Biosimilars: From Science to Market

MSc Biotechnology, Bioprocessing
And Business Management

2010-2011

BIOSIMILARS: SCIENCE TO MARKET

1055902
Supervisor: Dr. Neil Porter
Word Count: 15,169
A dissertation submitted in part fulfillment of the Degree of MSc. Biotechnology, Bio processing and Business
Management, University of Warwick, September 2011

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Acknowledgement

I would like to take this opportunity to thank my supervisor Dr. Neil Porter, for his invaluable
insight and guidance throughout my dissertation.

I would like to thank Dr. Crawford Dow, Dr. Steve Hicks and Dr. Charlotte Moonan for their
assistance and Adrienne Davis for her continuous support and encouragement throughout the
year.

Finally, I would like to thank my parents and friends, without whom this piece of thesis would
not have been possible.

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TABLE OF CONTENTS

List of Tables ............................................................................................................................................ v

List of Figures:.......................................................................................................................................... vi

Executive Summary................................................................................................................................ viii

1. Introduction: ........................................................................................................................................ 1

1.1 Biopharmaceuticals: ....................................................................................................................... 1

1.2 Biopharmaceutical Market:............................................................................................................. 4

2. Biosimilars: .......................................................................................................................................... 6

2.1 Terminology disputes: .................................................................................................................... 7

2.2 Differences between Biosimilars & Generic Drugs:.......................................................................... 8

2.2.1 Product differences: ............................................................................................................... 10

2.2.2 Manufacturing differences: .................................................................................................... 10

2.3 Manufacturing Process: ................................................................................................................ 13

2.3.1 Challenges: ............................................................................................................................. 13

2.3.2 Selection of platform: ............................................................................................................. 15

2.3.3 Purification:............................................................................................................................ 16

2.3.4 Formulation: .......................................................................................................................... 16

3. Biosimilars legislation & Regulations: ................................................................................................. 18

3.1 Regulatory framework Europe: ..................................................................................................... 19

3.1.1 Product specific guidelines: .................................................................................................... 24

3.1.2 Immunogenicity: .................................................................................................................... 26

3.1.3 Extrapolation:......................................................................................................................... 27

3.2 EU Biosimilar approval process: .................................................................................................... 28

3.2.1 Common technical document:................................................................................................ 28

3.3 United States Regulatory framework: ........................................................................................... 30

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3.4 Global Landscape:......................................................................................................................... 31

4. Case Study-Biosimilar Insulin: ............................................................................................................. 33

4.1 Manufacturing: ............................................................................................................................. 33

4.2 EMEA requirements: ..................................................................................................................... 34

4.3 Marvel’s Insulin rejection: ............................................................................................................. 35

4.3.1 Quality Aspects: ..................................................................................................................... 36

4.3.2 Non clinical aspects: ............................................................................................................... 36

4.3.3 Clinical Aspects:...................................................................................................................... 36

5. Market Analysis: ................................................................................................................................ 37

5.1 Biosimilars On market:.................................................................................................................. 37

Table 5.2: Unsuccessful biosimilar applications in the EU. Source: Greer, F.M., 2011.............................. 39

5.2 Market Size & Growth: ................................................................................................................. 40

5.3 Market potential:.......................................................................................................................... 40

5.4 Regional market analysis: ............................................................................................................. 42

5.5 Biologic class market analysis: ...................................................................................................... 43

5.6 Market Opportunities: .................................................................................................................. 45

5.6.1 Patent expiry: ......................................................................................................................... 47

5.7 Market share: ............................................................................................................................... 54

5.8 Sales: ............................................................................................................................................ 56

5.9 market Drivers: ............................................................................................................................. 56

5.9.1 Cost Savings (Global health care): ........................................................................................... 56

6. Issues & Challenges: ........................................................................................................................... 60

6.1 Cost of Product development: ...................................................................................................... 60

6.1.1 US region ............................................................................................................................... 61

6.2 Manufacturing Facility: ................................................................................................................. 61

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6.3 Substitution: ................................................................................................................................. 62

6.4 Market exclusivity:........................................................................................................................ 62

6.5 Innovator Strategies: .................................................................................................................... 64

6.6 Profitability of biosimilars: ............................................................................................................ 66

6.7 Marketing: .................................................................................................................................... 67

7. Conclusion: ........................................................................................................................................ 68

References: ............................................................................................................................................ 71

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LIST OF TABLES

Table 1.1: Comparison of the size of the chemical and biological medicine 2

Table 1.2: Biopharmaceutical market, estimated value and forecast 2009-2015 in
5
US$billion

Table 2.1: Biosimilars Terminology. 7

Table 2.2: Small molecule generics v/s biosimilars. 9

Table 2.3: Definitions of biological and chemical pharmaceuticals. 9

Table 2.4: comparison of generics, biosimilars & biologics. 11

Table 2.5: Biopharmaceutical processing with prokaryotic and eukaryotic expression
15
systems.

Table 3.1. Format of the dossier- modules of the CTD. 29

Table 5.1: Biosimilars approved by the EU. 38

Table 5.2: Unsuccessful biosimilar applications in the EU. 39

Table 5.3: Total World Biosimilar Market Potential 2006-2013 41

Table 5.4: World Biosimilar Market Potential by Region 2006-2013 43

Table 5.6: The world market potential for Biosimilars by Biological Class (EPO, G-CSF,
44
insulin, Interfereon, alpha, others) 2006-2013.

Table 5.7: Estimates of treatment cost per patient of selected biopharmaceuticals.
47
Source: Crandall, 2009.

Table 5.8: Blockbuster biological drugs set to lose patent protection per year through
49
2015. Source: Emmerich, R. (2010)

Table 5.9: Interferons on market and patent expiries. Source: 50

Table 5.10: Multiple sclerosis drugs on the market and patent expiries. 52

Table 5.11: Recombinant insulin products on the market and patent expiries 53

Table 5.12: Bbiosimilar companies sales and market share 55

Table 6.1: Interferons on market and patent expiries 65

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LIST OF FIGURES:

Fig 1.1: Differences in complexity (biotech’s interferon)-a protein naturally produced in
3
our body versus Traditional AsprinSource …………………

Fig 1.2: Evolution of the biologics market 2009-2015. 5

Fig 2.1: Biologic from production to drug use 14

Fig 3.1: Regulatory guidelines. 19

Fig 3.2: Market exclusivity. 25

Fig 4.1: Post fermentation steps in manufacturing process 34

Fig 5.1: World Biosimilar Market potential by region 2006-2013, products with currently
42
expired patents.

Fig 5.2: Expected Biosimilar market split in 2015 45

Fig 5.3: Forecast of the global biosimilar market value in $billion: 2008-12 46

Fig 5.4: Number and value of biological drugs set to lose patent protection per year
48
through 2015

Fig 5.6: Predicted market share of multiple sclerosis drugs (2007-2017) 51

Fig 5.7: Estimated patent expiry dates of selected proteins 54

Fig 5.8. Market Share of biosimilars in the off patent biologics market. 55

Fig 6.1: Patent protection and market exclusivity for top biologics losing patent 64
protection prior to 2018

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ABBREVIATIONS

EMEA – European Medicine Agency

FDA – Food and Drug Administration

EBE - European Biopharmaceutical Enterprises

EU – European Union

ICH- International Conference on Harmonization

CHMP-Committee For Medicinal Products For Human Use

BLA- Biologic License Application

DNA-Deoxyribo Nucleic Acid

CMC- Chemistry Manufacturing and Controls

CTD- Common Technical Document

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EXECUTIVE SUMMARY

According to the definition, biosimilars are different versions of existing branded
biologics, which have received legal approval and which gain access to the market after the
demonstration of pre-clinical and clinical data proving their similarity to the reference product.

Due to their complex structure and nature as well as their complicated manufacturing
process biosimilars have become the subject of rigid regulatory frameworks currently in the
European Union and to be followed by the rest of the world.

The aim of this dissertation is to offer a wide spectrum view of biosimilars in general but
also in comparison to traditional generic chemical drugs.

In order to do this, an overview of the current regulatory frameworks focusing on EU and
US will be presented in relation to the manufacturing process and subsequently the approval
process.

Following this, an analysis of the market of biosimilars is offered addressing issues such
as market opportunities and drivers as well as the challenges faced.

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1. INTRODUCTION:

The first generation of the biopharmaceuticals which are manufactured by the use of
recombinant technologies were launched in the 1980s and most of these products have either
already lost patent protection or are about to lose patent protection in the near future.
Biopharmaceuticals presently demand premium pricing due to various factors such as high cost
of manufacturing, superior safety and efficacy profiles and limited competition from other
biopharmaceutical companies. Since 1982 the global biopharmaceutical market has developed
significantly and was estimated to be worth $125 billion in 2010 (Greer, 2011).

Significant market opportunities for generic companies are provided by the expiry of the
patents first generation of biopharmaceutical/biotechnological products. Second-entry (follow-
on) biopharmaceutical/biotechnological products have a more complex route to the market as
compared to the generic versions of chemically-synthesized active ingredients. The different
terminology that is used to describe "biologically similar drugs" indicates the complexities in this
area. The generic industry tends to regard the biological similar drugs as the biogenerics, but the
research based industry argues that it is not possible to replicate precisely the biological process
for large molecules therefore, due to the nature of their production process; the generic of the
biopharmaceutical cannot exist (Marchant, 2007).

