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Global regulatory landscape of biosimilars: emerging and established market perspectives

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  • Sri Ram Cancer Center Mahatma Gandhi Medical College & Hospital

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Anita Krishnan,1 Rustom Mody,1 Hemant Malhotra21Lupin Limited, Biotech Division, Maharashtra, India; 2Division of Medical Oncology, RK Birla Cancer Center, SMS Medical College Hospital, Jaipur, India Abstract: Biological product development for launch in multiple geographies with varied regulatory expectations would require a planned and focused strategy, involving the selection of the appropriate reference product, defining the extent of process and product characterization and design of nonclinical and clinical studies. The development for established markets like the European Union and the United States, which have precedence in regulatory pathways, may face very different challenges compared to emerging markets, many of which are still in the nascent stages of regulatory guidelines. A clear and concise understanding of the regulatory framework of each region and awareness of the limitations of health care policies, with an added knowledge of the local factors that influence the biosimilar market, would be desirable for a good business strategy. Herein it is attempted to outline the stages of regional guideline implementation in the various global locations and compare the variability in regulatory requirement between them. The factors that could potentially impact biosimilars business in these regions are also outlined. Finally, the prevailing competition between manufacturers of innovative and biosimilar drugs, which could influence the availability of lifesaving off-patent drugs for critical diseases and the advent of more effective, alternate, or next-generation molecules, is also briefly described. Keywords: guidelines, India, comparability, EMA, US FDA, WHO
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http://dx.doi.org/10.2147/BS.S44052
Global regulatory landscape of biosimilars:
emerging and established market perspectives
Anita Krishnan1
Rustom Mody1
Hemant Malhotra2
1Lupin Limited, Biotech Division,
Maharashtra, India; 2Divisi on of
Medical Oncology, RK Birla Cancer
Center, SMS Medical College Hospital,
Jaipur, India
Correspondence: Hemant Malhotra
Division of Medical Oncology, RK Birla
Cancer Center, SMS Medical College
Hospital, Jaipur–302 004, India
Tel +91 141 2620600
Fax +91 141 2622899
Email drmalhotrahemant@gmail.com
Abstract: Biological product development for launch in multiple geographies with varied
regulatory expectations would require a planned and focused strategy, involving the selection
of the appropriate reference product, defining the extent of process and product characterization
and design of nonclinical and clinical studies. The development for established markets like the
European Union and the United States, which have precedence in regulatory pathways, may face
very different challenges compared to emerging markets, many of which are still in the nascent
stages of regulatory guidelines. A clear and concise understanding of the regulatory framework
of each region and awareness of the limitations of health care policies, with an added knowledge
of the local factors that influence the biosimilar market, would be desirable for a good business
strategy. Herein it is attempted to outline the stages of regional guideline implementation in the
various global locations and compare the variability in regulatory requirement between them.
The factors that could potentially impact biosimilars business in these regions are also outlined.
Finally, the prevailing competition between manufacturers of innovative and biosimilar drugs,
which could influence the availability of lifesaving off-patent drugs for critical diseases and the
advent of more effective, alternate, or next-generation molecules, is also briefly described.
Keywords: guidelines, India, comparability, EMA, US FDA, WHO
Introduction
Biological entities, larger in size but smaller in presence as compared to chemical
entities, have made a significant difference to patients around the world by provid-
ing targeted solutions to illness rather than symptomatic relief. The advent of newer
understanding of the molecular and cellular basis of diseases, such as cancer, arthritis,
and multiple sclerosis, through technological advances has led to biotechnology-
based therapies finding their importance and preference in the clinical and patient
community. The term “biological drug” or “biologics” could encompass a wide
variety of molecules, such as therapeutic/supplementary proteins, hormones, mono-
clonal antibodies, antibody fragments, pegylated proteins, albumin binding domain
antibodies, and deoxyribonucleic acid (DNA) vaccines. In terms of sheer size, these
molecules are often 100 to 1,000 times bigger than their chemical counterparts, in
turn making them complex. All protein biological entities are composed of a string
of amino acids that are sometimes disulphide bonded within or with other similar
or dissimilar subunits, bent into alpha-helix and beta-sheets typically forming the
1°, 2°, 3° and 4° structure, giving rise to pockets and crevices which are critical for
their functionality. Typically, recombinant proteins are produced by manipulating the
genetic blueprint of a living cell (prokaryotic or eukaryotic) with the gene of interest
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Krishnan et al
and culturing in liquid medium, to tap the expressed protein
of interest. This protein which is surrounded by a milieu of
other proteins, sugars, and lipids is chromatographically
isolated to a purity of more than 98% to form the drug
substance. The drug substance is the equivalent of an active
pharmaceutical ingredient in a pharma molecule, which is
then formulated with an appropriate buffer and excipients
to make the final injectable product called the drug prod-
uct. Due to the complex mode of production involving live
organisms in a stringently controlled environment, achieving
manufacturing consistency is an indomitable task. Though
every batch inherently has product quality differences, for
obvious reasons, the variations from batch to batch need to
be monitored to ensure conformance within a preset range.
The product even in the purest form is still associated with
a number of product variants; for example, posttranslational
modifications such as glycosylation, oxidation, and deamida-
tion variants. These variants are most often critical quality
attributes and have a high impact on the functionality of the
molecule. Thorough characterization of these posttransla-
tional modifications and other structural variations that are
not present in small molecules is scientifically challenging.
Apart from these, there are other process-related impurities
that arise from the host, such as host cell proteins, host cell
DNA, and endotoxins, which need to be controlled within a
safe limit. The product quality differences between batches
need to be thoroughly scrutinized in a regulatory application
and correlation to clinical trial results need to be drawn, to
avoid any safety hazard to the consumers. Therefore, a “one
size fits all” approach of regulatory review of a small mol-
ecule does not fit a biological drug (Figure 1).
Biosimilars are blockbuster drugs, in the sense that they
are affordable copies of the expensive originals, providing
much-needed affordable quality health care. A major part of
this affordability arises from the reduced clinical trial require-
ments, the permission for which is granted, when sufficient
biosimilarity is demonstrated.1–3 Since the biosimilar is the
end product of a biotechnological process, a system wherein
genetic manipulation and physiological environment is the
key factor, the active ingredient is similar to the original
biologic, but never identical. Unlike generics, where an
exact identical copy is anticipated, in biosimilars “process is
product,and subtle variations are inherent, since no sponsor
has knowledge of the originator’s process or cell lines. The
recombinant protein produced will bear the fingerprint of the
cell line and process, in terms of product- and process-related
impurities, since it is a highly controlled manufacturing
environment. Due to this complexity, regulatory requirements
of clinical, nonclinical, and analytical comparability of these
subtle differences to the originator are mandatory. These
regulatory requirements for biosimilar drug applications
weigh more than a generic drug application but less than a
new biologic drug application. In a generic application, it is
sufficient if quality, purity, and bioequivalence evidence is
presented. However, with biosimilars, apart from chemistry,
manufacturing and controls analytics, the emphasis is on
biosimilarity, preclinical, immunogenicity, and limited clinical
studies. As molecule exclusivity expires, sponsors all over the
globe attempt to produce these recombinant protein drugs.
In a business perspective, many factors such as development
timeline, cost of goods, drug accessibility, user friendliness,
and regulatory compliance are all factors that drive the mar-
ket in varied degrees in different geographical regions. With
multiple prospective manufacturers on the horizon, the need
arises for regulatory guidelines that ensure biosimilarity,
comparability, and interchangeability with respect to safety
and efficacy of the product. The major dictators in this domain
are the European Medicines Agency (EMA), the World Health
Organization (WHO), and the United States Food and Drug
Administration (US FDA), with a number of regional versions
of guidelines that have been formulated based on the above
mentioned templates. Here we attempt to compare the
regulatory scenario in emerging markets with regards to the
advanced European Union (EU) and US environment and also
to evaluate the driving forces for these two.
Denition of biosimilars
Biosimilars, although bearing in essence the same meaning
world over, have been defined in different ways and with
differences in nomenclature. A brief tabulation has been
presented below as a ready reckoner (Table 1).4–10
Market position of biosimilars
Biosimilars are legally approved subsequent versions of
innovator biopharmaceutical products following patent and
exclusivity expiry. However, the definition and nomenclature
of biosimilars differs among the various regulatory agencies
across the world. For example, they are known as similar bio-
logical medicinal products by the EMA and Korean Food and
Drug Administration (KFDA), as follow-on protein products
or follow-on biologics by the US FDA and Ministry of Health,
Labor, and Welfare (MHLW), and as subsequent entry biolog-
ics by Health Canada. Biological drugs constitute one of the
largest growing sectors of the pharmaceutical industry. By
2015, sales of biosimilars are expected to reach between US
$1.9–$2.6 billion and US $25 billion in 2020, a compound
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Global regulatory landscape of biosimilars
annual growth rate (CAGR) of 7.7%.11 Biosimilar products
encompass different therapeutic classes, like erythropoietins,
growth hormones, interferons, stimulating factors, low
molecular weight heparins, insulins, monoclonal antibodies,
and Fc fusion proteins. Of these, monoclonal antibodies have
been established as a major product class and occupy a large
sector of the biosimilar market space. This is primarily due to
the therapeutic success of these molecules and the prevalence
of diseases like cancer, arthritis, and psoriasis.
