&treeNumber=&searchGenericType=bios
imilars&genericsKeywordSearch=Submit. Accessed January
16, 2017.
40. Generics and Biosimilars Initiative (GaBi). Biosimilars
approved in Europe. http://www.gabionline.net/Biosimilars/
General/Biosimilars-approved-in-Europe. Accessed January
16, 2017.
41. Committee for Medicinal Products for Human Use (CHMP).
Refusal assessment report for Alpheon (recombinant human
interferon-alfa-2a). http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Public_assessment_report/
human/000585/WC500070792.pdf. Accessed January 16, 2017.
42. Committee for Medicinal Products for Human Use (CHMP).
Refusal of the marketing authorisation for Solumarv (insu-
lin human). http://www.ema.europa.eu/docs/en_GB/docu-
ment_library/Summary_of_opinion_-_Initial_authorisation/
human/003858/WC500196786.pdf. Accessed January 16, 2017.
43. Human Medicines Development and Evaluation. Filgrastim
ratiopharm (filgrastim): withdrawal of the marketing authori-
sation in the European Union http://www.ema.europa.eu/
docs/en_GB/document_library/Public_statement/2011/07/
WC500109157.pdf. Accessed January 16, 2017.
44. Human Medicines Development and Evaluation. Valtropin
(somatropin): withdrawal of the marketing authorisation in
the European Union http://www.ema.europa.eu/docs/en_GB/
document_library/Public_statement/2012/08/WC500130939.
pdf. Accessed January 16, 2017.
45. Committee for Medicinal Products for Human Use (CHMP).
Applications for new human medicines under evaluation
by the Committee for Medicinal Products for Human Use.
http://www.ema.europa.eu/docs/en_GB/document_library/
Report/2016/10/WC500213938.pdf. Accessed January 16,
2017.
46. US Food and Drug Administration. FDA approves first bio-
similar product Zarxio. http://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm436648.htm. Accessed
January 16, 2017.
47. US Food and Drug Administration. FDA approves Inflectra,
a biosimilar to remicade. http://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm494227.htm. Accessed
January 16, 2017.
48. US Food and Drug Administration. FDA approves Erelzi,
a biosimilar to Enbrel. http://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm518639.htm. Accessed
January 16, 2017.
49. US Food and Drug Administration. FDA approves Amjevita,
a biosimilar to Humira. http://www.fda.gov/newsevents/
newsroom/pressannouncements/ucm522243.htm. Accessed
January 16, 2017.
50. Apotex Inc. Apotex announces FDA has accepted for fil-
ing its biosimilar application for filgrastim (Grastofil™).
http://www.apotex.com/global/about/press/20150217-2.asp.
Accessed January 16, 2017.
51. Apotex Inc. Apotex announces FDA has accepted for filing its
biosimilar application for pegfilgrastim. http://www.apotex.
com/global/about/press/20141217.asp. Accessed January 16,
2017.
52. Generics and Biosimilars Initiative (GaBi).FDA accepts
application for pegfilgrastim biosimilar from Coherus. http://
gabionline.net/Biosimilars/News/FDA-accepts-application-
for-pegfilgrastim-biosimilar-from-Coherus. Accessed January
23, 2017.
53. Sandoz. Sandoz biosimilar pipeline.https://www.sandoz.com/
our-work/biopharmaceuticals/sandoz-biosimilar-pipeline.
Accessed January 23, 2017.
54. Adams B. FDA rejects Novartis’ biosim app for Amgen block-
buster. http://www.fiercebiotech.com/biotech/fda-rejects-
novartis-biosim-app-for-amgen-blockbuster. Accessed
January 16, 2017.
55. Generics and Biosimilars Initiative (GaBi). Hospira sub-
mits application to FDA for epoetin alfa biosimilar. http://
www.gabionline.net/Biosimilars/News/Hospira-submits-
application-to-FDA-for-epoetin-alfa-biosimilar. Accessed
January 16, 2017.
56. Generics and Biosimilars Initiative (GaBi). Boehringer Ingelheim
submits biosimilar adalimumab application to both EMA and FDA.
http://gabionline.net/Biosimilars/News/Boehringer-Ingelheim-
submits-biosimilar-adalimumab-application-to-both-EMA-
and-FDA?utm_source=GONL6&utm_campaign=455f92e754-
12 Annals of Pharmacotherapy 
GONL+V17A27-6&utm_medium=email&utm_term=0_
bfb08b6fa4-455f92e754-150179273. Accessed January 27, 2017.
57. Merck. Merck announces FDA accepts Samsung Bioepis’
biologics license application (BLA) for SB2 (inflix-
imab), an investigational biosimilar of remicade. http://
www.mercknewsroom.com/news-release/corporate-news/
merck-announces-fda-accepts-samsung-bioepis-biologics-
license-applicatio. Accessed January 16, 2017.