1.1 BIOPHARMACEUTICALS:

The biological medicines (biologic pharmaceuticals or biologics or biopharmaceuticals)
are the medicines which are produced using a living system or organism (EuropaBio 2005). The
division of drugs that are generated from biological sources and which include gene therapy,
vaccines, antibodies and other therapeutic products derived through biotechnology are called
as biologics or biopharmaceuticals (Wang, 2011).

Biopharmaceuticals are also considered as any substance used for the treatment or
management of diseases or injuries and is produced by natural organisms or recombinant
techniques consisting of proteins or other products derived from living organisms (Crandall,

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2009). Using biotechnology, biopharmaceuticals are produced, which are medical drugs.
Biopharmaceuticals are proteins which include antibodies, nucleic acids (DNA, RNA or antisense
oligonucleotides) which are used for therapeutic or in vivo diagnostic purposes and are
produced by means other than direct extraction from a native (non-engineered) biological
source. Through a distinctive process biopharmaceuticals are produced, where various types of
bioreactors are used in which the microbial cells are cultured to produce proteins (Pandey, R. K.
et al., 2011).

The first biopharmaceutical product approved for therapeutic use was recombinant
human insulin (rHI), which also goes by the trade name Humulin. Humulin was developed by
Genentech and marketed by Eli Lilly & Co. in 1982.

The chemical medicines are usually organic molecules whose molecular structure can be
unfailingly assessed and they are produced by a defined chemical pathway (Fox, 2010). In
laboratory the chemical medicines are defined by simple analytical methods. The conventional
chemical medicines are different in various ways to the biological medicines. One of the
apparent differences is the size of the biopharmaceuticals; the molecules of the
biopharmaceutical are much larger, have more complex spatial structures and are to a great
extent heterogeneous than the small molecules which make up chemical medicines (Table 1.1).

Table 1.1: Comparison of the size of the chemical and biological medicines. Source: EuropaBio,2005

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This makes it intricate to characterize biopharmaceuticals in a conventional way by
analyzing their individual components as is done for chemical medicines. A biopharmaceutical
product is molecule which is typically a protein with a complicated three dimensional structure
consisting of chain of hundreds of amino acids. Due the large size (Fig 1.1) and structure of the
molecules, the biopharmaceuticals are administered in injection form, whereas the chemical
medicines with small molecules come in pill form.

.
Fig 1.1: Differences in complexity (biotech’s interferon)-a
protein naturally produced in our body versus Traditional
AsprinSource: EuropaBio (2005) Biological and Biosimilar
Medicines.

The productions conditions must be strictly controlled for the manufacturing of
biopharmaceuticals as they are very sensitive to the production processes. There is an
occurrence of complex post-translational modifications such as glycosylation and pegylation to
the protein, so even the small change in the manufacturing process could have a major impact
on biological activity. If compared in the terms of production quality tests, there are over 2000
production quality tests for the manufacture of a biological drug and only an average of 200
required for small molecule drugs (Pandey et al, 2011).

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1.2 BIOPHARMACEUTICAL MARKET:

The biopharmaceuticals represent one of the most dynamic and potential segments of
the pharmaceutical sector and it has rapidly expanded over the past few years with
compounded growth rates which are beyond double digit figures, which are greater than the
performance of the overall pharmaceutical market (Taylor, 2009). In the field of biomedicine,
the biopharmaceuticals are well established and they have opened new avenues of therapy
options specifically in disease areas where earlier there were no therapies, or only insufficient
therapies were available (Kresse, 2009).

Since the early 1980s biopharmaceuticals have been a rising part of the pharmaceutical
sector. Biopharmaceuticals is one of the rapidly growing sectors in pharmaceutical industry,
growing at an average rate of 18-20% since 2007 (Crandall, 2009). There are many
biopharmaceuticals in the approval pipeline and it was projected that in 2010 for the market
place, 50% of drugs will be the result of biotechnology. There are some 165 biopharmaceutical
products which have gained approval. The total sales of recombinant protein-based drugs were
$54.5 billion in 2007 and in 2012 the sales are estimated to increase to $75.8 billion (Kresse,
2009).

Worldwide there are more than 400 new biopharmaceuticals under development or in
clinical trials and it has been recently estimated that biopharmaceutical sales will expand by 15-
20% annually in the future (Horikawa et.al, 2009). The biopharma market overall is forecasted to
grow at nearly 7% CAGR through to 2015 (Table 1.2), with MAbs (Monoclonal Antibodies)
showing higher growth of 9% (Evers, 2010). The biopharmaceutical market majorly comprises
of monoclonal antibodies, therapeutic proteins and vaccines. In terms of market size,
therapeutic proteins are the leaders (Fig 1.2), but Monoclonal Antibodies (mAbs) are the fastest
growing sector. MAbs (Monoclonal Antibodies) represents three quarters of the biologic market
and expected to dominate. Vaccines will have a steady growth rate and will hold their market
share. Therapeutic proteins are estimated to grow steadily but their growth rate will slightly
decline as compared to other product groups (Fig 1.2) (Evers, 2010).

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2009-$117bn
2015-$170bn
52%
46%
38%
33%

15% 16%

Proteins Vaccines Mabs

Fig 1.2: Evolution of the biologics market 2009-2015. Source: Evers, P. (2010) The Future of the Biologicals
Market.

Table 1.2: Biopharmaceutical market, estimated value and forecast 2009-2015 in US$billion

Source: Evers, P. (2010) The Future of the Biologicals Market.

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2. BIOSIMILARS:

The patent protection for most of the first- generation biopharmaceuticals began to
expire in 2004, opening the door to the so called ‘biosimilars’. A biosimilar is a medicine that is
similar but not identical to a biological medicine that has already been authorized (the
‘biological reference medicine’) (Zuniga & Calvo, 2009).

The biosimilars are also called follow-on biologics (FOB) or Subsequent Entry Biologics
which refer to the “generic” version of biologics or biopharmaceutical products that are
produced and sold on the market after the patents on the innovator’s biologics are expired.
However, the nomenclature of biosimilars is not universal (Wang, 2011).

Many definitions have been provided for “Biosimilars” by various authors. The
breakdown of the term “Biosimilars” can be done for the better understanding of the concept.
They are “biological medicinal products” which as the name suggests are similar to the
approved biological medicinal products in respect to quality, safety and efficacy. These
approved products are reference novel products which are already licensed and marketed. After
the reference product has lost patent protection and data/market exclusivity the independent
applicant can launch the biosimilar product after the approval. For the authorization of the
biosimilar product for marketing the applicant of the biosimilar producer or developer should
follow the procedure of regulations proving the similarity with the reference product. The
complex biological products are difficult to characterize completely, therefore the focus of the
“biosimilar” approach is generally on highly purified products consisting recombinant proteins
as the active pharmaceutical ingredient. According to the (Kresse, 2009) the approach is not
applicable to products which are derived from blood or plasma, immunologicals and other
upcoming therapies like gene or cell therapies. But the regulation bodies are prepared to accept
additional classes of compounds like polysaccharides such as low-molecular weight heparins.

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2.1 TERMINOLOGY DISPUTES:

There has been extreme confusion among the regulatory bodies and countries about the
terminology which could be applied to the biopharmaceuticals/biologics that could be probably
accesible generically due to loss of patent protection and market exclusivity of the original
therapeutic protein (Crandall, 2009).

The complexity of the biopharmaceutical industry and the science behind it leads to
significant controversies with reference to definitions, terminology and issues related to
biopharmaceuticals in terms of products, technologies, companies. Biopharmaceutical are
complex medicines as compared to the small molecule chemical drugs as they are
manufactured by the usage of living organisms. Biopharmaceuticals possess complex nature,
size and complexity therefore they usually cannot be technically classified to the same extent as
the conventional chemical drugs (Taylor, 2009). As it is complicated to provide a concise
definition for a biopharmaceutical, it is particularly tricky to define a generic biopharmaceutical
given the complexity of the products derived from biotechnology. Table 2.1 illustrates the
different names which are used in various regions of the world to describe generic
biopharmaceuticals.

Table 2.1: Biosimilars Terminology. Source: Taylor P., 2009.

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Most of the things associated with the concept of the biosimilars is controversial, even
the language related to the products. The term “biogenerics” is preferred by GPhA (Generic
Pharmaceutical Association), the generic industry trade group, as it indicates the possibility of
interchangeability and also improves the view of the public of generics as being as safe and
effective as the original product. Contrary to this belief the innovator companies approach is
different and use the term “follow –on biologics” (FOB). Different countries and regulatory
bodies of those countries make use of different terminology for generic biopharmaceuticals.
The European Union has the most established regulatory system for generic biopharmaceuticals
called EMA and this system makes use of the term “biosimilars.” The United States has switched
from the term “follow on protein product” to “follow-on biologic” to cover different kinds of
biologic product. Follow-on biologic is also considered as an umbrella term which covers both
biosimilars (i.e. products not having potential to substitute reference product) and biogenerics
(i.e. products having potential to substitute reference product) (Clark, 2009). At initial phases
most products have no proof of interchangeability and the European Union has an established
regulatory pathway as compared to the rest of the world which uses the term “biosimilar”
which will obliviously influence the regulatory system of United States and other countries.

