Biosimilars: An overview

Abstract

Biologics", considered one of the fastest growing sectors of the pharmaceutical industry, has introduced many new treatments to life-threatening and rare illnesses. The first generation of biopharmaceutical products manufactured using recombinant technologies was launched in the 1980s, and they are now on the way to patent expiration. As a result, research-based and generic pharmaceutical companies alike are pursuing the opportunity to develop "generic" substitutes for original biologics, herein referred to as biosimilars. However, the process of introducing a biosimilar to an innovator product is far more complex than the relatively straightforward process of introducing a generic equivalent to an innovator product based on a new chemical entity. Biologics are produced by cells in culture or whole organisms, which are inherently more variable than chemical synthesis methods. Therefore, unlike generic pharmaceuticals, it is impossible to generate the same or identical copy of an innovator product. In this way, biosimilars are "similar but not the same" or in other words biosimilars are "the twin but not the clone" to the original biologic innovator product. Therefore the field of biosimilars presents several important challenges, including i) verification of the similarity, ii) the interchangeability of biosimilars and innovator products, iii) the possible need for unique naming to differentiate the various biopharmaceutical products, iv) regulatory framework, v) commercial opportunities as well as guidelines to assist manufacturers in product development, vi) intellectual property rights, and vii) public safety.

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DOI: 10.2147/BS.S16120
Biosimilars: an overview
Bhupinder Singh Sekhon
Vikrant Saluja
Institute of Pharmacy, PCTE Group
of Institutes, Near Baddowal Cantt.
(Ludhiana), India
Correspondence: Bhupinder Singh Sekhon
Institute of Pharmacy, PCTE Group
of Institutes, Near Baddowal Cantt.
(Ludhiana), 142021, India
Tel +91-161-2888550
Email sekhon224@yahoo.com
Abstract: “Biologics”, considered one of the fastest growing sectors of the pharmaceutical
industry, has introduced many new treatments to life-threatening and rare illnesses. The first
generation of biopharmaceutical products manufactured using recombinant technologies was
launched in the 1980s, and they are now on the way to patent expiration. As a result, research-
based and generic pharmaceutical companies alike are pursuing the opportunity to develop
“generic” substitutes for original biologics, herein referred to as biosimilars. However, the
process of introducing a biosimilar to an innovator product is far more complex than the
relatively straightforward process of introducing a generic equivalent to an innovator product
based on a new chemical entity. Biologics are produced by cells in culture or whole organisms,
which are inherently more variable than chemical synthesis methods. Therefore, unlike
generic pharmaceuticals, it is impossible to generate the same or identical copy of an innovator
product. In this way, biosimilars are “similar but not the same” or in other words biosimilars
are “the twin but not the clone” to the original biologic innovator product. Therefore the field
of biosimilars presents several important challenges, including i) verification of the similarity,
ii) the interchangeability of biosimilars and innovator products, iii) the possible need for unique
naming to differentiate the various biopharmaceutical products, iv) regulatory framework,
v) commercial opportunities as well as guidelines to assist manufacturers in product development,
vi) intellectual property rights, and vii) public safety.
Keywords: biosimilars, biologics, innovator product, pharmacovigilance, regulatory
Introduction
“Biologics” represent one of the fastest growing segments of the pharmaceutical
industry. They refer broadly to substances produced by living cells using biotechnology
(ie, recombinant DNA technology, controlled gene expression, or antibody
technologies), which have introduced many new treatments to life-threatening and rare
illnesses such as cancer, diabetes, anemia, rheumatoid arthritis and multiple sclerosis.