With patents for top-selling monoclonal antibody drugs
poised to expire shortly or already expired, there is a clamor
among biosimilar manufacturers for the business.12 In a
way it is good for health care for two reasons: availability
of affordable drugs and research and development focus on
novel biologics. For registration of their products, biosimilar
sponsors have to prove equivalence or similarity to the ref-
erence product. Variations of smaller magnitude, especially
risks of immunogenicity, have to be shown as clinically
nonsignificant, because of safety and efficacy. These regula-
tory requirements have now evolved and been included in
the guidelines.
Evolution of guidelines
for biosimilars
After the first wave of off-patent drugs, EMA was the
first to create biosimilar guidelines in 2005, and the first
approval came about in 2006. EMA boasts the longest list of
approved biosimilars after the implementation of biosimilar
guidelines (Table 2).13 The responsibility of implementing
regulation (with respect to development, authorization,
and manufacturing of biotherapeutics) lies with member
states of the EU. EU guidelines to date stand as one of the
most stringent regulatory norms for biosimilar product
development. The chemistry, manufacturing and controls
package and other clinical requirements are extensive,
which ensures safety and efficacy of biosimilars produced
by the sponsors. Traditionally, sponsors have found it safe
to develop simple protein therapeutics like granulocyte-
colony stimulating factor, erythropoietin, somatropin, and
follitropin. However, recently two biosimilar monoclonal
antibodies of infliximab have been approved in a landmark
decision, indicating that even complex molecules can gain
biosimilar status in the EU if well developed.
In 2009, WHO developed a set of globally accepted
standards to ensure the safety, efficacy, and quality of similar
biotherapeutic products (SBPs). These were mainly targeted
to aid and ensure local regulatory authorities to adhere to
international standards.2 Ever since there has been a rapid
evolution of guidelines, and most countries have adopted the
general framework of EMA (Table 3) or WHO, while others
have established their individual national guidelines based on
these templates. Australia adopted the EU guidelines without
any changes, while Singapore and Malaysia amended their
guidelines mainly in accordance with the EMA guidelines.14
Brazil and Cuba chose the WHO and Canadian guidelines
as the basis for developing regulations for their respective
countries.15 However, there are considerable variations in
definitions, terminology, reference product for comparability,
Table 1 Denitions of biological medicines according to regional regulatory agencies
Nomenclature Agency Denition
Similar biological
medicinal product
EMA
(2006)4
Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality,
safety, and efcacy, of the new similar biological medicinal product and the chosen reference medicinal
product authorized on the basis of a complete dossier in the community.
Similar biotherapeutic
product
WHO
(2009)3
A biotherapeutic product which is similar in terms of quality, safety, and efcacy to an already licensed
reference biotherapeutic product.
Biosimilar Korea
(2009)6
A biological product which demonstrated its equivalence to an already approved reference product with
regard to quality, safety, and efcacy.
Subsequent entry
biologic
Canada
(2010)7
A biologic drug that enters the market subsequent to a version previously authorized in Canada, and with
demonstrated similarity to a reference biologic drug. A subsequent entry biologic relies in part on prior
information regarding safety and efcacy that is deemed relevant due to the demonstration of similarity to
the reference biologic drug and which inuences the amount and type of original data required.
Similar biologics India
(2012)8
Similar biologics contain well-characterized proteins as their active substance. The demonstration of similarity
depends upon detailed and comprehensive product characterization and preclinical and clinical studies carried
out in comparison with a reference biologic.
Biological product/
biosimilar
US FDA
(2012)9,10
“The biological product is highly similar to the reference product notwithstanding minor differences in
clinically inactive components,” and that “there are no clinically meaningful differences between the biological
product and the reference product in terms of the safety, purity, and potency of the product.”
Abbreviations: EMA, European Medicines Agency; WHO, World Health Organization; US FDA, United States Food and Drug Administration.
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Krishnan et al
Table 2 EMA-approved biosimilars
Product Active
substance
Authorization
date
Manufacturer/
Company
Omnitrope Somatropin April 12, 2006 Sandoz GmbH
Valtropin Somatropin April 24, 2006
(withdrawn
May 2012)
BioPartners GmbH
Abseamed Epoetin alfa August 28, 2007 Medice Arzneimittel
Pütter GmbH
Binocrit Epoetin alfa August 28, 2007 Sandoz GmbH
Epoetin alfa
hexal
Epoetin alfa August 28, 2007 Hexal AG
Retacrit Epoetin zeta December 18,
2007
Hospira UK Limited
Silapo Epoetin zeta December 18,
2007
Stada Arzneimittel
AG
Biograstim Filgrastim September 15,
2008
AbZ-Pharma GmbH
Ratiograstim Filgrastim September 15,
2008
Ratiopharm GmbH
Filgrastim
ratiopharm
Filgrastim September
15, 2008
(withdrawn
July 20, 2011)
Ratiopharm GmbH
Tevagrastim Filgrastim September 15,
2008
Teva GmbH
Filgrastim
hexal
Filgrastim February 6,
2009
Hexal AG
Zarzio Filgrastim February 6,
2009
Sandoz GmbH
Nivestim Filgrastim June 8, 2010 Hospira UK Limited
Somatropin
Biopartners
Somatropin August 5, 2013 BioPartners GmbH
Inectra Iniximab September 10,
2013
Hospira UK Limited
Remsima Iniximab September 10,
2013
Celltrion Healthcare
Hungary Kft
Ovaleap Follitropin
alfa
September 27,
2013
Teva Pharma BV
Grastol Filgrastim October 18,
2013
ApotexEurope BV
Bemfola Follitropin
alfa
March 27, 2014 Finox Biotech AG
Abbreviation: EMA, European Medicines Agency.
Generic
Quality Quality Quality
Biosimilar New biologic
Stability
Stability Stability
Biosimilarity
Comparability
Comparability
Interchangeability
Preclinical
Preclinical
Full clinical
Abbreviated clinical
Immunogenicity Immunogenicity
Potency Potency
Purity Purity Purity
Figure 1 Comparison of the requirements for biosimilar licensure pathway, with
regards to the generic (small molecule) and novel biologics pathways.
extent of data requirements, and other aspects. India released
official guidelines in June 2012,5 prior to which 20 biosimilars
were already approved for use within India under an ad hoc
abbreviated process (Figure 2).16
WHO regulatory framework
To assure safety, efficacy, and quality of biotherapeutic
products, WHO guidelines draw certain basic principles
which are mandatory for licensure of a biosimilar product.
This ensures successful regulatory submissions in most major
pharmaceutical geographies around the world.
• Reference product: The chosen reference biotherapeutic
product (RBP) should be licensed based on full quality,
safety, and efficacy data and should be authorized in the
country or region in question. Wherever it may not be
feasible, such as countries lacking nationally licensed
RBPs, additional criteria (such as the product should be
licensed and widely marketed in another jurisdiction)
may be applied.
• Quality: All aspects of quality and heterogeneity should
be assessed, including head-to-head comparisons with
the reference product. Due to unavailability of the drug
substance of RBP, comparison is performed mostly with
the commercial product. It is important to show that the
excipients do not pose interference in the analytical test
methods. Wherever this is not possible, extraction of drug
substance needs to be performed. In that case demonstra-
tion that product heterogeneity and relevant attributes
of the active moiety are not affected by the extraction
procedure is required. Where possible, the product should
be tested with and without manipulation.
• Nonclinical data: Data should include pharmacodynamic,
pharmacokinetic (PK), and comparative repeat-dose
toxicity studies in a relevant species. The selection of PK
study design, which could be single-dose studies, steady-
state studies, or repeated determination of PK parameters,
needs to be adequately justified by the sponsor. The
pharmacokinetics of the SBP and RBP are compared
in terms of absorption, bioavailability, and elimination
characteristics. Clinically relevant pharmacodynamic
(PD) markers should be selected and may be investigated
in the context of combined PK/PD studies.
• Clinical studies: Similarity of the efficacy of the SBP
and the RBP will usually have to be demonstrated in
adequately powered, randomized, and controlled clinical
trial(s). Although equivalence designs are the preferred
choice for the comparison of efficacy and safety of the
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Global regulatory landscape of biosimilars
SBP with the RBP, noninferiority designs may also be
considered if appropriately justif ied. Immunogenic-
ity should always be investigated in humans before
authorization.
• Pharmacovigilance: Monitoring, or a pharmacovigilance
plan, at the postmarketing phase is included in the guide-
line to supplement the limited clinical data that is present
during authorization. In some cases an associated risk
management plan is also advised.