2.2 DIFFERENCES BETWEEN BIOSIMILARS & GENERIC DRUGS:

Generic Medicines are the medicines which contain active substances whose safety and
efficacy are well established. Generic medicines must demonstrate that same dose of the
generic and reference product behave in the body in the exact same way which determines the
bioequivalence of the generic drug with that of the reference product (Zuniga & Calvo, 2009).
Quality in terms of the controls and standards for all manufacturing, preparation and processing
of the product should be maintained by the generic drug at the same standard to the reference
product. The generic drugs are generally considered as interchangeable with the reference
product because they are therapeutically equivalent to the reference product. The market
application procedure is relatively simple for generic medicines as there is no requirement of
results of clinical trials or the results of non clinical data like toxicological and pharmacological
tests. On the contrary it is completely opposite in the case of similar biological medicinal

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products (biosimilars) whose development procedure is complicated like all the
biopharmaceutical products. For the biosimilar products the generic approach is not applicable
due to factors such as the unique manufacturing process for each product and complexity of the
products derived through biotechnology (Table 2.2) (Zuniga & Calvo, 2009). Table 2.3 provides
the definitions of the generic drug, biopharmaceutical and biosimilars.

Table 2.2: Small molecule generics v/s biosimilars. Source: Chen, 2009.

Table 2.3: Definitions of biological and chemical pharmaceuticals. Source: Crommelin et al., 2005.

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2.2.1 PRODUCT DIFFERENCES:

The small molecule drugs called as chemical drugs due to their nature are able to
characterize chemically and this facilitates the generic manufacturers to evade the effort and
additional cost associated with clinical and non clinical evaluation and thereby proving their
product to be bioequivalent to the originator. The requirement of the accurate three
dimensional structures is necessary for the biological activity of the biopharmaceuticals, as this
structure helps in the interaction of the biopharmaceutical with other molecules like receptors
on cell surfaces, binding proteins and nucleic acids. During drug development there are various
profiles which should be fulfilled such as pharmacokinetic and pharmacodynamic profiles,
Clinical safety and efficacy profile all of which are influenced by the three dimensional structure
of biopharmaceutical, by the degree and location of its glycosylation sites, by its isoform profile
and by the degree of aggregation. The biosimilar product in order to prove equivalent to the
originator product has to have all these characteristics in addition to the primary (chemical)
structure to be identical to the original product and this makes the biosimilar different from
chemical generics which can be fully described by its chemical structure (Crommelin, 2005).

2.2.2 MANUFACTURING DIFFERENCES:

The manufacturing of the low molecular weight pharmaceuticals (chemical drugs) is
done by the sequence of controlled and conventional chemical reactions of the recognized
chemical reagents. Contrary to the chemical drugs, the biopharmaceuticals are manufactured
or produced by the harvesting of the proteins from the living cells which often results in the
additional secretion of various other substances along with the protein of interest (Table 2.4).
There is a general misunderstanding that biopharmaceutical product manufacturing is the
simple process of inserting the gene of interest in an appropriate cell line. However
biopharmaceutical manufacturing is a complex process which requires the attention of various
critical factors such as complex size and the three dimensional structures of biopharmaceuticals,
the unpredictable nature of the biological reactions with respect to chemical reactions, various

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secondary modification processes such as glycosylation, and potential chances of denaturation,
aggregation and degradation (Crommelin et al., 2005).

Table 2.4: comparison of generics, biosimilars & biologics. Source: Accenture (2009)

There are several stages involved in the production of the biopharmaceuticals which could
affect the final product.

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 The characteristic of the protein product is determined by the selection of the host cell and
the sequence of genes that codes for the desired protein.
 A master cell bank is established for protein production by extensive cell screening and
selection process and two master cell banks are never precisely the same
 During the fermentation process the fermentor, components of the culture medium and
physical conditions at which the cells are cultured on the large scale affects the protein
which is produced and it also affects behavior properties in the body.
 Purification is the critical step in manufacturing as various related proteins, DNA and other
purities are produced along with the protein of interest any change in the process could
affect the purity of the product.
 A range of analytical techniques is used to examine different characteristics of the protein
product. Even the advanced analytical tools are not sufficient to analyze product
characteristic that may change the clinical safety and efficacy. On the other hand by using
only few analytical techniques the low molecular weight compounds can be completely
characterized in terms of structure.
 The product should be stored cautiously due to the fact that if not stored in optimal
conditions, the product will lose its integrity.

The manufacturing of the biopharmaceutical is a more complex process as compared to the
small chemical synthetic drugs and to make exact reproduction of the innovator biologic
molecule is almost impossible (Greer, 2011). Every stage of the biopharmaceutical
manufacturing process is critical because the slightest change in the process can have
substantial change in the product and its efficacy in patients. The innovator faces a challenge to
maintain consistent batch to batch of biologic product in spite of possessing the patent
information and years of experience with the manufacturing process. Biosimilars cannot be
considered as regular generics as it is highly unlikely to manufacture a “copy” version of
biological products using the manufacturing process which is considerably different from the
innovators manufacturing process (Greer, 2011).

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2.3 MANUFACTURING PROCESS:

Biosimilar development constitutes of three important steps such as Chemistry
Manufacturing and Controls (CMC), preclinical and clinical trials. The traditional generic drugs
are approved under an abbreviated pathway through the Hatch-Waxman Act of 1984. This
pathway is not applicable to the biosimilars as they come under biologics which are governed by
different laws and regulations. The ICH Common Technical Document (CTD) has a module 3 on
quality which describes the CMC requirements for the biosimilars. The European Union follows
the CTD format for submission of application and it will be used by the U.S., when the regulatory
pathway is put into place.

2.3.1 CHALLENGES:

To develop a biosimilar from scratch is a relatively tough task as the biosimilar
developers have no access to the proprietary information of the innovators product’s
manufacturing process or specification of the product. Generally biosimilars development has
to go through a series of steps such as the authorized marketed biologic product should be first
recognized by the biosimilar developer and used as the reference biologic product or innovators
product. The second step is to then carry out a thorough characterization of the reference
product. The manufacturing process of the biosimilar is developed from the data which is
generated from the characterization of the reference product. This data will also be utilized for
the comparability exercise which is performed to prove the bioequivalence between the
biosimilar and reference product. Due to the lack of access to the innovators manufacturing
process the biosimilar product is manufactured from entirely different and new process as
compared to the innovator manufacturing process. The new process developed by biosimilars
manufacturers may use and carry out production process in different culture system and
equipments like fermentor (Chen, 2009).

The challenges faced by the biosimilar as well as the innovator manufactures are the
same when it comes to the biopharmaceutical/ biologics production. Specifically there are two
challenges: Firstly there should be a robust manufacturing process which produces a consistent

13

product which has to be tested to be same in the preclinical and clinical studies. The second
challenge is to maintain product reproducibility in terms of scale up of the process with same
site or when manufacturing occurs at different sites. These two challenges are never easily met
by the manufacturers for instance the studies on innovators epoietin alpha with that of the
epoietin which is manufactured outside the U.S. and European Union have differences in terms
of purity, efficacy and biological activity. This example indicates that slight change in the
manufacturing process will result in the change in the biological activity of the product (Sharma,
2007). Fig 2.1 illustrates the flow from drug production to the administration.

Fig 2.1: Biologic from production to drug use
Source: Chen, B., 2009

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2.3.2 SELECTION OF PLATFORM :

The development of the CMC is initiated by the selection of the production platform or
the expression system (Table 2.5). Depending on the type of protein to be manufactured an
appropriate technology is selected. The yeast expression system along with batch fermentation
is selected for the production of small peptides and proteins. The mammalian expression
system is selected as it provides the higher yields and reliable purification results and used for
the production of the monoclonal antibodies, complex proteins which contains disulphide
bonds and require glycosylation. Several stages in manufacturing are crucial and have influence
on the properties of the end product. Therefore after the selection and establishment of the cell
line which is crucial, a specific DNA sequence which codes for protein of interest is inserted
(Chen, 2009). Then extensive cell screening and appropriate methods are used to form a master
cell bank, so high levels of sterility and identity of the cells could be maintained. Throughout
the manufacturing process the cells are cultured under definite conditions so as to get
optimized results in terms of production and secretion of protein of interest. The structural
characteristics of the proteins are decided by the culture conditions in the mammalian cell
system and in the bacterial system they are later defined in the purification process (Sharma,
2007).