They involve a wide range of substances, including recombinant hormones, growth
factors, blood products, monoclonal antibody-based products, recombinant vaccines,
and advanced technology products (gene and cell therapy biological products).1 The
global biologic industry has come a long way since its first drug Humulin earned US
Food and Drug Administration (FDA) approval in 1982.2 Biologic sales now account
for about US$92 billion and are expected to worth more than US$167 billion by
2015.3 By 2014, biologics are expected to occupy six of the top ten positions in the
pharmaceutical industry.4 The ever-increasing pressure on healthcare budgets globally,
requires cost savings analogous to those arising from the generic versions of original
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innovator product.5–9 The pharma market is now open for
generic versions of biologics, referred to as “biosimilars” in
Europe, “follow-on pharmaceuticals” in the US and Japan,
“subsequent entry biologics” in Canada, “biocomparables”
in Mexico and, in this manuscript, “biosimilars”. These
terms arise from the loss of patent protection by many first-
generation innovator products in the last few years, and the
expectation that a few more will suffer the same fate in the
next few years. However, unlike the relatively uncomplicated
process of introducing a generic equivalent of an original
chemical based drug, the process of introducing a biosimilar
to an innovator product is far more complex. This is apparent
as i) biologics generally exhibit high molecular complexity
ii) biologics are produced by cells in culture or whole organ-
isms, and iii) major changes in the product can occur due to
very minor changes in the process.10,11
Various complexities associated with approval of a bio-
similar include: i) evidence of integrity and consistency of
the manufacturing process, ii) conformance of manufactur-
ing standards to applicable regulations, iii) demonstration
of product consistency with appropriate innovator product
or comparators using assays that should be relevant and
most of all standardized, so that several biosimilars of the
same biologic can be comparable, including comparative
pharmacokinetic and pharmacodynamic data and the extent
of clinical data, and iv) experience with the approved
product.12 Further, issues like post-translation modification
and immunogenicity are the key concern related to approval
of biosimilar products.13 Scientists are of the opinion that the
use of biosimilars is an opportunity for us to use cutting-edge
technology to solve health problems and guide clinical
processes.
Biologics versus small-molecule
drugs
Significant differences exist between biologics and typical
small-molecule drugs basically because of difference in ori-
gin (Tables 1 and 2). Chemical methods are generally used
to produce small-molecule drugs whereas biological prod-
ucts are synthesized usually by cells or living organisms.14
This difference in origin leads to difference in structure,
composition, manufacturing methods and equipment, intel-
lectual property, formulation, handling, dosing, regulation,
and marketing.
Compared with synthetic small molecules, biologics are
100 to 1000 times larger in size, having several hundred
amino acids (average molecular weight of 150 per amino
acid), biochemically joined together in a defined sequence
by peptide bonds to form a polypeptide. In contrast, conven-
tional drugs are far smaller, ie, molecular weight ,1000,
self-contained, organic molecules that are, usually, chemi-
cally synthesized.15 Further, the bigger the molecule, the
greater the number of atoms that make up its structure and
the greater its complexity. Thus, structurally, biologics are
more complex than low molecular weight drugs, consisting
of primary (amino acid sequence) and secondary (α-helix and
Table 1 Difference between innovator products and small-molecule drugs
Small-molecule drugs Biologic drugs
Product-related
differences
• Produced by chemical synthesis
• Low molecular weight
• Well-dened physiochemical properties
• Stable
• Single entity, high chemical purity, purity standards well
established
• Administered through different routes of administration
• Rapidly enters systemic circulation through blood capillaries
• Distribution to any combination of organ/tissue
• Often specic toxicity
• Often non-antigenic
• Biotechnologically produced by host cell lines
• High molecular weight
• Complex physiochemical properties
• Sensitive to heat and shear (aggregation)
• Heterogeneous mixture, broad specication which may
change during development, difcult to standardize
• Usually administered parenterally
• Larger molecule primarily reach circulation via lymphatic
system, subject to proteolysis during interstitial and
lymphatic transit
• Distribution usually limited to plasma and/or
extracellular uid
• Mostly receptor mediated toxicity
• Usually antigenic
Manufacturing
differences
• Completely characterized by analytical methods
• Easy to purify
• Contamination can be generally avoided, is easily detectable
and removable
• Not affected by slight changes in production process and
environment
• Difcult to characterize
• Lengthy and complex purication process
• High possibility of contamination, detection is harder and
removal is often impossible
• Highly susceptible to slight changes in production process
and environment

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Biosimilars
β-pleated sheet) structures, which are folded into complicated
3D tertiary structures.16 In some biopharmaceuticals, stable
associations of tertiary structures of individual proteins form
a quaternary structure. After synthesis, these structures are
often further modified by post-translational modifications
such as glycosylation or sialylation, which may be crucial
for biological activity.17 Furthermore, due to larger size and
structural complexity, the characterization of a biopharma-
ceutical presents an enormous challenge.