2004 2005 2006
EU
Final guideline implemented
Taiwan
WHO Saudi Arabia
Singapore Mexico
India
PRC
Italy
USA
Egypt
VenezuelaPeru
Colombia
Jordan
Iran
Peru
Chile
Brazil
Canada
S Africa
Japan
Korea
Malaysia
Turkey
Australia
Argentina
Draft version/concept paper
2007 2008 2009 2010 2011 2012 2013 2014
Figure 2 Evolutionary scale of guidelines in the last decade.
Abbreviations: EU, European Union; PRC, People’s Republic of China; S Africa, South Africa; USA, United States of America; WHO, World Health Organization.
WHO guidelines, although they followed the EMA guide-
lines chronologically, are not geography specific and thus
were a template for many other national regulatory agencies
(NRA). We scrutinized the regulatory landscape in all these
different global locations.
European Union (EMA)
The EU is the forerunner for the biosimilar market, as is
evident from the number of approved drugs, market size,
Table 3 European Medicines Agency guidelines relevant to biosimilar development and approval
EMEA/CPMP/BWP/3207/2000/Revision 1: Guidelines on comparability of medicinal products containing biotechnology-derived proteins as active
substance; quality issues.
Available from: http://www.ema.europa.eu/docs/en_GB/documentlibrary/Scientic_guideline/2009/09/WC500003573.pdf
EMEA/CPMP/3097/2002: Guidelines on comparability of medicinal products containing biotechnology-derived proteins as active substance; non-
clinical and clinical issues.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2009/09/WC500003963.pdf
CHMP/437/2004/Revision 1: Guidelines on similar biological medicinal products.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2013/05/WC500142978.pdf
EMA/CHMP/BWP/247713/2012/Revision 1: Guidelines on similar biological medicinal products containing biotechnology-derived proteins as active
substance; quality issues.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2012/05/WC500127960.pdf
EMA/CHMP/BMWP/572828/2011: Concept paper on the revision of the guidelines on similar biological medicinal products containing biotechnology
derived proteins as active substance; non-clinical and clinical issues.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2011/10/WC500115611.pdf
EMA/275542/2013: Concept paper on the revision of the guidelines on immunogenicity assessment of biotechnology-derived therapeutic proteins.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2014/03/WC500163623.pdf
EMEA/CHMP/BWP/157653/2007: Guidelines on development, production, characterization, and specication for monoclonal antibodies and related products.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2009/09/WC500003074.pdf
EMA/CHMP/BMWP/86289/2012: Guidelines on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2012/06/WC500128688.pdf
EMA/CHMP/BMWP/403543/2010: Guidelines on similar biological medicinal products containing monoclonal antibodies.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2010/11/WC500099361.pdf
Abbreviations: BWP, Biologics Working Party; BMWP, Biosimilar Medicines Working Party; CHMP, Committee for Medicinal Products for Human Use; CPMP, Committee
for Proprietary Medicinal Products; EMA, European Medicines Agency; EMEA, European Medicines Agency.
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Krishnan et al
Table 4 European Medicines Agency guidelines relevant to product-specic biosimilar development and approval
EMEA/CHMP/BMWP/94528/2005: Guidance on similar medicinal products containing somatropin.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2009/09/WC500003956.pdf
EMEA/CHMP/BMWP/32775/2005/Revision 2: Guidelines on nonclinical and clinical development of 4 similar biological medicinal products containing
recombinant human insulin and insulin analogs.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2014/04/WC500165988.pdf
EMEA/CHMP/BMWP/31329/2005: Guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2009/09/WC500003955.pdf
EMEA/CHMP/BMWP/301636/2008/Revision: Guidelines on nonclinical and clinical development of similar biological medicinal products containing
recombinant erythropoietins.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2010/04/WC500089474.pdf
EMEA/CHMP/BMWP/102046/2006: Guidelines on similar medicinal products containing recombinant interferon alpha.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2009/09/WC500003931.pdf
EMEA/CHMP/BMWP/118264/2007/Revision 1: Guidelines on similar biological medicinal products containing low molecular weight heparins.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2013/01/WC500138309.pdf
EMA/CHMP/BMWP/403543/2010: Guidelines on similar biological medicinal products containing monoclonal antibodies – nonclinical and clinical issues.
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2012/06/WC500128686.pdf
EMA/CHMP/BMWP/671292/2010: Guidelines on nonclinical and clinical development of similar biological medicinal products containing recombinant
human follicle stimulating hormone (r-hFSH).
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2013/03/WC500139624.pdf
EMA/CHMP/BMWP/652000/2010: Guidelines on similar biological medicinal products containing interferon beta.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientic_guideline/2013/03/WC500139622.pdf
Abbreviations: BWP, Biologics Working Party; BMWP, Biosimilar Medicines Working Party; CHMP, Committee for Medicinal Products for Human Use; EMA, European
Medicines Agency; EMEA, European Medicines Agency.
promulgation of the guidelines, and so forth. The EMA/
European Commission were the first to implement a well-
documented legal and regulatory pathway for the approval of
biosimilar products that is distinct from the generic pathway.
Clear definitions in terms of the analytical, preclinical, and
clinical data requirements have been specified in the guide-
lines, which are more detailed than those for generics. The
EMA requirements for comprehensive comparability studies
between the biosimilar and reference product are elaborately
defined in the EMA guidelines. The EMA guidelines are
some of the most stringent, and recommend a case-by-case
review of submissions, considering the diversity and com-
plexity of biological products.17
EMA first released general guidelines for quality issues
and nonclinical and clinical issues which encompass qual-
ity, consistency, the manufacturing process, safety, and
efficacy considerations. This was followed by far more
detailed product-specific guidelines, by EMA/ Committee
for Medicinal Products for Human Use (CHMP), for
products like erythropoietin, growth hormone, granulocyte-
colony stimulating factor (G-CSF), insulin, interferon
beta, low-molecular weight heparins, and monoclonal
antibodies.18 The list of guidelines/concept papers are
listed in Table 4. The EMA/CHMP guidelines are adopted
standards in countries like Australia, Canada, Japan, Korea,
and South Africa.1,15
United States of America (US FDA)
The market in the United States for recombinant therapeutics
reached $507 million in 2010 and $1.1 billion in 2011. The
market is expected to reach $1.3 billion by 2016, a CAGR
of 4.1%.19
In the US, approval for biological products is made
through the Public Health Service Act and for small molecule
drugs through the Federal Food, Drug, and Cosmetics Act.
Unlike EMA, the US FDA was a late entrant to the biosimi-
lars regulatory pathway. On March 23, 2010, the Biologics
Price Competition and Innovation Act (BPCIA) was signed
as part of the Patient Protection and Affordable Care Act,
which created a new licensure pathway for biosimilars
within the auspices of the US FDA. Biosimilar applications
can be submitted under section 351(k) of the Public Health
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Global regulatory landscape of biosimilars
Service Act. The BPCIA was considered equivalent to the
Drug Price Competition and Patent Term Restoration Act of
1984 or the Hatch–Waxman Act of generics, which enabled
the availability of affordable drugs for public health and
fostered innovation by the originator companies. However,
the generic manufacturers had to only establish the sameness
or exactness of their molecules to the approved originator
drug supported by bioequivalence studies and could rely to a
large extent on the safety data of the originator while seeking
approval. Since the biological products cannot be the same
or exact, provisions for demonstrating “similarity” had to be
included in the BPCIA. The Act defined the basic requirement
of a demonstration of biosimilarity between reference and
biosimilars that was proposed with the same mechanism of
action and same indications. The Act also proposes that the
sponsor’s product should be shown as interchangeable with
the originator’s product. Given the environment of major
resistance from originators, the Act also provided exclusivity
periods for reference biologics and some already approved
follow-on biologics. A complex framework addressing the
procedure for resolving patent disputes between the biologic
innovator and the biosimilar’s sponsor were also defined.
However, specific criteria for biosimilarity or interchange-
ability, such as the extent of analytical data, animal studies, or
clinical trial designs, were not defined. Until now, the BPCIA
has provided case-specific determinations to the sponsor’s
individual molecules rather than providing any criteria for a
class of molecules.20
The US FDA finally issued three draft guidance docu-
ments in 2012, recommending a stepwise approach to
demonstrate biosimilarity, laying importance on “totality of
evidence”:6,21,22
Quality Considerations in Demonstrating Biosimilarity
to a Reference Protein Product
Scientific Considerations in Demonstrating Biosimilarity
to a Reference Product
Biosimilars: Questions and Answers Regarding Imple-
mentation of the BPCIA of 2009.
The Scientific Considerations guidance calls for the
demonstration of biosimilarity between the reference and
biosimilar in terms of safety, potency, and purity, with no
clinically meaningful differences. The guidance insists on
the following main points:
Analytical studies: Demonstration of the product as highly
similar to the reference, notwithstanding minor clinically
irrelevant differences.