Table 2.5: Biopharmaceutical processing with prokaryotic and eukaryotic expression systems.
Source: Sharma, 2007

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2.3.3 PURIFICATION:

Impurities are unacceptable in the biologics manufacturing as impurities in the final
product could have clinical consequences. The process of purification has to get rid of all the
impurities which include cell proteins by host cells, DNA contamination, medium components,
viruses and other by products without causing any damage to the protein of interest. There
should be proper selection of the desired protein forms with suitable glycosylation and removal
of damaged forms in the purification process. Biosimilar manufacturers do not have access to
the purification process information of the innovator which leads to the differences in the purity
and protein structure. It is important for the biosimilar manufacturers to compromise on the
yield when it comes to purity as the purity leads to safety and efficacy status which is the
ultimate aim of the biosimilar. For instance in the erythropoietin purification, for the optimum
biological activity only the isoforms which are highly glycosylated are selected (Sharma, 2007).

2.3.4 FORMULATION:

The therapeutic performance and conformational stability of the biologic drug is
associated with composition of the formulation and choice of the container. These factors are
responsible for the protein degradation and aggregation. After going through composition of
formulation then sterile filtration and filling into the final container the final product is formed.
Components of the formulation consist of basic buffer which is for proper pH control and salt
which provides the isotonic adjustment. In order to avoid proteins from being absorbed to the
surface of containers or hydrophobic surfaces, surfactants are used in the formulation. In the
end container and closure reliability should be thoroughly checked for sterility. Biologics are the
heterogeneous mixtures which are not pure substances. Biologic products are produced under
the current Good Manufacturing Practice guidelines and to make sure they are produced
according to the predefined specifications there are various assays which could check the purity
and authenticity of the product. The biologics are sensitive to environmental changes such as
temperature, storage, handling and sunlight. For instance insulin vials exposed to temperature

16

more than 40C results in transformation of the product and increased chances of
immunogenicity and loss of biological activity (Sharma, 2007).

17

3. BIOSIMILARS LEGISLATION & REGULATIONS:

The regulatory bodies have recognized the fact that the manufacturing process is critical
in the production of biopharmaceuticals and variations in the process could lead to significant
differences in product characteristics which cannot be fully determined by the analytical
characterization. So the manufacturing process is considered and made part of the
determination of the product quality along with other testing protocols carried to determine
similarity. Therefore protein products which are manufactured by the independent
manufactures would never be identical to the innovator product, but at maximum would be
similar to innovator molecule possessing the same clinical attributes despite of not being the
same molecule (Kresse, 2009).

An ideal legal and regulatory process which allows the approval of the biosimilar
products has to attain equilibrium between various factors which involve the facility for market
entry for biosimilars, competition for products which have lost patent protection, to promote
research and development and provide incentives, and finally the most important is to evade
any risk associated with patient safety. Though it is considered that advent of biosimilars will
lead to reduction of redundant or even unethical clinical trials of animals as well as human and
biosimilars will propose economic benefits but biosimilars do not bring any innovative medical
progress as the original product is already available proving effective and safe to the patients.
Therefore the approval pathway for biosimilars should ensure that appropriate standards of
same level as innovative products should be maintained. Usually it is agreed that the regulatory
pathway for traditional low molecular generic drugs is not suitable for biologic or
biopharmaceutical medicines. There are initiatives and regulatory pathways already established
or under development in various regions of the world (Kresse, 2009).

Biosimilars are licensed and marketed in various regions of the world including the less
regulated markets such as India, China and South Korea. The category of the products which are
marketed in these regions include interferons, EPOs, growth hormones, enzymes, interleukins,
monoclonal antibodies etc. As compared to these less regulated markets there is a significantly
less number of biosimilar products available on the European market with only few categories

18

of products such EPO, filgrastim and somatropin. On the other side, however, there is the
establishment of a highly developed framework of regulations in the European Union for the
approval of biosimilar products. The regulatory framework of Europe by the EMA (European
Medicines Agency) (earlier called as EMEA, terms used alternatively in this report) has
influenced the regulatory authorities in other countries like Unites States, Japan and Canada
which will work on the similar lines (Zuniga & Calvo, 2009).

3.1 REGULATORY FRAMEWORK EUROPE:

The regulatory framework and process for the biosimilar product approval is defined by
the European Directive 2001/83/EC which is modified by Directive 2003/63/EC and Directive
2004/27/EC. These Directives provide detailed specific guidelines which have to be followed by
the biosimilar developers. These guidelines include an overarching guideline (Box 1) and also
other broad guidelines which are associated with quality of the product and clinical and non
clinical data which is to be provided by the biosimilar applicant (Fig 3.1). EMEA has also provided
product specific guidelines and are also in the course of developing supplementary guidelines
which will upgrade the main guidelines as new information is continuously added and found.
Box 2 states the guidelines which are being issued in the European Union in reference to
biosimilars.

Fig 3.1: Regulatory guidelines. Source: Kox, S., 2009

19

Box 1: Summary of biosimilar overarching guideline (EMEA/CHMP/437/04)

Source: Taylor, P., 2009.

20

Box 2: Summary of biosimilar overarching guideline (EMEA/CHMP/437/04)

PD= Publication date; ED= Effective Date. Source: Taylor, P., 2009.

21

As per the legislation the Committee for Medicinal Products for Human Use (CHMP) of
the European Medicines Agency (EMEA) has discretion to develop guidelines which determine
the amount of clinical trials required as per the product (Chu & Pugatch, 2009).

The pharmaceutical products resulting from biotechnology are registered in Europe
alone through a centralized procedure which results in a European Union license. The European
Union license is valid in all the member countries of EU (Zuniga & Calvo, 2009).

The biosimilar developers for the marketing authorization of the product have to fulfill the
following requirements which are set by EMEA:

 Data on the comparability studies should be provided between the applicant biosimilar
product and reference innovative medical product.
 Non clinical studies data which are generally required in limited details as compared to
applications for the innovative product.
 To prove safety and efficacy of the biosimilar product clinical studies are required.
 An obligation to provide post market pharmacovigilance arrangements as part of the
approval process (Zuniga & Calvo, 2009).

EMEA has developed biosimilar regulatory guidelines with major distinctions from the
generic medicines approval process considering the fact that biosimilars are not expected to be
identical to the innovator biologic medicines. The fact that conventional generics are different
from biosimilars is recognized by European legislation and mentioned in the Article 10(4) of EU
Directive 2001/83/EC which has been modified by Directive 2004/27/EC (Kresse, 2009).

Establishing bioequivalence alone of the biosimilars to the innovator biologic is not sufficient
to get market approval. The basic fundamental idea behind the guidelines is that the biological
activity of the biosimilars cannot be determined if the active substance is different from the
innovative biologic. Analyzing the pharmacokinetic properties of the biosimilars will not offer
satisfying results on whether the similar but not identical nature of the active substances has
lead to changes in clinical safety and efficacy profile. Therefore the biosimilar applicant to
demonstrate the similar product quality, safety and efficacy profile to the innovator biologic has

22

to perform further clinical and non clinical studies according to the EMEA clinical and non
clinical guidelines (Box 3) to acquire market approval (Fox, 2010).

Box 3: Summary of Biosimilars Clinical & non clinical Guideline Principles for
MEA/CHMP/42832/05

Source: Zuniga & Calvo, 2009

23

3.1.1 PRODUCT SPECIFIC GUIDELINES:

Apart from general regulatory guidance issued for all biosimilar categories, EMEA has
additionally issued guidelines which are specific to the product class such as EPO, G-CSF, human
soluble insulin, somatropins, low molecular weight heparin and interferon alpha. The guidelines
for other product category such as monoclonal antibodies or biosimilar medicinal products
containing monoclonal bodies have been in the stages of finalization. The Biosimilars Medicinal
Products Working Party (BMWP) is in the process of preparation of the guidelines for the Similar
Biological Medicinal Products containing Follitropin alpha and beta-Interferon. Currently
according to the EMA (2010) there is also revision and maintenance of the existing overarching,
non-clinical and Clinical guidelines by Biosimilars Medicinal Products Working Party (BMWP).

The product specific guidelines explain in details the extent and type of studies, both in
terms of clinical and non clinical, which should be carried out and presented to the regulators to
obtain approval for the product. The guidelines not only expect the biosimilar product to be safe
and effective but also to be comparative in nature and most importantly to identify variation in
response between the biosimilar and innovative biologic. It is of important concern that the
minute differences of biosimilars to innovative product with reference to quality are not
acceptable by the guidelines and even if they are anticipated then proper explanation regarding
the implications caused by the variation should be provided. As per the guidelines, it is crucial
that the biosimilar applicant demonstrates that the quality, safety and efficacy of the biosimilar
are similar to that of the innovators biologic it seeks to copy. The attributes of the biosimilars
should display equivalence and cannot be worse, better or different from the innovator biologic
product. If the biosimilar is different or better than the original biologic, which is not an
alternative as it implies there is lack of similarity, then the biosimilar product may have to be
withdrawn from the application process, would get rejected or have to apply for new product
application necessitating a need to pursue a full stand alone pathway (Fox, 2010).

Given that the data submitted by the biosimilar applicant are less than the innovator,
the approach of the EMEA to acquiring authorization of a biosimilar, in that, there is no
standard data set which is applicable to all classes of biologics, is sensible. There is a variation

24

among different classes of biologics in terms of benefit and risk profile, whether surrogate
markers are available and validated, adverse events possible and clinical indications. EMEA
provides product class specific guidelines that suggest the data and studies which are supposed
to be conducted but does not provide the exact equivalence margins. Therefore the guidelines
do not lay down set standards for approval and there is possibility to maneuver when it comes
to settling exact standards for approval of any biosimilar (Fox, 2010).