Despite the availability of a wide range of novel tech-
niques for characterizing structure and physicochemical
properties, the inherent complexity of biopharmaceuticals
means that the picture will be incomplete even if all available
methods are used. Typically, it is impossible to fully define
these characteristics for any given product, and they may vary
with different manufacturing processes.18 In contrast, tradi-
tional small-molecule drugs have a well-defined and stable
chemical structure, which can be completely characterised
by analytical methods.19 Moreover, biopharmaceutical pro-
duction methods are also more complex, involving several
steps and subject to variation affecting the biological and
clinical properties of the drug (Figure 1).20 In short, the
sensitivity of biological production to manufacturing con-
ditions far exceeds that of chemical production.21 Further,
pre-clinical and clinical development of biologics are a major
issue with manufacturing costs easily reaching 100-fold of
those of small molecules.22–25 Another important difference
between biopharmaceuticals and low molecular weight drugs
is their immunogenicity. Nearly all therapeutic proteins
induce antibodies, irrespective of whether these proteins are
(partly) non-human or completely human homologs. They
may decrease efficacy or may induce severe side effects by
neutralizing endogenous factors.26 Thus complex and often
expensive biologics raise critical commercial challenges
compared with small-molecule drugs – the most important
of which pertains to developing a viable pricing, distribution
and reimbursement model that is intrinsically geared to the
special characteristics of biologics and the expectations of a
diverse customer population.27 Because biologics now com-
prise about a third of the medicines approved, understanding
whether their biological differences translate into commercial
and economic differences is important for understanding
health care economics, effective innovation incentives, and
anticipated public health improvements. Because of innate
biology, production, and dosing regimes, biologics often
differ from small molecule medicines in their product devel-
opment, regulatory approval, distribution, and commercial
paths. Thus, although they have the same medical goal – to
treat disease – small-molecule and biologics therapeutics dif-
fer substantially in ways that might affect innovation, safety,
costs, clinical adoption, patient access, and pricing.28
Regulation aspects of biosimilars
A generic drug is a much less expensive copy of an innova-
tor drug product. Generics can be produced when the patent
on a drug has expired, for drugs which have never held
patent, in countries where a patent(s) is/are not in force,
and where the generic companies certify that the branded
companies’ patents are either invalid, unenforceable, or
will not be infringed. Generic drug manufacturers apply
for marketing approval of generic drugs under the Abbrevi-
ated New Drug Application (ANDA) pathway established
by FDA. Moreover, generic drug applications are termed
“abbreviated” because they are generally not required to
Table 2 Comparison of generic, biosimilar, and innovator products
Process Biologic Biosimilar Generic
Manufacturing Produced by biological process in
host cell lines
Sensitive to production process
changes – expensive and specialized
production facilities
Reproducibility difcult to establish
Produced by biological process in
host cell lines
Sensitive to production process
changes – expensive and specialized
production facilities
Reproducibility difcult to establish
Produced by using chemical synthesis
Less sensitive to production process
changes
Reproducibility easy to establish
Clinical
development
Extensive clinical studies, including
Phase I–III
Pharmacovigilance and periodic safety
updates needed
Extensive clinical studies, including
Phase I–III
Pharmacovigilance and periodic safety
updates needed
Often only Phase I studies
Short timeline for approval
Regulation Needs to demonstrate “comparability”
Regulatory pathway dened by
Europe (EMEA)
Currently no automatic substitution
intended
Needs to demonstrate “similarity”
Regulatory pathway dened by
Europe (EMEA)
No automatic substitution allowed
Needs to show bioequivalence
Abbreviated registration procedures
in Europe and US
Automatic substitution allowed
Abbreviation: EMEA, European Medicines Agency.

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innovator products. These differences imply that biosimilars
should not be approved and regulated in the same way as
conventional generic drugs.
The regulatory pathway for approval of biosimilars is
more complex than for the generic innovator product because
the design of a scientifically valid study to demonstrate
the similarity of a highly process-dependent product is not
easy. Further, the analytical tests currently available are
not sophisticated enough to detect the slight but important
structural differences between innovator and biosimilar
products. Modest differences may have clinical implications
and pose a significant risk to patient safety. Therefore, it is
considered necessary that biosimilars must be assessed for
clinical efficacy and safety by valid preclinical and clinical
studies before marketing approval.19,29–31
The European Medicines Agency (EMEA) has moved
ahead of the rest of the world in this direction, and issued a
number of general guidelines that detail the requirements for
market approval (Table 3).32–41 In addition to these guidelines,
product-class-specific guidelines have been issued for the
development of biosimilars based on recombinant erythro-
poietin, somatotropin, human granulocyte colony-stimulating
factor, human insulin, recombinant IFN-a, and low molecular
weight heparins (Table 3). Generally, the approval process
varies according to the products, because significant differ-
ences exist between them, and allow products to be assessed
on a case by case basis.42
In the US, after the approval of biosimilar Omnitrope
in 2006, the FDA stated that no other biosimilar will be
approved until a specific regulation has been issued.43 The
Pathway for Biosimilars Act of 2009 and the Patient Pro-
tection and Affordable Care Act of 2010 have provided
greater clarity, and a reasonably clear mandate from the US
Congress for the FDA to act more openly and decisively on
an abbreviated approval pathway for biological products.