Animal studies: Including toxicity studies, PK and PD
measurements, and immunogenicity studies.
Human clinical studies: Including PK and PD
measurements, immunogenicity results, and safety
and efficacy data, plus equivalence studies showing
comparability on both upper and lower margins. It
also recommends sponsors to establish an early meet-
ing with US FDA officials with preliminary data and
product development plans and understand the require-
ments of submission, while also drawing a schedule of
milestones/meetings for future work.
The Quality Considerations guidance dwells more on the
physicochemical characterization needs of the application.
The US FDA considers certain important underlying factors
while evaluating applications, like manufacturing process
consistency, structural similarity, potency assays relevant
to mechanism of action, PD studies extending the under-
standing of the mechanism of action, comparative PK, and
immunogenicity. In physicochemical characterization, the
emphasis is on display of primary and higher order structure
and post-translational and chemical modifications, whereas
in biological characterization, comparative potency and
receptor binding assays are the expectations. The commercial
history and experience of the sponsor could also be added
valid points. Another major consideration of the BPCIA is
the interchangeability of biosimilars. A sponsor must dem-
onstrate that the biosimilar drug produces the same clinical
effects as the originator in patient studies. This ensures
automatic interchangeability of the biosimilars with the
reference originator product, without the need for clinician’s
discretion. Once approved or licensed for marketing, the
clinician will not have to intervene regarding switching/
swapping these drugs.6
The Questions and Answers Guidance provides a set of
answers that biosimilar sponsors require early on, like appre-
hensions regarding differences in formulation, exclusivity
issues, and meeting schedules. This guidance also provides a
list of definitions distinguishing terms such as “chemically syn-
thesized polypeptide,” “biological product,” and “protein.
Japan (Pharmaceuticals and Medical
Devices Agency)
Japan’s national regulatory agency is the Pharmaceuticals and
Medical Devices Agency (PMDA); it is one of the countries
that had defined regulatory pathway for biosimilars early
on in 2009.22,23 The pathway is very similar and in line with
the EU in terms of comparability data requirements. Also in
Japan, the regulation of biosimilars principally follows the
guidelines of the International Committee on Harmoniza-
tion, especially guideline Q5E, which deals with changes
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Krishnan et al
in manufacturing process and the evaluation of comparabil-
ity, and guideline Q6B, which concerns the comparability
of products. The PMDA has been supporting biosimilar
development in Japan by consulting with pharmaceutical
companies.
Recombinant plasma proteins, recombinant vaccines,
PEGylated recombinant proteins, and nonrecombinant pro-
teins that are highly purified and characterized are defined
in the scope of the guideline. However, some inclusions of
EU, like polyglycans (low molecular weight heparin) and
synthetic peptides have been excluded since extensive char-
acterization is not required for simple molecules without
higher order structures.15 Comparative stability studies with
reference biologics is not mandatory in Japan.
The detailed guidelines are outlined in:22,23
“Guidelines for the Quality, Safety, and Efficacy Assur-
ance of Follow-on Biologics” (Yakushokushinsahatu
0304007 by MHLW/March 4, 2009)
“Nonproprietary Name and Brand Name of Follow-on
Biologics” (Yakushokushinsahatu 0304011 by MHLW/
March 4, 2009)
“Revision of Marketing Approval Application” (Yakush-
okushinsahatu 0331015 by MHLW/March 4, 2009).
Although EMA guidelines are the template for MHLW,
the requirements of comparative stability, which may not
be needed always in Japan, pose as differentiators. So is the
case with toxicology studies, wherein impurities need not
be evaluated through nonclinical studies. Somatropin and
epoietin alfa have been authorized for marketing in Japan
following the abovementioned route. The PMDA has been
supporting biosimilar development in Japan by consulting
with pharmaceutical companies before any formal guide-
lines were drawn. Recently PMDA has made great efforts
to reduce the time lag of the approval process. The time
period required for the approval of standard products has
reduced by almost half, from 21 to 12 months, and priority
products from 12 months to 9 months. The application lag
of PMDA when compared with the US FDA is large, about
a year, whereas the postapplication lag is much less, about
a month.24,25
A survey interview of representatives from various types
of companies, including contract manufacturing companies,
bioventures, generic manufacturers, biotechnology compa-
nies, and pharmaceutical companies having a high level of
activity in the field of biopharmaceutical development, was
conducted to derive opinions from key leaders. Among the
regular discussions, it was also stated that incentives for
development of innovator biopharmaceuticals should not
suffer in the competitive race with biosimilars, since com-
panies developing innovator products are taking a huge risk
given the number of unpredictable events that may occur
during nonclinical and clinical studies. The survey discus-
sions stated that only one to two companies had a biosimilar
product under development, using the company’s own unique
manufacturing technologies. The other survey participants
revealed that their companies were not engaged in biosimilar
development, nor did they have any plans to do so. Four
respondents reflected their company’s vision to focus on
new- or second-generation biopharmaceuticals than devel-
opment of biosimilars. Some opinions that could be worth
noting were the possibility of using offshore manufacturing
contractors in India or the People’s Republic of China.26
Korea (KFDA)
The market for biosimilars in Korea is promising, as it has
been in other parts of the world. Samsung, the electronics
giant in Korea, announced its entry to the biosimilar arena
with an investment of $389 million for an anticipated 5-year
period in 2009. The regulatory framework of biosimilar prod-
ucts in Korea had been established by 2009. It is governed by
Pharmaceutical Affairs Act, Notification of the Regulation
on Review and Authorization of Biological Products, and the
Guideline on Evaluation of Biosimilar Products. The Pharma-
ceutical Affairs Act is the supreme regulatory authority for
all licensure of biologic products. The KFDA operates within
the confines of the former. The Notification of the Regulation
on Review and Authorization of Biological Products serves
as the guiding document for all biosimilars.15,27
Since the Korean guideline for biosimilar products coin-
cided with the timeline of the WHO regulatory guidelines,
most of the requirements are similar except for that of the
clinical evaluation to demonstrate similarity. Equivalence
testing, where the upper and lower margins need to be speci-
fied with justified preset limits, is mandatory with KFDA,
whereas in WHO it is preferred to the noninferior mode of
testing where only the lower margin is specified. This opens
the possibility for extrapolation of efficacy data to other
indications of the reference product.3,27
Canada (Health Canada)
The federal regulations that evaluate the safety, efficacy, and
quality of subsequent entry biologics that are developed on
expiry of patents for biological drugs in Canada is Health
Canada. “Guidance for Sponsors: Information and Submis-
sion Requirements for Subsequent Entry Biologics (SEBs)”
was issued by Health Canada in 2010.4
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Global regulatory landscape of biosimilars
Similar to WHO, the Canadian guidelines states that
the biologic drug that was authorized based on a complete
clinical data package with sufficient safety and efficacy data
could qualify as a suitable reference. Additionally, the product
should be subjected to advanced analytical testing for exten-
sive characterization and should meet appropriately defined
criteria/limits. Health Canada insists on the physicochemical
and biological characterization, extensive in-process analysis
of all critical intermediates, full scale stability data, ranging
of impurities, ranging studies of reference and product to
plot the differences in variability, nonclinical and clinical,
and safety and efficacy data. Postmarketing requirements like
adverse drug reaction report, periodic safety update reports,
suspension or revocation of notice of compliance (NOC) of
authorization in the event of any compromise of the safety
of drug have all been defined in the guidance.4
The only biosimilar that was authorized in Canada was
somatropin. The recent authorization of monoclonal antibodies,
remsima and inflectra, in January 2014 is an indication of accep-
tance of good quality, affordable “subsequent entry biologics.
This may induce the much-awaited first 351k biosimilar filing
with the US FDA this year. This may also have a cross-border
influence and increase the public outcry for affordable drugs in
the US, where biosimilars are still not recognized. There have
been incidents of people organizing bus trips to Canada from the
US as part of medical tourism to buy affordable copies.28,29
The People’s Republic of China (State
Food and Drug Administration)
The People’s Republic of China and India are always compared
in every sphere due to their large economies. The People’s
Republic of China has a major presence in manufacturing
chemicals, intermediates, and large-volume active substances,
while India’s strengths have been sourcing active substances
and finished dose products. At the CPhI worldwide preconnect
conference, panelists Ina Lennon (Chiral Quest) and Gurpreet
Sandhu (Reva Pharmachem) compared the pharmaceutical
scenarios in the two countries.30 Both have had their share of
challenges, like devaluation of the rupee in India and retention
of metropolitan talent in the People’s Republic of China. India
has an edge over the People’s Republic of China in language
skills and experience of regulatory authorities. India boasts the
largest number of US FDA-approved facilities outside the US.