The Regulatory pathway for biosimilars in the European Union was in effect from 2005
and since then there have been 14 biosimilar approvals and 7 products received negative
opinion or were rejected by the EMEA (Fig 3.1 & 3.2). The biosimilar applicant requires clinical
studies consisting of 200 to 500 subjects which depend on the product class of the biosimilar. In
contrast the innovator biologics have to conduct clinical trials on thousands of subjects to
achieve a range of clinical indications. This indicates the extent of reduction of clinical trials for
the biosimilar applicant (Fox, 2010).

Fig 3.2: market exclusivity. Adapted from Kox, S., 2009

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3.1.2 IMMUNOGENICITY:

The generic drugs are different from the biosimilars in various aspects and one critical
aspect is their capability to produce immune response. A change in immunogenicity profile is of
most important concern as it can have enormous consequence on the product safety (Zuniga &
Calvo, 2010). The implications which are caused by immunogenicity are difficult to predict. The
formation of antibodies can either have harmless clinical effects or can result into serious
diseases and some cases considerable adverse events. Immunogenicity effects can be explained
by the example of Eprex which is an EPO product marketed by Johnson & Johnson in the
European Union with no significant immunogenic concerns for almost 10 years prior to 1998
when regulatory bodies requested for change in the product. Johnson & Johnson modified the
Eprex formulation by interchanging human serum albumin with polysorbate 80 and glycine
which resulted in pure red-cell aplasia (PRCA). Pure red-cell aplasia is a severe type of anemia.
The antibodies which are produced due to Eprex neutralize all the exogenous rHuEPO and also
cross react with endogenous erythropoietic proteins which results into ineffectiveness
erythropoiesis and serum EPO is not detectable. J&J later found out that the polysorbate 80 in
the single use syringes reacted with rubber stoppers to leach plasticizers which triggered the
immune reaction and caused PRCA. In 2003 there was 90% reduction in PRCA by changing
uncoated rubber stoppers to Teflon coated rubber stoppers (Chen, 2009).

The EMA approval process in association to immunogenicity concerns with biosimilar
products can be explained with clinical and non clinical testing and comparability decision of the
biosimilar product Retacrit® with the innovator product Eprex®/Erypo®. The applicant offered a
database of studies which was considered as sufficient by the EMA which consisted of a report
on studies of clinical immunogenicity within a time period of twelve month taking data from 227
subjects with renal anemia which was later updated to additional 585 subjects. The toxicity,
pharmacokinetic and pharmacodynamic analysis and biologics safety and efficacy are often
affected due to anti-drug antibody (ADA) reactions. The safety issues are also related with
neutralizing ADA (nADA). In case of Retacrit® and reference product Eprex® the serum samples
were acquired for the determination of ADA before dosing and through the safety studies. A

26

validated radioimmunoprecipitation assay was used for the testing of the Anti-EPO antibodies
which indicated that there was a low occurrence of ADA in the subjects which were treated
either with the biosimilar Retacrit® or the innovator product and also no patients who were
ADA positive showed signs of PRCA. These results indicated that there was no need for the
NADA tests, but for post marketing surveillance a validated nADA testing was available. The
EMA has not concluded on the specific value of the predictive immunology but its usage is
recommended. For example the transgenic mouse models could be helpful to estimate
probable immunogenicity of the protein in question. Generally in preclinical immunogenicity it
is difficult to recognize that the estimations are relevant without clinical data to validate
preclinical assessments (Barbosa, 2011).

The European biosimilar regulatory pathway has specific consideration towards the
biosimilars immunogenicity issues and post marketing activity to identify potential concerns.
The estimation of immunogenicity of biosimilars cannot be determined by only preclinical trials.
As a result clinical trials along with a post marketing surveillance plan are mandatory for the
authorization of biosimilars (Zuniga & Calvo, 2009). In context to the persistent chronic
treatment, there is a requirement of immunogenicity data for about a year of treatment before
authorization (EMEA/CHMP/BMWP/42832/05).

3.1.3 EXTRAPOLATION:

With the appropriate justification, as per the relevant guidelines, the extrapolation of
clinical data, for indications for which the drug has not been evaluated in clinical trials, has been
allowed for biosimilars. According to guidelines provided by the EU, extrapolation is not
allowed, but is considered on a case by case basis based on various factors such as complexity of
the product and mechanism of action etc. CHMP guidelines allow extrapolation based on
known mechanism of action and the sensitive indication where, if significant differences would
exist between biosimilar and the reference product, they would be detected in that particular
population (Ruiz & Calvo, 2010). The extrapolation of safety is not approved for any indications.
EMEA has approved recombinant granulocyte –colony stimulating factor for the reduction in

27

neutropenia after cancer chemotherapy, but the approval of other indications of reference
product were made by extrapolation considering that mechanism of action of biosimilar is the
same. (Zuniga & Calvo, 2010).

3.2 EU BIOSIMILAR APPROVAL PROCESS:

According to the European Directive 2004/27/EC the conducting of the comparability
studies between the biosimilar and the reference product is necessary but the requirements for
probable test are not addressed. The comparability exercise is of various types which include
physiochemical, biological, Pre-clinical and clinical. The reference biologic product under
consideration must be a medical licensed product on the basis of the complete document as per
the necessities of article 8 of Directive 2001/83/EC modified by Directive 2001/83/EC (Zuniga &
Calvo, 2010). The reference product chosen to compare with the applicant should be same
throughout the comparability programme. Comparability should be in terms of product quality
and manufacturing process as the safety and efficacy of the product is directly associated to the
manufacturing process.

3.2.1 COMMON TECHNICAL DOCUMENT:

The biosimilar applications should be made completely in agreement with the Common
Technical Document (CTD) presentation (CPMP/ICH/2887/99). It is structured into five different
modules which biosimilar applicants have to follow as shown in Table 3.1. The information to
be provided is not restricted to first 3 modules, but additional data will be required. Generally
the supplemental data is determined on a case by case basis in relation to specific scientific
guidelines (Directive 2003/63/EC) (Zuniga & Calvo, 2010).

28

Table 3.1. Format of the dossier- modules of the CTD. Source: Zuniga & Calvo, 2009

3.2.1.1 MODULE 1:

In module 1 a brief document is to be submitted comprising information about the
details of the product, the manufacturing process involved, raw materials used, and its active
substance. It also involves other information about the comparability exercise such as changes
made during development which would affect the safety and efficacy and detailed description
of the reference product.

3.2.1.2 MODULE 2:

Module 2 expects the data on normal requirements which includes the general idea and
synopsis of the quality, clinical and non-clinical data.

3.2.1.3 MODULE 3:

A complete quality document which provides information on chemical, pharmaceutical
and biologic information is required for biosimilars. In addition to this information,
comparability studies should be provided as per the guidelines of EMEA.

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3.2.1.4 MODULE 4:

The non-clinical studies to determine the differences and similarities between the
applicant product and reference product are to be demonstrated in module 4. It is crucial to
identify the biological product characteristics of the biosimilar based on studies related to
physiochemical and biological characterization.

3.2.1.5 MODULE 5:

To demonstrate the safety and efficacy of the biosimilar at the clinical level the studies
conducted at non clinical level are not sufficient. It is essential to submit the design of the
clinical program to the regulatory agency. The extent of the biosimilar trial depends on the
specific class of the product (Zuniga & Calvo, 2010).

The approval of the biosimilars in the European Union will lead into formation and
publication of public report which is called European Public Assessment Report (EPAR). The
EPAR is designed for the public and is written in collaboration with the biosimilar applicant. The
main purpose of the report is to explain and provide the transparency of the biosimilar
application and regulatory process involved during the approval period (Zuniga & Calvo, 2009).

3.3 UNITED STATES REGULATORY FRAMEWORK:

The Regulations framework of Biologics in the United States is regulated by Public Health
Service Act (PHSA), but for few exceptions such as insulin and human growth hormone which
come under the Food Drug and Cosmetics Act (FDCA). FDCA has a regulatory pathway for the
generic drugs of the conventional chemical drugs, but PHSA does not have any approval system
for the generic versions of biologics (Clark, 2009). According to the standards of FDCA, the
biological drugs are authorized on the basis of identity, effectiveness and purity rather than on
efficacy and safety. Even though there are no biosimilar approval options by the PHSA, there are
still few biosimilar products out in the United States market. For example Omnitrope by Sandoz
a biosimilar version of recombinant human growth hormone which is similar to Genotropin by
Pfizer was authorized by the FDA in 2006 for the United States. The approval of Omnitrope was

30

made through a New Drug Application (NDA) which used the route 505(b) (2). This route is
different from the generic approach which is called as Abbreviated New Drug Application
(ANDA) in various ways such as there is no need for sameness which gives room for satisfactory
similarity. The applicant using the 505(b) (2) route can use the available research which implies
that the FDA without citing the trade secrets of Pfizer could evaluate Sandoz’s Omnitrope (Clark,
2009). The complicated biosimilar products such as interferons cannot be approved through this
regulatory pathway.