However, in Canada, the first Subsequent Entry Biologic
(SEB) Omnitrope™ was approved on April 20, 2009.
Recently, Health Canada published its finalized guidance
document for the approval of SEBs with the intention that
this document would serve as an administrative aid to guide
SEB decision-making.44
In fact, the regulations covering the market approval of
biosimilars are still evolving around the world. With prog-
ress in the US, Australia, Canada, Japan, Turkey, and other
countries around the world already armed with a regula-
tory framework for biosimilar medicines, there is a need to
reach global agreement on criteria and guidelines for such
products. This objective is inspired by ethical and scientific
Cell culture
Cell bank establishment
and characterization
Protein production
Protein purification
Host cell expression
Desired gene isolation
Insertion into vector
Analysis
Formulation
Storage and handling
Figure 1 Typical steps in manufacturing of a biologic product.
include preclinical and clinical data to establish safety and
effectiveness. The generic manufacturer needs to demon-
strate only pharmaceutical equivalence and bioequivalence
between the generic and innovator products, in order to gain
approval for their generic product.
This approach cannot be extrapolated to biosimilars,
however, because the active substance of a biopharmaceuti-
cal is a collection of large protein isoforms and not a single
molecular entity, as is generally true for conventional small-
molecule drugs. Thus the active substances in two products
are highly unlikely to be identical and, therefore, unlike
generics, biosimilars are only similar and not identical to the

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Biosimilars
principles as well as economic considerations, and will have a
significant positive therapeutic impact for millions of patients
living with life-threatening and chronic diseases.
Quality, safety, and efcacy
The quality, safety, and efficacy of a biosimilar product
must be approved by the relevant regulatory body before
marketing approval can be gained, which requires an
appropriate comparability exercise. The EMEA requires
comparison of the biosimilar product with the innovator
product to determine absence of any detectable differences.
The quality comparison between the biosimilar and the
innovator product is crucial, because the quality of a pro-
tein product affects its safety and efficacy. It is known that
biopharmaceutical manufacturing is a multistep process,
involving cloning of the appropriate genetic sequence into a
carefully selected expression vector, selection of a suitable
cell expression system, and scale-up and purification, up
to formulation of the end product18 (Figure 1). Towards the
particular manufacturing process used, biopharmaceuticals
exhibited great sensitivity, and variation in product quality
was commonly observed, even when the exact same process
of manufacturing was used. The challenge then remains
to assess and quantify these differences, and determine
whether the new product is as safe and efficacious as the
innovator product. Further, variability of source material
has also been known to affect product quality. Thus the
product is affected both by the host cell and the processing
steps that follow. In addition, protein molecules can be
degraded during processing steps and impurities created
in these steps can contribute to decreased potency and/
or increased immunogenicity.45 With the large number of
quality attributes (Table 4), acquiring a complete knowledge
of the impact of each of the attributes on clinical safety and
efficacy is not feasible.46 However, the recent guidelines
of the International Conference on Harmonization Q8
on pharmaceutical development,47 and the roll-out of the
Quality by Design48 and Process Analytical Technology49
initiatives from the FDA have improved understanding of
the impact of manufacturing processes and their starting
materials, on product quality.
Biochemical characterization of the protein product
requires sophisticated analytical tools to detect the possibili-
ties of changes to the product. Further, the characterization
of the product requires a variety of methods for different
attributes or, alternatively, with orthogonal methods for
the characterization of a given attribute, thus developing
a comprehensive finger-printing of a protein product.50,51
However, key challenges remain that continue to require
attention, primarily because of the high complexity of the
products, processes, and raw materials that are part of the
manufacturing of biotechnology products.