The pace is picking up in the People’s Republic of China, but
most of the players are focusing on the huge internal market,
which is investment friendly.30
Over 40 biopharmaceutical products have been already
approved by the State Food and Drug Administration in the
People’s Republic of China, which include a majority of
biosimilars. Guidance for Review and Approval of Biosimilar
Products guidelines was announced by the Department of
Health in 2008, and is mainly based on EMA guidelines with
consideration of local regulatory environment:22
Guidelines for Registration of Drugs (2010)
Guidance for Review and Approval of Recombinant
Protein Drugs (2002)
Guidance for Review and Approval of Biosimilar Product
(2008)
Points to Consider for Common Technical Documents
(CTD) in Review and Approval of Biosimilar Product
(2010).
India (Central Drugs Standard Control
Organization)
Mohal Sarabhai (Asenco) in the 2013 CPhI meeting explored
the strengths of India, including regulatory compliance, a large
talent pool, the ability to develop new and differentiating tech-
nologies, and low manufacturing costs. India is often called
the “Pharmacy of the World” due to all these factors.30
The apex regulatory bodies22 under the government of
India that are involved in the approval process of SBPs are:
Central Drugs Standard Control Organization
The office of Drug Controller General of India
Review Committee on Genetic Manipulation
Genetic Engineering Approval Committee.
As far as the products are concerned, various biosimilar
products being marketed currently include erythropoietin,
human growth hormone, recombinant human insulin, G-CSF,
and interferon. Industry statistics indicate that in 2010, epo-
etin alfa (erythropoietin biosimilar) occupied more than 40%
of the market share, followed by filgrastim (G-CSF biosimi-
lar) with a 33% market share and somatropin (human growth
hormone biosimilar) with a 25% market share.
The Indian biosimilar industry is estimated to be a US
$338 million industry that has been growing at a CAGR of
30% since 2008. There are around 25 Indian companies oper-
ating in the biosimilar space, marketing close to 50 products
in the Indian market and a few of these products in some of
the unregulated markets.
Islamic Republic of Iran (National
Regulatory Authority)
The National Regulatory Authority in the Islamic Republic
of Iran is the Ministry of Health and Medical Education,
which is the official body for establishing quality standards
for the regulation of medicinal products. The Division of
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Krishnan et al
Pharmaceuticals and Narcotic Affairs is the principal govern-
ing agency; the other divisions which share some overlapping
responsibilities are the Drug Control Laboratory (FDCL), the
Adverse Drug Reaction Centre, Clinical Trials Evaluation
Committee, and the Centre for Diseases Control. The office
of biologics, in collaboration with FDCL and the Adverse
Drug Reaction Centre, is responsible for the marketing autho-
rization and licensing, lot release, and regulatory inspections
of biologics products.31 A wide list of locally manufactured
biopharmaceuticals such as interferons, pegylated interfer-
ons, somatropin, follitropin, filgrastim, and erythropoietin
are available in the Iranian market. Others, such as B-mab,
T-mab, R-mab and E-cept, are in registration phases.32
The Iran NRA prepared a draft guideline on the registra-
tion of biosimilars based on the WHO draft guideline of 2009.
After some amendments, the final draft has been finalized and
approved in September 2010 by the Iran expert committee
on biologicals, followed by the approval from the Head of
the Iran US FDA in February 2011. Since the guideline has
been drawn per WHO guidelines, the framework includes
similar requirements.31
The Iranian guidelines are similar to the WHO guide-
lines in several areas, including head-to-head comparison
of an SBP to a reference product in quality, requirement
of extensive characterization beyond typical monograph
specified test methods, demonstration of similarity at the
levels of both drug substance and drug product between
the RBP and SBP, equivalence in dosage form, clinical trial
with a small sample size, and route of administration.31 The
major difference that emerges on a comparison is that WHO
does not recommend an SBP as a choice for RBP. However,
in Iran, an SBP with US FDA or European Medicines
Agency approval and accessible periodic safety update
reports which is licensed in Iran and has a good marketing
history can be considered an RBP. This helps in cases where
the original drug is not registered. Also, Iran specifically
recommends that specifications for an SBP should be the
same as for the reference product, but does not consider
a head-to-head comparative accelerated stability study as
mandatory.31 Presently, the Iranian NRA does not insist
on comprehensive clinical trials; it relies more on national
postmarketing surveillance data for drug safety. Also, Iran
imposes an import tariff as high as 65% on imported drugs
in a bid to promote locally manufactured drugs, which as
per EMA/US FDA/WHO regulatory norms may not be
called “highly similar.” However, since the national adverse
drug reaction reporting system is well established and
implemented, there is no safety concern.32
Jordan (Jordan Food and Drug
Administration)
The Jordan Food and Drug Administration (JFDA) comprises
two main directorates, the Drug Directorate and Food
Directorate, for drug and food safety, respectively. An indi-
vidual registration department that comes under the auspices
of the drug directorate performs regular registering of drugs
for approval. The Technical Committee for the Registration
of New Drugs is the committee responsible for registration of
originator, new drugs, and biological and biosimilar products.
The chairman of this committee is the secretary general of
the Minister of Health, and the vice chairman is the director
of the drug directorate.33
The committee decides on registration of new drugs and
drugs that have a registered equivalent. It does this within a
maximum period of 180 days from the date of the submis-
sion of the application of completed documents. In addition,
the committee also ensures protection of the information in
this application.
Since 2008, the JFDA had started to review applications
for biosimilars on the basis of EMA guidelines. Emphasis
has been laid on postmarketing surveillance, since to date
no clinical studies have been conducted in Jordan. There is
an ongoing debate regarding interchangeability and sub-
stitutability of the biosimilar product with the RBP, just as
anywhere else in the world. The draft guidelines had been
formulated and were available for comments till January
2014. The basis for these guidelines has been the EMA, the
International Conference on Harmonisation, WHO, and also
the lessons learned from submitted applications since 2008.
Following the scope for customization of guidelines to be
country specific as per WHO, the choice of RBP has been
specifically defined as the first product registered interna-
tionally with a particular active ingredient.33,34
Middle East
A group of physicians and neurologists interested in multiple
sclerosis, endocrinology, and pharmacology from across
Middle Eastern countries convened to discuss the appropri-
ate procedure for approval of biosimilars. In the absence of
regional guidelines, they recommended the implementation
of EMA guidelines for the requirements of safety, efficacy,
and pharmacovigilance. The meeting minutes were published
in 2008. The expert group recommended demonstration of
consistent process with adequate quality control methods
and comparable PK and PD of biosimilar and reference
drugs. Double arm direct comparative clinical trials and
postmarketing surveillance were also mandatory as per the
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Global regulatory landscape of biosimilars
recommendation. Efforts need to be initiated to have regional
guidelines according to the group of expert physicians.35
The business of biologics
in emerging markets
Biopharmaceuticals are different from small molecule
chemical drugs in terms of the complexity which makes
characterization difficult as well as a regulatory requirement.
Generic drugs may not have the same elaborate and stringent
approval processes, but face similar marketing concerns as
biosimilars. Both generics and biosimilar markets share the
same concerns, which are varied between established mar-
kets like EU/US and other emerging markets. According to
Hordur Thoralissonn (Actavis Inc.), the term “emerging” is
used to define the level of development of generics rather
than development of the country per se. Extrapolation of such
general issues apart from regulatory hurdles could be done
from generics to biosimilars quite seamlessly. Peter Wittner
(Interpharm Consultancy) suggested that a Darwinian sur-
vival of the fittest theory is almost invisibly present in the
generics market to provide affordable drugs, which we may,
in all probability, extend to biosimilars as well. According to
him the European markets are attractive but need extensive
and careful preparation before entry. Spain and Italy were
good markets according to him, considering the underuse
of generics in these countries. The “pharmerging” countries
like the BRIC nations (Brazil, Russia, India, and the People’s
Republic of China) according to him can prove to be attrac-
tive and huge, but their poor infrastructure, reduced health
insurance coverage, and so forth can be intimidating.36
Bill Haddad (Biogenerics Pharma GmbH) and
Richard Dicicco (Harvest Moon Pharmaceuticals USA
Inc.) discussed the prospects of biosimilars in the SMi’s
13th Annual Meeting (2010). They were of the opinion
that the emerging” markets could be a better investment
proposition than the US and EU markets. The former is
reportedly biosimilar unfriendly, as it favors everlasting
and perpetual patents, and the latter has such stringent
guidelines that it does not make it any cheaper to develop
biosimilars than original drugs; also, 15 of the member
countries in the EU have laws to prevent substitution. There-
fore, the private sector of pharmerging markets is attractive,
since the cost of drugs is only about 25% cheaper than
the developed counterparts. Also, government supply of
these drugs through tenders could be good options in Latin
America and the Middle East. Other factors which should
potentially be evaluated before market penetration include
protectionism (favoring of local players); the presence of
import bans, limitations, or tariffs; reduced access to health
care in challenging terrains; cold chain management; and a
preference for dosage regimens that prevent frequent visits
to the health care practitioner. Most generic sponsors enter
into strategic partnerships with local manufacturers to gain
access in these niche markets. This could be in the form of
shifting production to local manufacturing units, support
of science and technology needs, providing research and
development support, helping to build quality systems, or
providing innovative delivery devices that are better than
those of the originator for self-administration. Superge-
nerics or biobetters also offer higher pricing margins and
exclusivity in the market.36
Competitive biosimilar space
Contrasting emerging and established markets for the launch
of affordable drugs is one side of the biosimilar coin. The
other side is the emerging resistance of the global biotech
giants against the industry of biosimilars. Originator com-
panies have been devising newer strategies to combat the
biosimilar competition. The originators frequently change
delivery devices (switching from vials to prefilled syringes
to autoinjectors) and changing of presentations (from liquid
to lyophilized) combined with the withdrawal of older pre-
sentation/device. This is a matter of concern for biosimilar
sponsors, who have to adapt their biosimilar development
to a different presentation/device with the discontinuation
of the original marketed reference standard. Some other
strategies, like patenting of analytical methods by the
innovator to evaluate critical quality attributes, limits the
biosimilar sponsor in accurately determining the potency
of their product, since the method is patented beyond the
molecule’s patent life. The same also applies to formulation
patents, which often have patent life beyond the molecule’s
patent life. Frequent process changes by the originator gives
rise to reference standards that are considerably different,
and the biosimilar sponsor is left in the lurch with a near-
to-completion process but without a comparable reference.