58. GenericsandBiosimilarsInitiative(GaBi).MylanandBioconsubmit
trastuzumab biosimilar to FDA. http://gabionline.net/Biosimilars/
News/Mylan-and-Biocon-submit-trastuzumab-biosimilar-to-
FDA?utm_source=GONL6&utm_campaign=afd0d766a5-
GONL+V16L09-6&utm_medium=email&utm_term=0_
bfb08b6fa4-afd0d766a5-150179273. Accessed January 27, 2017.
59. Griffith N, McBride A, Stevenson JG, Green L. Formulary
selection criteria for biosimilars: considerations for US
health-system pharmacists. Hosp Pharm. 2014;49:813-825.
doi:10.1310/hpj4909-813.
60. Li E, Ramanan S, Green L. Pharmacist substitution of biologi-
cal products: issues and considerations. J Manag Care Spec
Pharm. 2015;21:532-539.
61. Danzon PM. Pricing and reimbursement of biopharmaceu-
ticals and medical devices in the USA. In: Culyer AJ, ed.
Encyclopedia of Health Economics. New York, NY: Elsevier;
2014:127-135.
62. Committee for Medicinal Products for Human Use (CHMP).
Questions and answers on biosimilar medicines (similar
biological medicinal products). http://www.ema.europa.
eu/docs/en_GB/document_library/Medicine_QA/2009/12/
WC500020062.pdf. Accessed January 16, 2017.
63. US Food and Drug Administration.Considerations in demon-
strating interchangeability with a reference product: guidance
for industry: draft guidance.http://www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM537135.pdf. Accessed January 23, 2017.
64. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison
of EP2006, a filgrastim biosimilar, to the reference: a phase
III, randomized, double-blind clinical study in the prevention
of severe neutropenia in patients with breast cancer receiving
myelosuppressive chemotherapy. Ann Oncol. 2015;26:1948-
1953. doi:10.1093/annonc/mdv281.
65. Jørgensen K, Olsen I, Goll G, et al. Biosimilar infliximab
(ct-p13) is not inferior to originator Infliximab: results
from the 52-week randomized nor-switch trial. United Eur
Gastroenterol J. 2016;4:abstractLB15.
66. Park W, Yoo DH, Miranda P, et al. Efficacy and safety of
switching from reference infliximab to CT-P13 compared with
maintenance of CT-P13 in ankylosing spondylitis: 102-week
data from the PLANETAS extension study. Ann Rheum Dis.
2017;76:346-354. doi:10.1136/annrheumdis-2015-208783.
67. Yoo DH, Prodanovic N, Jaworski J, et al. Efficacy and safety
of CT-P13 (biosimilar infliximab) in patients with rheuma-
toid arthritis: comparison between switching from refer-
ence infliximab to CT-P13 and continuing CT-P13 in the
PLANETRA extension study. Ann Rheum Dis. 2017;76:355-
363. doi:10.1136/annrheumdis-2015-208786.
68. Cauchi R. State laws and legislation related to biologic medi-
cations and substitution of biosimilars. http://www.ncsl.
org/research/health/state-laws-and-legislation-related-to-
biologic-medications-and-substitution-of-biosimilars.aspx.
Accessed January 16, 2017.
69. Center for Drug Evaluation and Research. List of licensed biolog-
ical products with (1) reference product exclusivity and (2) bio-
similarity or interchangeability evaluations to date. http://www.
fda.gov/downloads/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications/
TherapeuticBiologicApplications/Biosimilars/UCM439049.
pdf. Accessed January 16, 2017.
70. Tomaszewski D. Biosimilar naming conventions: pharmacist
perceptions and impact on confidence in dispensing biologics.
J Manag Care Spec Pharm. 2016;22:919-926. doi:10.18553/
jmcp.2016.22.8.919.
71. World Health Organization. Biological qualifier: an INN
proposal. http://www.who.int/medicines/services/inn/WHO_
INN_BQ_proposal_2015.pdf?ua=1. Accessed January 16,
2017.
72. US Food and Drug Administration. Nonproprietary naming of
biological products: guidance for industry.http://www.fda.gov/
downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM459987.pdf. Accessed January 18, 2017.
73. Stevenson JG, Green L. Biologics, pharmacovigilance, and
patient safety: it’s all in the name. J Manag Care Spec Pharm.
2016;22:927-930. doi:10.18553/jmcp.2016.22.8.927.
74. Human Medicines Development and Evaluation. Concept
paper on extrapolation of efficacy and safety in medi-
cine development: final. http://www.ema.europa.eu/docs/
en_GB/document_library/Scientific_guideline/2013/04/
WC500142358.pdf. Accessed January 16, 2017.
75. Hallersten A, Furst W, Mezzasalma R. Physicians prefer
greater detail in the biosimilar label (SmPC): results of a survey
across seven European countries. Regul Toxicol Pharmacol.
2016;77:275-281. doi:10.1016/j.yrtph.2016.03.021.