Virtually all therapeutic proteins induce some level of
antibody response. The immune reaction can vary from low-
titer, low-affinity, and transient IgM antibodies to a high-titer,
high-affinity IgG response, with consequences ranging from
none to severe or life threatening. Many factors determine
the appearance of immunogenicity, including patient char-
acteristics and disease state, and the therapy itself influences
the generation of an immune response. Product-related
factors such as the molecule design, the expression system,
post-translational modifications, impurities, contaminants,
formulation and excipients, container, closure, as well as
degradation products are all implicated.52
It is fundamental to conduct pre-clinical and clinical
studies to understand the safety, efficacy, and quality of
both the innovator product and biosimilar medicines. Pre-
clinical studies are not yet capable of assessing the clinically
Table 3 Overview of European Medicines Agency biosimilar guidelines
Applicable to all biosimilars
Overarching Guideline on similar biological medicinal products32
Quality Guideline on similar biological medicinal products containing biotechnology-derived proteins as active
substance: quality issues33
Non-clinical and clinical Guideline on similar biological medicinal products containing biotechnology-derived proteins as active
substance: non-clinical and clinical issues34
Immunogenicity Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins35
Product specic – Annexes non-clinical and clinical
Guidance on similar medicinal products containing recombinant erythropoietins36
Guidance on similar medicinal products containing somatropin37
Guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor38
Guidance on similar medicinal products containing recombinant human insulin39
Non-clinical and clinical development of similar medicinal products containing recombinant interferon alpha40
Guideline on non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight heparins41

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relevant immunogenicity potential of these product-related
factors. Understandably, most of the focus has been on
assessing immunogenicity of protein products by non-clinical
studies.53–55 Despite advances in biochemical characterization
and other non-clinical methods for assessment of immunoge-
nicity, the unpredictability of the human immune system still
necessitates detailed safety assessments, which will rely heav-
ily on clinical trials. This is why clinical experience, through
clinical trials and extensive pharmacovigilance programs,
remains the most reliable way to assess immunogenicity.56–58
The best example of unexpected things happening with
protein drugs that have been well characterized is Hospira’s
biosimilar epoetin zeta (Retacrit®), which was approved by
EMEA. Eprex® (Amgen/Johnson & Johnson) is synthetic
erythropoietin (epoetin alpha) and is used to replace the eryth-
ropoietin that is lacking in people who cannot make enough,
usually because their kidneys are not working properly. Epo-
etin alpha is also used to treat people with cancer who develop
anemia because of chemotherapy treatment. Although pre-
approval physicochemical, in vivo, and animal testing showed
that it was biosimilar to its innovator product epoetin alpha
(Eprex), it had lower potency in clinical trials.59 Accordingly,
current analytical techniques are unable to assess immunoge-
nicity and potency. This is evident from the Eprex case which
showed that one protein can be different from another in ways
that cannot be detected in the laboratory, but are seen only
by the body’s exquisitely sensitive immune system. If one
change to a well-established complex manufacturing process,
made by the manufacturer who has intimate knowledge of the
process, can cause a problem with immunogenicity, surely
the risk is even greater with an entirely new manufacturer
and process – as with biosimilar.60
Recently launched efforts, such as the EMEA concept
paper on immunogenicity assessment of monoclonal antibodies
intended for in vivo clinical use, are expected to provide
further clarity on this topic.61 Further, when the Committee
for Medicinal Products for Human Use (CHMP)/EMEA
evaluations to date were examined, any difference in host cell
expression system, purity, and formulation appears acceptable if
the clinical data show no negative effect.62 Besides safety of an
innovator product, evidence suggested that efficacy can also be
a concern. The products were characterized for similarity in the
types of glycoforms present, the relative degree of unfolding,
in vitro potency, presence of covalent aggregates, and presence
of cleavage aggregates. The biochemical discrepancies between
the different copy products were most likely caused by the
differences in the cell lines and the manufacturing process.63
EMEA status of biosimilars:
approval or rejection
In the EU, a total of 14 brand name biosimilars (based on
4 reference products) from nine companies were approved
Table 4 Methods for QSE assessment of biosimilars
Attributes Methods
Primary sequence (peptide map and amino acid
sequence analysis), immunogenicity (immunoassay)
other identity indicators
IE, HPLC, gel electrophoresis
Potency Cell-based bioassay, gene expression bioassay, ADCC, CDC
Conformation Near/far UV circular dichroism spectroscopy, Fourier transform infrared
spectroscopy, X ray crystallography and differential scanning calorimetry