The case of postapproval process changes for Enbrel,
Rituxan, Mabthera, and Aranesp37 is a well-known example.
The changes in physicochemical profile correlated with an
altered potency profile. Nevertheless, they were available
in the market with the same unaltered labels, indicating a
comparable clinical profile that was acceptable to the regu-
latory authorities. On the contrary, WHO requires a suffix
for glycosylated molecules which do not fall in the “highly
similar” category, leading to molecules with extended names
like epoietin zeta.38
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Krishnan et al
Nomenclature of biosimilars
The WHO established the “International Nonproprietary
Names” (INN) mode of nomenclature for biological and
biotechnological substances which are indicative of the
active ingredient and a classified group. The WHO has clas-
sified families of molecules and has provided appropriate
stems and prestems that follow the typical INN schemes
with prefixes and suffixes. This scheme has been recognized
by all regulatory agencies the world over and sponsors use
a brand name apart from this “generic” name. This avoids
conflicts with existing names and instills confidence in
the prescriber and user. The INN mode has a provision
for glycosylated proteins to use different suffixes if gly-
cosylation variations are extensive. However, in a recent
WHO meeting there was lobbying from the innovators to
consider a two-part name for biosimilars, with an INN first
half and a second part indicating that this is a biosimilar.39
The originator companies, even after process changes of
a glycosylated molecule, still retained the same primary
INN on their label. This is one of the contentious issues
with the biosimilar sponsors, as there will be no unifor-
mity in the concept of naming and will eventually lead to
apprehension of prescriber and user about a possibility of
inferior quality in a biosimilar due to a different name. This
could become contradictive, with the regulatory approval
indicating a highly similar product but yet with a different
name. The Pharmaceutical Research and Manufacturers
Association (PhRMA) and the Generic Pharmaceutical
Association (GPhA) in the US are still at loggerheads
on this issue. The PhRMA has put forth the requirement
of “Distinguishable Nonproprietary Names,” which will
facilitate accurate attribution of adverse drug reactions to
the right product during the tracking process, relieving the
public of doubts. This, they predict, would alleviate confu-
sions in a market that is anticipated to be flooded with a
combination of biosimilars, interchangeable biosimilars,
and multiple innovator biologics very soon, resulting in
effective pharmacovigilance. However, the biosimilars
sponsors quote that every adverse drug reaction tracking
is through batch numbers, brand name, and manufacturer
and is never general.40
Interchangeability
Since biological drugs can never be exact copies, the ques-
tion whether they can be substitutes of original biologics
remains unclear. The major concern about interchangeabil-
ity is that repeated switches between the biosimilars and the
reference biological may increase immunogenicity, leading
to adverse reactions. Some inherent differences arising due
to a postapproval process or a formulation change could
lead to differential immunogenicity that may not necessar-
ily be assessed through characterization or clinical trials
during the time of application/approval, but may become
evident during postapproval surveillance/pharmacovigi-
lance. But this would be the case even for an originator
drug that has undergone a process change but is marketed
with the same name. Even during pharmacovigilance the
studies are typically designed on patient population and
never follow a single patient, making it very difficult to
track the status of interchangeability issues. Therefore, it
would be difficult for regulatory bodies to certify that the
drug is truly interchangeable without adequate data. There
has been considerable debate over this issue in the EU and
US.20,41 According to EMA, approved biosimilar status
signifies that the biosimilar can be used interchangeably
with reference drugs. However, automatic substitution is
not possible according to EU pharmaceutical law govern-
ing similar biological medicinal products. The EMA in a
public consultation for the revision of the 2005 Guideline
has included a new element wherein a statement mentions
that a biosimilar application when assessed for marketing
authorization does not certify the interchangeability status.
Since these provisions come under the national laws of the
EU Member States, the EMA does not have the power to
make such a determination. According to the EMA, auto-
matic substitution does not yet prevail for any approved
biosimilar.42 The EU Generics Association also claims
that more than 12 countries have rules against automatic
substitution. However, France has now permitted the switch-
ing of biosimilars and generics with the originals as part of
a new law concerning the social security budget (Article 47
of the Law of 23 December 2013), which came into effect
on January 1, 2014.43 In the US, the US FDA has the power
to make such announcements, although no such proclama-
tion has been made so far. The guidances issued in 2012 do
not discreetly address this. A survey of prescribers by the
Alliance for Safe Biologic Medicines in 2012 indicated that
they prefer different names so that they do not have to use
their discretion for substitution/switching.44,45 Even as new
guidelines are being drawn globally, in both established and
emerging markets, this whole cloud of confusion prevails
regarding the three facets of interchangeability:
1. Automatic substitution of originator with biosimilars
2. Switching of originator drug with biosimilar drug and
vice versa
3. Naming of biosimilar drugs.
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Global regulatory landscape of biosimilars
Conclusion
The generic companies and biosimilar associations have united
to counter misconceptions regarding their drugs. They have
been applying continuous pressure on the regulatory agencies
to favor the manufacture of generic/biosimilar drugs for the
benefit of the patient population with low-cost alternatives.
Unifying the approval pathway globally will abolish the need
for bridging studies, which could make biosimilar development
cost effective (since the sponsors will then have a single product
development cycle for all geographies) but with the same stan-
dards of safety and efficacy. The European Generic Medicines
Association and the GPhA, together in the Transatlantic Trade
and Investment Partnership negotiations, have put forward
their support for regulatory convergence of pharmaceuticals
in the US and EU. They recommend combined regulatory
approval pathway and compliance inspections. The com-
bined development costs could be about $200–$300 million
less per product than the individual route, leading to a huge
cost difference that can be passed on to the patients in terms of
low-cost medicines. There is a great deal of importance being
laid on a unified International Committee on Harmonization
authorized reference standard for biosimilar development,
which would be acceptable to all regulatory agencies. This will
bring down the development costs and fulfill the global aspi-
rations of biosimilar companies. The public looks toward the
biosimilar companies for lowering of costs of older drugs and
in parallel are looking up to the innovator drug companies for
new and more effective therapeutics. The war between “origi-
nator” and “biosimilar” sponsors is being closely watched, and
the public hopes that there will be harmonization of regulatory
expectations that are important to ensure safety and efficacy
of biosimilars across regulatory agencies while also ensuring
that patients have access to biosimilars.
Disclosure
The authors report no conflicts of interest in this work.
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Biosimilars
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... Malaysia has erected stringent regulatory barrier to generic copies of biologics. Europe for example has approved 20 biosimilars to date [56] while there are only a few such products in Malaysia. Even more non-EMA approved biologics are widely available in India, and middle income Latin American and Asian countries [56] but none of these could enter Malaysia. ...
... Europe for example has approved 20 biosimilars to date [56] while there are only a few such products in Malaysia. Even more non-EMA approved biologics are widely available in India, and middle income Latin American and Asian countries [56] but none of these could enter Malaysia. Malaysia's experience with epoetin has shown that the best way to lower the price of medicines quickly and steeply is by allowing competitive supplies. ...