President Obama approved the “Patient Protection and Affordable Healthcare Act” in
March 2010. The main objective of this act was to form legislation by designing a regulatory
pathway which will save healthcare cost and creating a flexible route for the approval certain
biologic which reduces the cost of development. The 351 (k) route is the new regulatory
pathway for biosimilars which is provided by the Biologics Price Competition and Innovation Act
(BPCIA) as part of the Affordable Care Act. According to the pathway the biosimilar should be
compared to the single innovative reference product which is authorized under 351 (a) route.
Two types of products will be provided by this pathway, Biosimilar and Interchangeable
biosimilar. For obtaining the interchangeable biosimilar approval exact guidelines and
requirements are under discussion. The manufacturers should also comply with patent
disclosure arrangements as per the act. The authority of describing the guidelines for regulatory
framework is given to FDA and they have not yet revealed data requirement for approval
(Greer, 2011).

3.4 GLOBAL LANDSCAPE:

International Conference on Harmonization (ICH) aims to synchronize the approval
process and regulatory requirements of drug or biologics in the United States, EU and Japan.
Biosimilar regulatory framework is already established in EU and Japan but the legislation is still
under discussion in US (Chen, 2009).

There is establishment of the regulatory pathway have taken place in various countries
of the world such as Brazil, Taiwan, Mexico, Argentina, India, Canada and South Africa. There is

31

a direct acceptance of the guidelines of EMEA in Australia and on similar basis regulation are
established in Malaysia, Japan and Turkey. The approval pathways followed by various
countries are not clear in terms of scientific reasoning, therefore the World Health Organization
(WHO) adopted a guideline to evaluate similar biologic products which will result in availability
of the regulated biosimilar products worldwide (Kresse, 2009).

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4. CASE STUDY-BIOSIMILAR INSULIN:

In general biologics are complex molecules to produce and biosimilar insulins present
special challenges. Their therapeutic window is narrow and the accuracy of their dosing is
dependent on the product formulation and quality of the administrative device. Therefore for
these specific reasons EMA has issued strict guidelines which the biosimilar applicant must
follow to receive approval of the biosimilar soluble insulin (Sauer, T. and Kramer, I., 2010).

4.1 MANUFACTURING:

The recombinant human insulin production is a highly complicated process (Fig 4.1). The
first step is the isolation of the human insulin gene which has specific sequence which codes for
the human insulin. After the isolation the gene is attached to the vector and then it is inserted
into a host cell which is generally E.coli or a yeast species. The recombinant cells which are
formed are screened which results in the formation of the master cell bank, then further
cultured and fermented. After fermentation the protein which is produced is isolated, purified
and is folded in order to form secondary structure. To achieve biologically active insulin, the
secondary structure is enzymatically cleaved. Different adsorption and chromatographic
techniques are employed for the purification of the recombinant insulin. To prevent the insulin
from losing its biological activity or avoid aggregation of the product and bacterial growth, the
purified product is subjected to crystallization, lyophilization and formulated by addition of
other compounds such as protamine is added for long acting formulation (Marre & Kuhlmann,
2010). If there is any change in the various sequential process of insulin production such as
change in vector selection or change in formulation will result in an insulin product which will be
identical to the innovator insulin product in terms of structure and amino acid sequence but its
clinical properties will differ from the innovator product.

33

Fig 4.1: Post fermentation steps in manufacturing process. Source: (Marre, M. & Kuhlmann, M., 2010)

4.2 EMEA REQUIREMENTS:

For the market approval of the soluble insulin biosimilars, EMEA has laid down specific
guidelines which explain the requirements to be fulfilled by the applicant. As per the guidelines
like all the biosimilars, insulin as a biosimilar product should be analyzed with the comparative
technique to prove equivalence with the reference product. For biosimilar insulin approval the
preclinical studies are required which consist of in vitro pharmacodynamic studies, in vitro
affinity bioassays and receptor binding assay for insulin as well as IGF-1.

34

The requirement of EMEA is at least one pharmacokinetic single dose crossover study in
patients suffering from type 1 diabetes by subcutaneous administration to compare the
biosimilar with the reference product. To check the biosimilar insulins hypoglycaemic response
profile, clinical activity must be determined in pharmacodynamic study designed as a double
blind crossover, hyperinsulinaemic, euglycaemic clamp study (Sauer and Kramer, 2010). For
biosimilar insulin clinical efficacy trial is not needed but there is a requirement of clinical safety
study. For at least the period of 12 months, the insulin product immunogenicity should be
inspected through the clinical studies. Six months of comparative phase should be included in
the clinical trials. To detect any clinically important immunogenicity that may occur in the long
term, the developers should design a pharmacovigilance plan (Marre & Kuhlmann, 2010).

4.3 MARVEL’S INSULIN REJECTION:

Marvel Life Sciences Ltd in March 2007 submitted a biosimilars application for market
approval of recombinant insulin in three different formulations. Marvel Life Sciences Ltd
presented their data from their studies intended to show the similarity between Marvel’s insulin
and the reference insulin product in experimental models and in humans. The consequence of
Marvel’s insulin on the blood sugar levels was studied in Twenty-four healthy volunteers with
that of the reference insulin product and these studies were presented to the EMEA. Another
important study was also presented which involved 526 diabetes mellitus patients who either
received Marvel’s insulin or reference insulin for the period of 12 months.

There were various issues found by CHMP regarding the data and application submitted
by Marvel Life Sciences. CHMP found that data on many critical aspects of the application were
not enough and unclear. Review of the application was done by EMEA, considering the
application CHMP formed a conclusion that the three formulations of biosimilar insulins by
Marvel Life Sciences Ltd were not comparable with the reference insulin. The CHMP rejected
Marvel’s insulin on the grounds of Quality, Clinical and Non-Clinical aspects.

35

4.3.1 QUALITY ASPECTS:

The Proper evaluation of the application was not possible because sufficient amount of
data was not submitted on the development and manufacture of the drug substance as well as
the drug product. There was confusion whether the reference product used for the
comparability exercise was valid or not. The explanation provided for the process like
fermentation, harvesting, purification and modification in the application were not in complete
details. The comparability exercises to detect impurities in the insulin product to that of the
reference product were not adequate to draw a conclusion that Marvel’s insulin was biosimilar
to the reference insulin. There was a huge confusion that the dossier submitted during
application was unable to specify two different presentations of the drug product (vials and
cartridges).The important details such as drug substance batch number, size and site of
manufacture and details of where the batches have been used for clinical and pre-clinical trials
were absent in the dossier (Joshi, 2009).

4.3.2 NON CLINICAL ASPECTS:

Based on the data submitted, the committee was not able to review the comparability of
Marvel’s insulin with the reference product due to insufficient explanation.

4.3.3 CLINICAL ASPECTS:

The pharmacodynamic studies did not provide the result of lowering the blood glucose
level as compared to the reference product. The sufficient pharmacokinetic studies were not
carried out such as single dose crossover comparative studies by the use of subcutaneous
injection as per the guidelines. The immunogenicity of the insulin product was not completely
evaluated and validated. Additionally the pharmacovigilance plan presented in the dossier was
not up to the requirement of the EMEA guidelines (Joshi, 2009).

Due to inadequate studies and lack of well presented data in January 2008 it was
declared by the EMEA that Marvel Life Sciences Ltd have withdrawn applications for all three
insulin formulations (Marre & Kuhlmann, 2010).

36

5. MARKET ANALYSIS:

The focus of the market analysis in this thesis is based on major markets such as the
United States and the European Union.

5.1 BIOSIMILARS ON MARKET:

The expiration of patents of a number of first generation of biologics has led to the
approval of various biosimilar drugs by the European Medicines Agency (then EMEA, now EMA)
in Europe. EU in 2003 held discussions on the follow on biologic recombinant proteins concept
and then later the guidelines on biosimilars were established and took effect in 2005. The
Committee for Medicinal Products for Human Use (CHMP) according to the guidelines for
biosimilars requires complete characterization in terms of physical, chemical and biological of
the biosimilar product as compared to the reference product. To prove the safety and efficacy
of the biosimilar product widespread characterization, clinical and non clinical data is required
but as per the guidelines the amount of data required will be less than the application of the
innovators drug (Greer, 2011). Omnitrope, a biosimilar version of somatropin was the first
biosimilar drug to get approval from the EMEA in April 2006. Another Human growth hormone
called Valtropin was approved by EMA immediately two weeks after the approval of Omnitrope.
Table 5.1 illustrates that to date the EMA has approved 14 biosimilars products which include
the versions of somatropin, EPO and filgrastim. Nine different biosimilar companies have
successfully launched 7 biosimilar molecules under 14 different trade names (EBE 2010).

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Table 5.1: Biosimilars approved by the EU. Source: Greer, F.M., 2011

Table 5.2 shows that several applications such as interferon alpha-2a and insulin
received negative opinion and some applications were not successful, either rejected or
withdrawn voluntarily.