Glycosylation Monosaccharide composition analysis, oligosaccharide prole, CE, LC-MS,
MS/MS, ESI, MALDI-TOF
Phosphorylation Peptide mapping with MS
Truncation SE-HPLC, gel electrophoresis, AUC, peptide mapping with MS, RP HPLC
Glycation Peptide mapping with (MS, HPLC), methylation, isomerization (RP HPLC)
Pegylation HPLC, CE
Aggregation SE-HPLC, gel electrophoresis, Light scattering and AUC
Oxidation Peptide mapping with MS
Deamidation Capillary IEF, peptide mapping with MS, and CEX-HPLC, C-terminal lysine
(capillary IEF, peptide mapping with MS, and CEX-HPLC), misfolds (RP-HPLC)
Host cell proteins ELISA, DNA, endotoxin (Limulus amebocyte lysate assay)
Binding Cell assays, spectroscopy, ELISA
Biological activity Cell assays, animal models
Abbreviations: IE, ion exchange; HPLC, high performance liquid chromatography; ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent
cytotoxicity; CE, capillary electrophoresis; LC–MS, liquid chromatography–mass spectroscopy; MS/MS, tandem mass spectrometry; ESI, electrospray ionization; MALDI-TOF,
matrix-assisted laser desorption/ionization time of ight MS; AUC, analytical ultracentrifugation; CEX, cation exchange; IEF, isoelectric focusing; SE, size exclusion; RP-HPLC,
reverse phase HPLC; ELISA, enzyme-linked immunosorbent assay; QSE, quality safety and efcacy.

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since the pathway for regulatory approval of biosimilars
was established (Table 5).64 In 2006, the EMEA rejected an
application for approval of a biosimilar interferon product due
to concerns about product characterization, manufacturing,
and quality control.65 Also, in December, 2007, Marvel Life
Sciences officially notified CHMP that it wished to withdraw
its applications for marketing authorizations for a range of
biosimilar insulins, based on the decision of the CHMP not to
grant an extension to the timeframe given to them to respond
to a list of questions.66 Concerns raised by the CHMP over
biosimilarity, drug product, and substance, and both clinical
and non-clinical aspects, highlights that the approval pathway
for biosimilars is not straightforward, with products requiring
assessment on a case-by-case basis.67
EMEA provides information on the approval process for
human medicines (the European Public Assessment Report,
EPAR), including a scientific discussion on the clinical data
submitted for approval. Generally, the EPARs for biosimilars
have stated that the biosimilar received approval because
it was shown to have a quality, safety, and efficacy profile
comparable to the innovator product.68–75
Pharmacovigilance of biosimilars
Pharmacovigilance is particularly concerned with adverse
drug reactions. Recently, pharmacovigilance concerns have
been widened to include innovator product and biosimilars.
Clinical trials and post-authorization pharmacovigilance
are considered essential to guarantee the product’s safety
and efficacy over time. Pharmacovigilance, as part of a
comprehensive risk management programme, will need to
include regular testing for consistent manufacturing of the
drug.76 The most critical safety concern relating to biophar-
maceuticals (including biosimilars) is immunogenicity.77,78
Minimization of immunogenicity has to begin at the mol-
ecule design stage by reducing or eliminating antigenic
epitopes and building in favorable physical and chemical
properties.79 Pharmacovigilance is important in the bio-
similars market because of the limited ability to predict
clinical consequences of seemingly innocuous changes in
the manufacturing process and the scientific information
gap.56 The Eprex example also underscores other critical
points. First, careful post-market monitoring of the safety
of a biologic, whether innovative or biosimilar, is extremely
important. Increased pharmacovigilance with biopharma-
ceuticals was highlighted with the Eprex (epoetin alfa)
pure red cell aplasia issue. CHMP guidelines emphasize
the need for particular attention to pharmacovigilance,
especially to detect rare but serious side effects.56 Phar-
macovigilance systems should differentiate between inno-
vator product and biosimilar products, so that effects of
biosimilars are not lost in the back–ground of reports on
innovator products.80 Further, the risk management plan for
biosimilars should focus on increasing pharmacovigilance
measures, identify immunogenicity risk, and implement
special post-marketing surveillance. Although International
Nonproprietary Names (INNs) served as a useful tool in
worldwide pharmacovigilance, for biological products,
they should not be relied upon as the only means of prod-
uct identification. In addition, biological products should
always be commercialized with a brand name or the INN
plus the manufacturer’s name.81
To improve patient safety through enhanced pharma-
covigilance, Novartis supports the recent initiative in the
EU to review and improve the pharmacovigilance system
of medicinal products in Europe. In addition, valid pharma-
covigilance procedures should be mandatory for all products
of a certain category (eg, biopharmaceutical) and not depend
on whether the relevant brand is an innovator product or a
biosimilar product.82
Biologicals carry specific risks. Safety problems, for
example infliximab and the risk for tuberculosis, have been
identified via spontaneous reports of suspected adverse drug
reactions (ADRs). Data obtained from the ADR database
(VigiBase), maintained by the WHO Collaborating Centre
for International Drug Monitoring, indicated that biologicals