Preprint
Full-text available
Background Upper middle income countries have made substantial progress towards universal health coverage. We investigated whether the coverage extended to diseases that incur catastrophic health spending, the contribution of pooled financing and the factors driving it in Malaysia. Methods We adapted the WHO definition of catastrophic health spending to define costly treatment as one that cost, at prevailing market price, more than 10% of the median annual household income in Malaysia. Coverage is defined as the proportion of patients in a year who were in need of a treatment and who received it. Data to estimate coverage and financing were extracted from the published and grey literature, as well as secondary data sources available on disease epidemiology and healthcare in Malaysia. Results We found coverage varies from universal for dialysis, cataract surgery, medicines for organ transplant and CML, to practically none for HCV, stroke, psoriasis and epilepsy surgery. Coverage of targeted therapies for solid cancers, knee replacement surgery, anti-TNF for arthritis and coagulation factors for haemophilia were poor while iron chelation for thalassemia, coronary revacularization, epoetin and anti-retrovirals were barely adequate. Coverage correlates negatively (r=-0.82) with health benefits foregone, and is entirely driven by the contribution of pooled financing (r=0.99 p<0.0001). The relative effectiveness of a treatment, its budget impact, media coverage and political influence of the disease area have little influence on financing. Only effectiveness of the leadership representing the therapy area is influential; an increase in one point on the leadership effectiveness scale is associated with 30% increase in the contribution of pooled financing. Conclusion Coverage for catastrophically costly treatments is uneven and inequitable in Malaysia, despite most of these are affordable. Decisions on coverage are driven by political-economic consideration.
... The European Medicines Agency (EMA) requires a full clinical trial to demonstrate safety and efficacy for each indication of a new biologic therapy, whereas for biosimilars the key regulatory requirement is availability of clinical data to prove comparable safety and efficacy to the reference biologic. 20 While interchangeability with the originator product is inherent in generic drugs due to the reproducibility of their manufacture, granting of biosimilar status by a regulatory body does not necessarily imply interchangeability. [21][22][23] There is a large number of biosimilars in development and approaching registration; therefore we need to be able to assess how to use them in practice. ...
Article
Biological therapies have been in use for treating psoriasis for a decade now, and they have greatly improved disease outcomes and quality of life for patients. The success of biologic therapies has been assisted by the development of evidence-based guidelines for their use, and the achievement of consensus on treatment goals. The future of biologic therapies for psoriasis will be different from the past decade, with new anti-inflammatory targets for antibodies being developed and the increasing availability of biosimilar versions of existing antibodies as patents expire. While reduced costs may exert a pressure to switch to biosimilars, it is important to appreciate that they may not be identical in efficacy. Biologics are large, complex molecules, produced by biosynthetic means, which inherently lead to variations in structure. These slight variations in the manufacture of biologics can lead to clinically relevant changes in efficacy. As more biosimilars become available, their interchangeability becomes an important challenge for use in clinical practice, both between a biosimilar and the originator, and between two different biosimilars. Thus, robust trials of interchangeability are urgently needed. Caution in the use of an increased range of biosimilars will also be needed as switching between drugs can potentially increase immunogenicity and neutralise the drug’s efficacy. The introduction of biologic therapies has been a great achievement in the treatment of psoriasis. The new biologics and biosimilars coming into practice will need to be used with care, for which robust data on safety, efficacy, and interchangeability will be needed, as well as continuing pharmacovigilance.
... Many of developing countries' regulatory bodies adopt international standards and/or regional reference standards, rather than developing their own [50]. [52]. India has approved biosimilars of rituximab, filgrastim, pegfilgrastim, trastuzumab, and epoetin alfa [6]. ...
Article
Health care costs attributed to biologics have increased exponentially in the recent years, thus biosimilars offer a possible solution to limit costs while maintaining safety and efficacy. Reducing expenditure is vital to health care especially in developing countries where affordability and access to health care is a major challenge. We discuss the opportunities and the challenges of biosimilars in the field of hematopoietic cell transplantation (HCT) in low- and lower-middle income countries. Developing countries can potentially invest in the forecasted costs reduction by utilizing biosimilars. This can be used to decrease the costs of procedures such as HCT, which is a rapidly growing field in many developing regions. The introduction of biosimilars in the developing regions faces many challenges which include, but are not limited to: legal and regulatory issues, lack of research infrastructure, and the presence of educational barriers. Thus, collaborative efforts are needed to ensure an effective and safe introduction of biosimilars into low- and lower-middle income countries.
... From its first biosimilar approval in 2015 to 2017, four biosimilars have been sanctioned in the USA for the treatment of 23 indications [27]. Canada also issued their guidelines in 2010 under the approval of their federal authority, Health Canada [28]. The first anticancer mAb biosimilars were approved in Europe in 2017 [29,30]. ...
Article
Full-text available
The coming wave of patent expiries of first generation commercialized biotherapeutical drugs has seen the global market open its doors to close copies of these products. These near perfect substitutes, which are termed as “biosimilars”, do not need to undergo intense clinical trials for their approval. However, they are mandated to produce identical similarity from their reference biologics in terms of clinical safety and efficacy. As such, these biosimilar products promise to foster unprecedented access to a wide range of life-saving biologics. However, seeing this promise be fulfilled requires the development of biosimilars to be augmented with product trust, predictable regulatory frameworks, and sustainable policies. It is vital for healthcare and marketing professionals to understand the critical challenges surrounding biosimilar use and implement informed clinical and commercial decisions. A proper framework of pharmacovigilance, education, and scientific exchange for biologics and biosimilars would ensure a dramatic rise in healthcare access and market sustainability. This paper seeks to collate and review all relevant published intelligence of the health and business potential of biosimilars. In doing so, it provides a visualization of the essential steps that are required to be taken for global biosimilar acceptance.
... 6 Now, recombinant human erythropoietin (rHuEPO) is commercially available in the global biopharmaceutical market in different types and generations. 7 Biological activity and resistance to elimination from the circulation remain the main goal in rHuEPO production. Indeed, different rHuEPO analogs have been obtained based on these properties. ...
Article
Recombinant human erythropoietin (rHuEPO) as a glycoprotein growth factor has been considered a biological drug for treatment of anemic patients with chronic renal failure or who receive cancer chemotherapy. Biological activity and circulation time are 2 parameters that are important to achieve EPO's efficacy. Previous efforts for increasing EPO's efficacy have focused on glycosylation modification via adding more sialic acid antenna and generates more negative charged protein. Evidences cleared that EPO's activity increased by numbers of N-glycan moieties with presence of sialic acids at their terminus. Correlation between bioactivity and glycosylation with terminal sialylation is theoretically achieved using the calculation of the amount of charge profile of the EPO variants called "I-number." Here, we studied and compared the relationship between bioactivities of different EPOs that contained various I-numbers and the effect of their secondary and tertiary protein structures on measured in vivo efficacy. Eight recombinant EPOs batches were produced under the same condition. I-numbers found out by EPO's charge profiles determination using capillary electrophoresis and activities were studied upon erythroid precursor cell stimulation in mice. Analyzing the bioactivity, I-number, and structural studies revealed that in spite of I-number, conformational changes in protein structure and presence of aggregated species impact bioactivity substantially.
... 14 The current debate concerns the use of distinct nonproprietary names (International NonProprietary Name [INN]) versus identical ones for the biosimilar and the reference product. 15 The subject is conflictive even between regulatory agencies. The FDA currently adopts the suffix strategy, in which 4 random letters are added to the INN. ...
Article
The Pan American League of Associations for Rheumatology (PANLAR) is an umbrella organization of rheumatology national societies in the Americas, encompassing 21 countries. Of those, 19 nations are located in Latin America and the Caribbean region.1 The aims of PANLAR are 2-fold: (1) stimulate and promote the study and research of rheumatic diseases for their prevention, treatment, and rehabilitation to benefit patients with rheumatic disease in the American continent; and (2) stimulate the continu- ing development of rheumatology.2 Within this framework, one of the new missions of PANLAR is to organize an annual rheumatology meeting to further strengthen scientific knowledge of rheumatic musculoskeletal diseases after the first rheumatology review course on rheumatoid arthritis; this year's course has focused on biosimilars and its main challenges in the Americas.3 The course “Biosimilars Update” took place in Lima, Peru, from September 6 through September 8. The meeting was attended by 361 health professionals, including rheumatologists, pharmacists, researchers, and students from 13 American coun- tries, providing a scientific environment of exchange and open discussion, exposing the different situations with biosimilars be- tween several American nations. The objective of the present arti- cle is to report the discussions conducted and the main topics presented during the course.
Article
Full-text available
Background: The aim of the study was to identify, interpret, and compare the current perspectives of regulatory agencies in six member countries of BRICS-TM (Brazil, Russia, India, China, South Africa, Turkey, and Mexico) on the different criteria used for biosimilar development and marketing authorisation process. Methods: A semi-quantitative questionnaire was developed covering the organisation of agency, biosimilar development criteria and marketing authorisation process and sent to seven regulatory agencies covering the BRICS-TM countries. All data was kept anonymous and confidential. Data processing and analysis was carried out; descriptive statistics were used for quantitative data and content analysis was employed to generate themes for qualitative data. Results: Out of the seven regulatory agencies included in the study, six representatives provided the responses. The perspectives of these six regulatory agencies varied on a number of aspects relating to the review criteria for biosimilar development and licencing process. The most prevalent model for data assessment is the “full review” of a marketing authorisation application. There is lack of a standard approach across the agencies on sourcing of the reference biological product, in vivo toxicity studies and confirmatory clinical studies. Most agencies restrict interaction with biosimilar developers and any scientific advice is non-binding. The marketing authorisation approval depends on scientific assessment of the dossier, sample analysis and GMP certification. The agencies do not issue any public assessment report specifying the summary basis of biosimilar approval. Conclusion: Regulatory agencies across the six emerging economies are steadily improving the regulatory mechanism in the area of biosimilars. However, there remains scope for increasing the effectiveness and efficiency of the processes by encouraging open and transparent interaction with developers, adopting a flexible approach toward accepting advanced analytical data in lieu of clinical studies and enhancing regulatory reliance amongst agencies. This will help to simplify the new biosimilar development programmes and make them more cost-effective.