38

Table 5.2: Unsuccessful biosimilar applications in the EU. Source: Greer, F.M., 2011

In the United States there is no legislation for a clear regulatory approval pathway for
biosimilars but still Omnitrope, a biosimilar version of somatropin was authorized by the use of
the Abbreviated New Drug Application (ANDA) process under the Hatch-Waxman Act following
EU approval (Horikawa et.al, 2009). There were various biosimilars approvals before Omnitrope
which didn’t achieve to receive as much attention as Omnitrope. These approvals include
different recombinant biologic drugs with trade names such as Glucagen, Hylenex, Hydase and
Amphadase. Fortical by Unigene which is similar to Miacalcin by Novartis used for the treatment
of osteoporosis was the first biosimilar recombinant DNA product to be authorized by FDA by
the 505(b) (2) route under NDA (Clark, 2009).

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5.2 MARKET SIZE & GROWTH:

The patent expirations from the year 2009 through 2013 are expected to trigger the
battle the approval and production of biosimilars (Crandall, 2009). The potential of the total
worldwide market for the biosimilar products is quite significant amounting up to several billion
dollars annually. Significant opportunity for the biosimilars market is also created as the
biologics worth $25 billion are expected to go off-patent by 2016 (Business Insights Ltd, 2009).
The biologic market has outperformed the pharmaceutical market which is driven by high prices
for the therapies which cannot be managed by traditional drugs. In 2007 Biologics contributed
more than 10% of the global pharmaceutical revenues. The annual rate of growth for the
biologics is growing at the rate of 12%-13% which is almost double the global pharmaceutical
industry rate of growth (Business Insights Ltd, 2009).

The growth of the biosimilars market is also fueled by the rapid penetration of the novel
biologics in the global pharmaceutical markets and the gradual expiry of the patents of the
novel biologics. There was 5.9% growth in the global biosimilars market in 2007 to reach the
value of approximately $1 billion (Business Insights Ltd, 2009). The growth of the biosimilars will
be majorly driven by the four drug classes - erythropoietin (EPO), filgrastim, human Growth
Hormone (hGH) and insulin in the future. The revenues from the biosimilars are currently less
because one of the profitable markets, such as the U.S. is facing regulatory restrictions but after
the regulatory framework is established there will be a number of products which could have
market authorization and thereby increasing the revenues and size of the biosimilar market
(Crandall, 2009).

5.3 MARKET POTENTIAL:

There is a range of reports which provide estimates on worldwide biosimilars market
figures and forecast. As this market is highly speculative the range of figures and estimates
provided by the various reports vary.

40

The total global biosimilar market potential for the period of 2006-2013 is forecasted for
the currently expired patents by Crandall (2009) which indicates that by the year 2013 the
revenues generated would be $358 million at the 17.0 percent growth rate and for the period of
2006-2013 the compound annual growth rate would be 32.5% (Table 5.3).

Table 5.3: Total World Biosimilar Market Potential 2006-2013 (Products with currently expired
patents).Source : Crandall M., 2009.

Fig 5.1 represents the steady growth of the global biosimilar market and its potential
with currently expired patents.

41

Fig 5.1: World Biosimilar Market potenatial by region 2006-2013,
products with currently expired patents. Source: Crandall, 2009.

5.4 REGIONAL MARKET ANALYSIS:

The European Union and the U.S. are the major markets for the sales and revenue
generation from the biosimilars. As compared to any other region worldwide the products in
the U.S. perform better in reference to sales and the drug approval in the U.S. generally sets the
standard for the approval abroad. Marketers consider that the U.S. market is generally most
favorable. Lack of regulation is holding back the biosimilar market from expanding in the U.S.
Although in the U.S. there is no clear developed pathway for the authorization and approval of
the biosimilars as compared to other countries, currently only few approvals of biosimilars can
be seen for the regions other than the U.S. There is some progress with a range of biosimilars
approvals in markets such as Eastern Europe, Asia and South America but still the sales revenues
are quite less as compared to the major markets such as the U.S. and Europe. Novartis, is the
main competitor in the biosimilar market, as this company has made progress in early phase of

42

the market. In less regulated and less developed markets like India, Rituxan and Neupogen are
substituted by the generic counterparts (Crandall, 2009). Table 5.4 shows the distribution of
market potential for biosimilars in major markets such as Europe and the United states and the
rest of the world from currently expired patents.

Table 5.4: World Biosimilar Market Potential by Region 2006-2013 (Products with currently
expired patents). Source: Crandall M., 2009.

5.5 BIOLOGIC CLASS MARKET ANALYSIS:

Table 5.6 shows the forecast for market potential and revenue generated from individual
product categories which are currently marketed. The biosimilar versions of the blood products
like erythropoietin and G-CSF are in great demand in the global biosimilars market. Sales
revenues generated from these products alone in the period of 2008 were estimated to be $62
million (Crandall, 2009). This sales figure consists of the sales of the products in the European
Union as well as in the less regulated market throughout the world where relaxed laws of

43

biosimilars exist. Despite of the fact that insulin is the favorable for biosimilar production due to
the reasonably less complex manufacturing process, the sales of the biosimilar insulin is
relatively low as compared to the total market of insulin. Another key product in biosimilar
products is HGH which is favorable for production in the U.S. and Europe, but the sales results
are much lower than predicted by producers. Global sales for the biosimilar HGH is about
$15million for the year 2008 and with the growth rate of 21.9% during the projected period
(Crandall, 2009). The category of biosimilar drugs which involves autoimmune and oncology
products shows a rapid growth with sales estimated to be $39 million throughout 2008
(Crandall, 2009). The accessibility of the monoclonal antibodies and multiple sclerosis
therapeutic biosimilar versions is found in regions of the world where there is less regulation
and the patent laws are not strict.

Table 5.6: The world market potential for Biosimilars by Biological Class (EPO, G-CSF, insulin,
Interfereon, alpha, others) 2006-2013. This forecast includes currently marketed classes only.
Source: Crandall M., 2009.

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It has been reported by (Emmerich, 2010) that by the year 2015 the European and
United States biosimilar market size could reach US$ 10 billion. The monoclonal antibody (mAB)
segment is anticipated to generate most revenues. The Biosimilars’ largest market share is
expected from the revenues generated from mAB such as Remicade and Rituxan. Fig 5.2
indicates the predicted market share among various classes of biosimilar drugs by 2015. The
market is dominated by various companies which will lead in variation in market penetration
between products. For example biosimilar insulin market penetration is considered low
because the market is dominated by other three originator companies and on top of that
advanced injection system is required for insulin.

Fig 5.2: Expected Biosimilar market split in 2015
Source: Emmerich, R. (2010)

5.6 MARKET OPPORTUNITIES:

The global biosimilar sales estimates (Fig 5.3) were reported by Clark (2009) for a period
of five years ending in 2012. The estimates provided in the report were based on biosimilar
activities in Europe as the US market, due to lack of regulatory framework, is not likely to show
any momentum during this period. Even though the biosimilar market value would be around
$13 billion for the period 2009-2012 which is quite considerable, this biosimilar market is

45

actually predicted to represent only a small percentage of total pharmaceutical and generic
sales of the future.

Fig 5.3: Forecast of the global biosimilar market value in $billion:
2008-12. Source: Clark, T.D., 2009

The prices of the biosimilar products will generally be 20% to 30% less than the
corresponding innovator products. The average price of biologic could be $16,425 p.a. which is
around 20 times the cost of the chemical generics (Emmerich, 2010). As compared to the 90%
savings from traditional generics the savings of 30% from biosimilars is not significant, but, if
considering a situation where the treatment of the metastatic cancer through the biologic drug
can cost up to $200,000 a year, savings of mere 30% amounts to much more than a 90% savings
on a drug which costs $1000 (Emmerich, 2010). The biologic drugs are expensive at an average
daily cost of $45 or 22 times that of conventional drugs. Table 5.7 provides the estimates of the
treatment cost per patient of selected biopharmaceuticals. The first wave of the
biopharmaceutical drugs accounting up to $10 billion market have already lost patent
protection and by 2018 further biopharmaceutical drugs of $20 billion market will lose patent
protection (Clark, 2009). These figures and circumstances has led to immense interest towards
the market opportunities generated by the biosimilars industry.

46

Table 5.7: Estimates of treatment cost per patient of selected biopharmaceuticals. Source:
Crandall, 2009.

5.6.1 PATENT EXPIRY:

The expiry or pending expiry of patents of the biopharmaceuticals products such as
interferons, human growth hormone and epoietins is the most serious problem faced by the
biopharmaceutical industry. The expiry of patents of many blockbuster biologic products has
created immense market opportunities for biosimilar industry in markets where the innovator
companies are already established. When it comes to patent protection, there are numerous
patents which are generally issued by the innovator companies for specific APIs (Active
Pharmaceutical Ingredient The extent to which the innovator companies can go to protect and
extend patent protection of these patents poses extreme difficult issues for the prospective
biosimilar companies (Taylor, 2009).