Table 5 Biosimilars approved or rejected timeline
Biosimilar Reference Approval/Rejection
year
Omnitrope Somatropin 2006*
Valtropin Somatropin 2006*
Binocrit Epoetin alpha 2007*
Epoetin alpha Epoetin alpha 2007*
Hexal
Abseamed Epoetin alpha 2007*
Silapo Epoetin zeta 2007*
Retacrit Epoetin zeta 2007*
Filgrastim Filgrastim 2008*
Ratiopharm
Ratiograstim Filgrastim 2008*
Biograstim Filgrastim 2008*
Tevagrastim Filgrastim 2008*
Filgrastim hexal Filgrastim 2009*
Zarzio Filgrastim 2009*
Nivestim Filgrastim 2010*
Alpheon Roferon-A 2006**
Human insulin Humulin 2007**
Notes: *Approved, **Rejected

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have a different safety profile compared with all other drugs in
the database and, within the group of biologicals, differences
exist between mechanistic classes. In addition, because not all
adverse reactions can be predicted or detected during devel-
opment, spontaneous reporting remains an important tool for
the early detection of signals.83 Further, pharmacovigilance
plans developed and implemented by manufacturers are fre-
quently part of the post-approval commitments to regulatory
agencies to provide follow-up safety assessments. It was years
of pharmacovigilance that allowed physicians to determine
that the problem with Eprex occurred possibly because the
switch to polysorbate 80 caused the drug to react to the rubber
stopper used in vials. Pharmacovigilance of biosimilars from
a regulatory point of view has been reported.84
Commercial opportunities
Biosimilar development is a landmine of complexities
with respect to regulatory, manufacturing, and marketing
aspects, making it one of the most expensive development
propositions in the pharmaceutical industry. Like generic
pharmaceuticals, biosimilars enter the market with the aim of
reducing healthcare cost, but entry to the biosimilar market
carries higher costs, greater risks, and more time and exper-
tise in relation to the clinical development of these products.
Furthermore, the marketing and launch of biosimilars
requires a different strategy than small-molecule generics.
The considerable costs to obtain FDA approval, and the sub-
stantial costs to develop manufacturing capacity, will limit
the number of biosimilar competitors. In this scenario, very
few biosimilar manufacturers are likely to attempt entry for
a given innovator product and are unlikely to introduce their
drugs only at discounts normally in the range of 10% to 30%
of the innovator product price. Further, the lack of automatic
substitution between a biosimilar and an innovator product
will slow the rate at which a biosimilar can obtain market
share. Therefore, it is easy to see that currently, the type and
amount of resources required for biosimilar development can
create high barriers of entry, not just for small to mid-sized
companies, but even for the larger, well-established generics
players and global biopharmaceutical companies.85–87 Gaining
market share for a biosimilar could be challenging when there
is no added benefit over the innovator and insignificant cost
savings. The price decrease can be achieved when multiple
biosimilars are introduced to the market.88
On the other hand, if a substantial price decrease is
not viable for a biosimilar, a better strategy seems to be to
develop a biosimilar as a new product. It would benefit the
sponsor to use a scientific rationale and its own nonclinical
and clinical testing, most of which will be required anyway,
to develop its product as a unique innovator product, and gain
the benefit of extended market exclusivity.89
Biosimilars in clinical practice
Despite the comparability of biosimilars to the innova-
tor product, clinicians and health care workers should be
aware of some of the issues that have emerged during the
development and approval of these products, which highlight
the challenges of biosimilars.65 The use of biosimilars is
essentially a change in clinical management.90 By taking a
leading role in educating patients and medical professionals
about the risks and benefits of biosimilars, the Pan American
and Health Education Foundation is actively involved in
improving patient safety.91
The role of nurses in the use
of biosimilars
Nurses are used to administering generic versions of
chemically synthesized drugs which have identical thera-
peutic properties, and cause the same adverse events as,
their branded counterparts. Biosimilars, however, are not
identical to the innovator biopharmaceutical products
they seek to replicate. The lack of nursing awareness and
education about biosimilars can lead to medication errors,
adverse events, or a delay in desired therapeutic gain for
the patient.92
The complex nature of innovator products and biosimilar
biopharmaceuticals requires that nurses are better informed
about their differences (to the extent they exist), use, and
effects. Experts are of the opinion that responsibility must
be placed on manufacturers, professional bodies, and pre-
scribers to ensure that the nursing profession has continued
access to updated information on current and emerging
biopharmaceutical products. In addition, safe use of such
products should be embedded in education, policies, and
procedures. Furthermore, the challenges and the need for
increased awareness of biosimilars in nursing and clinical
practice have been reported.93 In addition to education, it is
essential that nurses take meticulous records when adminis-
tering biopharmaceuticals.