Chapter
Biologicals or biologics replicate endogenous substances such as enzymes, hormones, or antibodies. They are derived from living cells or tissues of human, animal, and/or bacterial or viral origin using biotechnology. Biosimilars are highly similar versions of innovator biologics and provide more affordable treatment options. Biosimilars are approved via abbreviated pathways that avoid duplicating costly clinical trials. Most countries (or umbrella organizations) have embedded specific regulations for biologics approval. Summary of the various regulatory frameworks is provided in this chapter. Biobetters are considered as new products under existing regulatory frameworks. Biosimilars have established “similarity” to an innovator biologic. Biobetters work on the same target but claim superiority in structure, function, or other properties and thus are expected to have enhanced clinical profile. In conclusion, global initiatives are urgently required to harmonize biologics approvals to allow biotech industries to develop their products uniformly for all countries and provide timely market access.
Article
Introduction: Biosimiliar, a copy of reference biological product, is making a buzz across the globe for its upper edge therapeutic usage. According to the market research report published by P&S Intelligence, biosimilars market is expected to generate $26.7 billion revenue by 2024, advancing at a CAGR of 29.6% during the forecast period. The first biosimilar to medicine Omnitrope, was approved in Europe by EMA (European Medicines Agency) in year 2006. Till date countries like US, China, Japan, India and many more have generated regulatory guidelines for biosimilars. Aim: Current study addresses the issues and challenges faced by Industry and regulators with their potential solutions and recommendations. Materials and methods: The questionnaire having 21 important questions/comments was given to participants after explaining the purpose of the study. The response in terms of responders V/s non-responders, agree V/s disagree, yes V/s no was recorded and analyzed by descriptive statistics. Results and discussion: The study shows the limitation regarding the qualified personnel involved in biosimilars, as approx. 91% people believe that there is lack of expertise in this field. The same can be achieved through government initiatives for bridge courses which is also strongly felt by the major (83.6%) stakeholders participated in the study.
Article
Purpose This article aims to analyse the key regulatory guidelines across the globe concerning biosimilars. Materials and methods Review of the current literature. Results Biosimilars are well regulated with the majority of regulators having enforced the guidelines for the development and approval, and new biosimilar drugs are appearing on the horizon to provide a therapeutic option to a wider population base because of its cost-effectiveness and proven safety. Due to their extensive analytical data, clinical data and pharmacovigilance studies, their development should not be considered similar to generic drugs. Conclusion This review discusses the biosimilars, their regulation globally and their difference from generics from ophthalmic perspective.
Article
Full-text available
The arrival of biosimilars has led to considerable debate on how they can be used in clinical practice. A particular concern is related to the question of whether a biosimilar can be safely interchanged with the originator product or other biosimilars. Here we will discuss challenges to the regulatory approach for establishing interchangeability, in the sense of considering biosimilar versions as therapeutic equivalents that could – depending on National or Federal Law – be substituted at the pharmacy level, and compare these to the weight of real-world evidence of the risks of potential differences that could modify longer-term clinical benefit-to-risk. Our discussion will be mainly focused on monoclonal antibodies. We conclude that it will be highly challenging to establish interchangeability of biosimilars, and it should be questioned whether the ‘higher’ standard required for designation of interchangeability adds to the benefit for patients.
Article
Full-text available
Biosimilars (or follow-on biologics) are a new class of medicine which enters the market subsequent to a previously approved version. They have demonstrated similarity to innovator biologic products in terms of quality, safety, and efficacy. The EMA has taken the lead in the regulatory approval framework for biosimilar products, and WHO has published guidelines on the evaluation of biosimilars in order to facilitate the global harmonization. Based on EMA and WHO guidelines, many other countries such as Canada, Japan and Korea have also issued their own guidance for evaluating follow-on biologics. The US FDA was authorized to approve follow-on biologics by the BPCI Act passed by the US Congress on March 23, 2010, and has just issued a draft guidance in early 2012. The basic concepts and main principles of approving biosimilars are similar among various nations, notwithstanding some differences in regard to the scope, the choice of reference product, and the data requirement. This article reviews the regulatory approval pathway of biosimilar products in different regions.
Article
Full-text available
Biosimilar medicinal products ('biosimilars') have become a reality in the EU and will soon be available in the US. Despite an established legal pathway for biosimilars in the EU since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in 'extrapolated' indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biological Medicinal Products (BMWP) of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators.
Article
Full-text available
After the expiration of patents on originator biological products, Jordanian local manufacturers and the agents of international pharmaceutical companies in Jordan started to submit registration dossiers for biosimilar products. The Jordan Food and Drug Administration (JFDA) is the national regulatory authority responsible for the registration of biosimilar products. Biosimilars are registered under the same regulations used for drugs until specific guidelines for registration of biological and biosimilar products are released. Those regulations are called Criteria of Registration of Drugs, Vaccines, Sera and Biological Products, the Renewal of its Registration and the Cancellation of Any of them which was published in the official gazette in 2004 under the Provisional Law Number 80 of the year 2001, Drug and Pharmacy Law and its amendments of the year 2003. Also, the JFDA follows the EMA guidelines on similar biological medicinal products for specific active biological substances for non-clinical and clinical studies requirements and the EMA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. A post marketing surveillance study is requested after a biosimilar product is authorized. The JFDA keeps pace with all advances in the regulatory issues related to biosimilars in order to be capable of authorizing biosimilar products with a safe, effective and good quality profile.
Article
The objective of this article is to facilitate regulatory requirements for the approval process of Biosimilars and the need for Biosimilar product class-specific guidelines in Regulated (EU, US, JAPAN) and emerging markets (KOREA, CHINA, INDIA). Biosimilars are biological products that are the replicas of their innovator biopharmaceuticals. Specified regulations, and approval process of generic version of biologicals exists depending on the country. Each class of biologic varies in its benefit/risk profile, the nature and frequency of adverse events, the breadth of clinical indications, and whether surrogate markers for efficacy are available and validated. But most of the countries do not have specific guidelines for potential market biological products like monoclonal antibodies (mAbs), interferon beta, and insulin. European Medicines Agency (EMA) has developed product class-specific guidelines to biosimilars that define the nature of comparative studies.
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This article examines the biogenetic regulatory environments in the emerging markets of China and India. We review what biogenetic companies must do to have their products registered and approved for sale in both China and India. In recent years, sweeping changes to both drug regulatory landscapes have occurred, and we evaluate the effects of these changes on the biogenetics sector. We weigh the costs and benefits of producing biogenetics in China versus producing them in India, and we conclude that both nations provide unique opportunities for biogeneric companies.
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A day before the start of the 2013 Conference on Pharmaceutical Ingredients (CPhI) Worldwide, the world's leading pharmaceutical networking event, a number of attendees gathered for the Fifth Annual Pre-Connect Conference to discuss trends in business development, manufacturing and regulatory arenas. Of the six modules presented at the meeting, one was dedicated to the sourcing environment in emerging markets, with special attention paid to developments in India and China. Other modules evaluated the current trends in the creation of generics and supergenerics in emerging markets. Additionally, there were updates on issues surrounding the regulatory and development hurdles that biosimilars and biobetters are facing today. Common themes for both discussions include appropriate pricing and erosion demographics for generics and biosimilars, licensing scenarios, commercialization strategies, and how to stay competitive and find novel innovations within new delivery systems, improved formulations and modifications to create better quality active pharmaceutical ingredients.
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Biologics such as monoclonal antibodies are much more complex than small-molecule drugs, which raises challenging questions for the development and regulatory evaluation of follow-on versions of such biopharmaceutical products (also known as biosimilars) and their clinical use once patent protection for the pioneering biologic has expired. With the recent introduction of regulatory pathways for follow-on versions of complex biologics, the role of analytical technologies in comparing biosimilars with the corresponding reference product is attracting substantial interest in establishing the development requirements for biosimilars. Here, we discuss the current state of the art in analytical technologies to assess three characteristics of protein biopharmaceuticals that regulatory authorities have identified as being important in development strategies for biosimilars: post-translational modifications, three-dimensional structures and protein aggregation.