In the United States the Congressional Budget Office has estimated that out of the $40
billion exhausted on the biopharmaceutical products in 2007, the products which contributed to

47

the three quarters of the spending will lose patent protection by the year 2019. The government
initiatives will be benefited by the cost reductions through the period of 2010-2019 which
would amount up to $9.1 to $11.7 billion and during this period the private insurance programs
would experience 0.2% reduction in premiums (Clark, 2009).

Reports have mentioned that there are major opportunities for the biosimilar
manufacturers during the period of 2010 to 2015 as throughout this period 45 biologic drugs
patent will expire and their value is more than $60 billion in global sales (Emmerich, 2010). Fig
5.4 shows the number of biologic drugs set to lose patent protection per year during the period
of 2010 to 2015 and annual global sales.

Fig 5.4: Number and value of biological drugs set to lose patent protection per year through 2015
Source: Emmerich, R. (2010)

48

Table 5.8 shows that the blockbuster biologic drugs such as Enbrel, Remicade, Rituxan
with the global sales in billions lose the patent protection in major markets like US and Europe
from 2012 to 2015.

Table 5.8: Blockbuster biological drugs set to lose patent protection per year
through 2015. Source: Emmerich, R. (2010)

5.6.1.1 PATENT EXPIRY BY BIOPHARMACEUTICAL CLASS:

5.6.1.1.1 ERYTHROPOIETINS (EPO S ):

The biologic drugs have different classes based on the therapy areas. In the
erythropoietins (EPOs) category there are many products which have been repeatedly reported
to have gone off patent in December 2004. First generation EPOs by Amgen such as Epogen
(epoetin alfa) and Johnson & Johnson’s Procit and Eprex have gone off patent. It has been
reported that Amgen is also involved in patent disputes on various development patents of EPO
with Wyeth, Roche. Various disputes are resolved but the terms and agreements are not
disclosed which could indicate that parties resolved disputes by cross licensing their patents
(Taylor, 2009).

5.6.1.1.2 INTERFERONS ALPHA (2A & 2B):

Interferons Alpha market segment has two fundamental products Pegasys and
PegIntron. The usages of these two products are done in the treatment of hepatitis C
frequently with the combination of ribavirin. Standard interferon products such as Roferon
(interferon-ά 2a) and Intron-A (interferon-ά 2b) which were introduced before Pegasys and

49

PegIntron are still marketed but are not as effective as PEGylated products (Pegasys and
PegIntron) and so they are prescribed to a lesser extent than PEGylated products(Taylor, 2009).

Table 5.9 shows the expiry dates of the patents of major Interferon Alpha products
which currently exist on the market and indicates use of improved method such as pegylation as
a strategy to lengthen the market exclusivity following the expiry of patents of the standard
interferon products as both the standard and pegylated interferon products are from same
companies.

Table 5.9: Interferons on market and patent expiries. Source: Taylor, P. (2009)

5.6.1.1.3 INTERFERONS BETA (1A & 1B):

Some most important patents have recently expired of a class of biopharmaceuticals
which constitute of interferons (beta-1a and beta-1b). For the treatment of Relapsing/Remitting
Multiple Sclerosis the principal product used is Avonex which belongs to key group of
interferons and is manufactured by Biogen Idec. For the production of beta interferon there are
various companies which have pending patent applications or issued patents in the United
States, Europe and other major market and countries and these patents are regarded as the
Taniguchi patents. There also some other patents which are called as Roche patents and the
Rentschler patents which are pending patent applications or issued patents for interferon beta
by the companies EMD Serono Pfizer and Bayer. Biogen Idec has access to rights in different
countries and markets of the world such as United States, Europe and Japan for production and
marketing of Avonex as per the Taniguchi, Roche and Rentschler issued patents (Taylor, 2009).

50

The Taniguchi patents are going off patent in the United States in 2013 and they have
already expired in other parts of the world. The Roche patents have expired in most countries of
the world and they will expire in May 2008 in the United States. The European Union Rentschler
patents expire in July 2012. Other interferon beta-1a products such as Betaferon (Betaseron) by
Bayer and Rebif by company Merck Sereno for multiple sclerosis have lost patent protection in
the United States in 2007 and most European Union countries in 2008. In a couple of years time
the pricing and sales of Betaferon (Betaseron) would be significantly affected due to the expiry
of the patents in Europe. Table 5.10 summarizes the currently available multiple sclerosis dugs
on market and patent expiry dates of these products. Fig 5.6 shows the predicted market share
of the multiple sclerosis drugs on market which would lose market share due to the entry of the
biosimilar version of the multiple sclerosis drug.

Fig 5.6: Predicted market share of multiple sclerosis drugs (2007-2017)
Source: (Taylor, 2009).

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Table 5.10: Multiple sclerosis drugs on the market and patent expiries. Source: Taylor P., 2009.

5.6.1.1.4 HUMAN INSULIN AND INSULINS ANALOGUES:

Insulin products such as Humulin and Novolin are used for the treatment of diabetes.
These insulin products are structurally identical to the naturally occurring insulin in human
pancreas. Later on insulin analogues were available in the market such as Lantus, Humalog,
NovoLog, Levemir and Apidra which are modified to make their properties better than natural
human insulin (Taylor, 2009). Table 5.11 shows that the original recombinant insulin products
such as Humulin and Novolin first launched in the market have lost their patent protection in
the year 2001 and 2002 respectively, but the insulin analogs which were introduced later will
expire during the 2013 to 2018 period.

52

Table 5.11: Recombinant insulin products on the market and patent expiries. Source: Taylor P.,
2009.

5.6.1.1.5 MONOCLONAL ANTIBODIES ( M AB):

Monoclonal Antibodies are an important category in the biopharmaceuticals consisting
of complex proteins which have a wide range of therapeutic applications such as cancer,
rheumatoid arthritis, asthma and psoriasis. Monoclonal Antibodies products have generated
sales revenue which is more than $21 billion in 2007. The Mab drug or product which first
succeeded commercially in the market and generated significant revenues was Rituxan as it
proved to be effective than most of the other therapies available on the market. Considering
the success of the Rituxan the drug developers launched various other Mab products such as
Avastin, Herceptin, Remicade, Humira and Erbitux. The innovator companies manufacturing
Mab are going to face competition from the biosimilar developers as major Mab products are
about to go off patent from 2012 (Taylor, 2009). Fig 5.7 illustrates the patent positions of the
leading biopharmaceutical products which are already expired or are about to lose patent
protection in the near future.

53

Fig 5.7: Estimated patent expiry dates of selected proteins
Source: Taylor, 2009.

5.7 MARKET SHARE:

The current market share of the biosimilars contributes to only a small part of the sales
volume of the biologic drugs which are gone off patent. It has been reported that since 2005
only 25% of the biologic drugs have their patent status as expired and this indicates the
opportunity of more than $20 billion sales for biosimilars (Emmerich, 2010).

The Indian and Chinese biosimilar manufactures have launched more than 50 biosimilar
products in less regulated markets which is significantly high as compared to the US and
European manufactures (Emmerich, 2010). Fig 5.8 shows the market share for biosimilars in the
off patent biologics market. In the biologics market 23% of the biologic have gone off patent
and out of these 23%, the biosimilars market share is less than 5% which indicates the attractive
market opportunity for biosimilars to expand.

54

Fig 5.8. Market Share of biosimilars in the off patent biologics market. Source: Emmerich, R., 2010

Table 5.12 illustrates that the biosimilar market is quite small in the regulated markets
with less than 20 biosimilar products in the market.

Table 5.12: Bbiosimilar companies sales and market share. Source: Emmerich, 2010.

55

5.8 SALES:

Table 5.12 shows the global sales and the market share of the major biosimilar
companies which have launched biosimilar products. The market of the biosimilars is highly
fragmented and the global biosimilar companies represent only 15% of the market share.
Sandoz has the highest market share of 4.1% and global sales revenue of $23 million in the first
half of 2008(Emmerich, 2010). Sandoz has significant growth from 2007 due to the successful
authorization and introduction of Omnitrope which is a biosimilar human growth hormone and
Epoetin alpha hexal and Binocrit (epoetin products) in the European Union.

5.9 MARKET DRIVERS:

5.9.1 COST SAVINGS (GLOBAL HEALTH CARE):

The biopharmaceutical companies invest in huge amounts in the biologic product
development and manufacture due to the complex nature of the biologics as compared to the
investment involved in the development of traditional chemical generic. In 2010, the total
integrated sales of the top 12 biologic products were around $30 billion in the U.S. (Bourgoin,
2011). The Price of the biologic products indicates the development cost involved in biologic
products. The predicted standard cost of the biologic product per year is around $16,000 and
some of the other biologic products are more costly than the estimated price. For the treatment
of colorectal cancer, the therapies consisting of the biologic products can cost up to $10,000 per
month which is quite expensive (Bourgoin, 2011). In the U.S. and many other parts of the world
the government, federal and state initiatives like Medicare, Medicaid and NHS are responsible
for covering the expenses of these products. Therefore it is a great deal of interest to such
organizations, taxpayers and patients seeking for the prospect of cost savings through Biosimilar
products.

As compared to the chemical generics, the patient or the payer agency will not reap
significant savings in context with biosimilars but the savings could be appreciated when

56

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