Challenges facing biosimilars when educational cur-
riculum or materials are designed, are adequate advice to
patients and colleagues, assessing medication substitution,
and assessing and evaluating patients, thus requiring nurses
to be proactive in being well informed about the biophar-
maceuticals that are available, and to gain knowledge and
training that is current and evidence-based.94

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9
Biosimilars
The role of hospital pharmacists
It is of utmost importance that the hospital pharmacist
is aware that the innovator products and biosimilars are
not interchangeable, because patients must be carefully
monitored if their treatment is changed between products.
Moreover, patient welfare is foremost and for pharmacists,
the knowledge that biosimilars are not generics, and the pos-
sible implications for clinical outcomes when products are
switched, will help ensure patient safety.95
Additionally, biosimilars are deemed to contain a new
active ingredient, whereas interchangeable products are not.
The Eprex example also provides a rationale for not consid-
ering a biosimilar to be interchangeable with an innovative
product. FDA has stated that it has not determined how inter-
changeability can be established for complex proteins.96,97
Systematic checklists have been proposed for the evalu-
ation of biopharmaceuticals coming on to the market, which
have provided additional reassurance for the pharmacist. For
example, the Pharmacy Checklist for Retacrit (epoetin zeta)
provides information on manufacturing, protein and product
formulation, batch consistency, supply reliability, good
handling practice, clinical efficacy, and clinical safety and
tolerability.98 The successful introduction of EU biosimilar
erythropoietins, such as Retacrit gives hospital pharmacists
the opportunity to reduce costs and improve the treatment
of patients with anemia.
Conclusions and perspectives
The problems of biosimilars are in active debate around the
globe. A critical evaluation is needed for more efficient, cost
effective widespread availability of biosimilars. Because
biosimilar products are very complex molecules, factors such
as the robustness of the manufacturing process, structural
similarity to the parent molecule, level of understanding
of the mechanism of action, quality of pharmacodynamic
assays utilized, demonstrated comparability in pharma-
cokinetics and immunogenicity, quantity and quality of
clinical data, and the innovator’s experience with the parent
product needs to be considered critically before marketing
approval of biosimilars can be granted. The decision on
interchangeability is still pending and under such a desig-
nation, the substitution of the biosimilar for the innovator
product without involving the prescribing physician is not
appropriate. In this respect, physician awareness of potential
differences between biopharmaceuticals and biosimilars and
the impact on safety and efficacy is vital for patient safety.
Clinicians require comprehensive information on biosimilars,
and biopharmaceuticals in general, to make knowledgeable
treatment decisions. In addition, pharmacovigilance will be
essential to track down any safety and efficacy problems that
may arise from the use of biosimilars. Further, the regulations
for the naming and the labeling of biosimilar products should
be the responsibility of a single authorized body and should
be globally acceptable. Although biosimilars have begun
to enter the global market, the biosimilar manufacturers’
long-term capability to manufacture a consistent product
still remains to be proven. At present, even though European
legislation is in place to assess and grant marketing approval
for biosimilars, the EMEA guidelines only provide a road
map and leave challenging areas still to be explored and
monitored. Approvals of biosimilar products should continue
to be dealt with on a case-by-case basis.
Disclosure
The authors declare no conflicts of interest.
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