76. Committee for Medicinal Products for Human Use (CHMP).
QRD general principles regarding the SmPC information for
a generic/hybrid/biosimilar product. http://www.ema.europa.
eu/docs/en_GB/document_library/Regulatory_and_pro-
cedural_guideline/2012/05/WC500127589.pdf. Accessed
January 16, 2017.
77. European Commission. A guideline on summary of prod-
uct characteristics (SmPC), revision 2. http://ec.europa.eu/
health/files/eudralex/vol-2/c/smpc_guideline_rev2_en.pdf.
Accessed January 16, 2017.
78. US Food and Drug Administration. Labeling for biosimilar
products: guidance for industry: draft guidance. http://www.
fda.gov/downloads/drugs/guidancecomplianceregulatoryin-
formation/guidances/ucm493439.pdf. Accessed January 16,
2017.
79. Olsen K. ASBM labeling survey. https://safebiologics.org/
wp-content/uploads/2016/04/February-2015-Labeling-
Report.pdf. Accessed January 16, 2017.
80. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association
between serum concentration of infliximab and efficacy
in adult patients with ulcerative colitis. Gastroenterology.
2014;147:1296-1307.e5. doi:10.1053/j.gastro.2014.08.035.
81. Arias MT, Vande Casteele N, Vermeire S, et al. A panel to pre-
dict long-term outcome of infliximab therapy for patients with
Stevenson et al 13
ulcerative colitis. Clin Gastroenterol Hepatol. 2015;13:531-
538. doi:10.1016/j.cgh.2014.07.055.
82. Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction
serum infliximab trough level and decrease of C-reactive pro-
tein level are associated with durable sustained response to
infliximab: a retrospective analysis of the ACCENT I trial.
Gut. 2014;63:1721-1727. doi:10.1136/gutjnl-2012-304094.
83. Dotan I, Ron Y, Yanai H, et al. Patient factors that increase
infliximab clearance and shorten half-life in inflamma-
tory bowel disease: a population pharmacokinetic study.
Inflamm Bowel Dis. 2014;20:2247-2259. doi:10.1097/
MIB.0000000000000212.
84. Ternant D, Aubourg A, Magdelaine-Beuzelin C, et al.
Infliximab pharmacokinetics in inflammatory bowel disease
patients. Ther Drug Monit. 2008;30:523-529. doi:10.1097/
FTD.0b013e318180e300.
85. Ordas I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF
monoclonal antibodies in inflammatory bowel disease: phar-
macokinetics-based dosing paradigms. Clin Pharmacol Ther.
2012;91:635-646. doi:10.1038/clpt.2011.328.
86. Vaughn BP, Sandborn WJ, Cheifetz AS. Biologic concentra-
tion testing in inflammatory bowel disease. Inflamm Bowel Dis.
2015;21:1435-1442. doi:10.1097/MIB.0000000000000312.
87. Gils A, Van Stappen T, Dreesen E, Storme R, Vermeire S,
Declerck PJ. Harmonization of infliximab and anti-infliximab
assays facilitates the comparison between originators and bio-
similars in clinical samples. Inflamm Bowel Dis. 2016;22:969-
975. doi:10.1097/MIB.0000000000000709.
88. Malickova K, Duricova D, Bortlik M, et al. Serum trough inf-
liximab levels: a comparison of three different immunoassays
for the monitoring of CT-P13 (infliximab) treatment in patients
with inflammatory bowel disease. Biologicals. 2016;44:33-36.
doi:10.1016/j.biologicals.2015.09.005.
89. Mica A, Mutomba M, Green L. Steps to ensure adequate
supply of biological medicines: considerations for the
healthcare provider. GaBi J. 2013;2:136-143. doi:10.5639/
gabij.2013.0203.038.
90. Centers for Medicare and Medicaid Services. Medicare
Program; Revisions to Payment Policies Under the Physician
Fee Schedule and Other Revisions to Part B for CY 2016.
Washington, DC: Office of the Federal Register, National
Archives and Records Administration; 2015:70886-71386.
91. Centers for Medicare and Medicaid Services. Part B biosimi-
lar biological product payment and required modifiers. https://
www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-
B-Drugs/McrPartBDrugAvgSalesPrice/Part-B-Biosimilar-
Biological-Product-Payment.html. Accessed January 16,
2017.
92. Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implica-
tions for health-system pharmacists. Am J Health Syst Pharm.
2013;70:2004-2017. doi:10.2146/ajhp130119.
93. Centers for Medicare and Medicaid Services. Medicare pre-
scription drug benefit manual: chapter 6—part D drugs and
formulary requirements. https://www.cms.gov/Medicare/
Prescription-Drug-Coverage/PrescriptionDrugCovContra/
Downloads/Part-D-Benefits-Manual-Chapter-6.pdf.
Accessed January 16, 2017.
94. Ventola CL. Evaluation of biosimilars for formulary inclu-
sion: factors for consideration by P&T committees. P T.
2015;40:680-689.