Biosimilars report

October 2010

Biosimilars: Surveying the
Market Landscape
A FirstWord Dossier Market Intelligence Report

Biosimilars: surveying the market landscape

Biosimilars: surveying the market landscape: Biosimilars: surveying the market landscape
Published October 2010
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Contents
Executive summary ............................................................................................... 1

Introduction .......................................................................................................... 3

Biosimilars are not generics .................................................................................... 5

Manufacturing .................................................................................................... 6

Safety and immunogenicity ................................................................................. 7

Automatic substitution and naming .................................................................... 8

Development ..................................................................................................... 9

Marketing ......................................................................................................... 10

Market acceptance.......................................................................................... 11

Patents ............................................................................................................ 12

Regulatory picture ................................................................................................ 12

EU ................................................................................................................... 13

Guidelines ..................................................................................................... 14

Substitution ................................................................................................... 15

Data exclusivity ............................................................................................. 15

Pre-approval trials .......................................................................................... 15

Post-marketing surveillance (pharmacovigilance) ............................................... 16

Extrapolation ................................................................................................. 18

Monoclonal antibodies ..................................................................................... 19

USA ................................................................................................................. 21

Legislation ..................................................................................................... 22

Substitution/interchangeability ......................................................................... 23

Data exclusivity ............................................................................................. 23

Extrapolation to other indications ..................................................................... 24

Patent information exchange ........................................................................... 24

Biological products approved as drugs .............................................................. 25

October 2010 i

All Contents Copyright © 2010 Doctor's Guide Publishing Limited. All Rights Reserved

Other markets .................................................................................................. 26

Global biosimilars strategy .............................................................................. 28

Target biopharmaceutical products ......................................................................... 30

Somatropin (growth hormone) ........................................................................... 33

Epoetin (erythropoietin)..................................................................................... 34

Filgrastim ........................................................................................................ 37

Insulin ............................................................................................................. 39

Interferon alfa .................................................................................................. 41

Interferon beta ................................................................................................. 43

Low-molecular-weight heparins .......................................................................... 45

Monoclonal antibodies and anti-inflammatory fusion proteins ................................. 47

Immunomodulators – anti-TNF antibodies ......................................................... 49

Cytotoxic mAbs ............................................................................................. 49

Follitropin (follicle-stimulating hormone; FSH) ...................................................... 50

Vaccines .......................................................................................................... 50

Enzymes .......................................................................................................... 51

Imiglucerase ................................................................................................. 51

Blood coagulation factors ................................................................................... 52

Biosimilars companies .......................................................................................... 53

Generics manufacturers ..................................................................................... 53

Sandoz ......................................................................................................... 54

Teva ............................................................................................................ 55

Hospira ........................................................................................................ 56

Stada ........................................................................................................... 57

Mylan ........................................................................................................... 58

Watson ......................................................................................................... 58

Actavis ......................................................................................................... 58

ii October 2010


Apotex .......................................................................................................... 59

Other generics manufacturers .......................................................................... 59

Innovator pharmaceutical companies ................................................................... 60

Merck & Co. ................................................................................................... 60

Pfizer ............................................................................................................ 61

GlaxoSmithKline ............................................................................................. 61

Eli Lilly .......................................................................................................... 62

AstraZeneca .................................................................................................. 62

Companies in India and other emerging markets ................................................... 62

Biocon .......................................................................................................... 63

Dr Reddy’s .................................................................................................... 64

Reliance Life Sciences ..................................................................................... 64

Intas............................................................................................................. 65

Wockhardt ..................................................................................................... 65

Ranbaxy (Daiichi Sankyo)................................................................................ 65

Cipla ............................................................................................................. 66

Other markets ............................................................................................... 66

Future prospects .................................................................................................. 67

Index .................................................................................................................. 70

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iv October 2010



Executive summary
Cheaper biological drugs are an economic and healthcare necessity. Yet only recently have
accelerated approval pathways for lower-cost versions of off-patent biologics come into
existence. Biosimilar competition is now possible in all the major markets, including the
USA, the EU, Japan, Canada and Australia. But biosimilars are far more complex than
generics. The residual lack of stakeholder confidence that surrounded standard generics in
some markets may be even tougher for biosimilars to overcome.

The balancing act by the regulatory agencies must weigh safety and effectiveness against
economics. The regulatory system needs to ensure that biosimilars are as safe and
effective as the reference product. But is this even possible for such complex molecules?
Economically, there is a need to balance the incentive to innovate with the need for lower
prices and greater access.

In Europe, an abbreviated approval pathway for biosimilars has existed since 2006, with
the simplest of the biological medicines seeing competition for several years. In March
2010, the USA—the largest potential biosimilars market—created legislation that allows
the creation of a pathway for abbreviated approval. This report summarises the current
regulatory situation in the EU and the USA, and touches on the situation in emerging
markets. This is put into context by considering the differences between biosimilars and
generics.

In the market for traditional drugs, relatively few compounds account for a
disproportionate share of sales and profits. The same is true for biological medicines. As in
the traditional generic drug market, it is these outstanding performers that will attract the
most interest from biosimilars manufacturers, where the number of entrants is strongly
related to the size of the branded product’s sales before entry. The biosimilars marketed
so far are mostly simple, first-generation biological products such as somatropin, epoetin
and filgrastim. The report looks at the markets for these products and other first-
generation biological drugs, and considers the biosimilars that have already been
approved.

These incursions into biosimilars are only the first wave. The monoclonal antibodies are
the products that manufacturers believe will reap the biggest rewards. However, they are
more complex than the first-generation biologicals. Even pioneering EU regulators will not
issue a draft guideline until the end of 2010. The report considers the issues surrounding

October 2010 1


biosimilar monoclonal antibodies and highlights those that are likely to be the first targets
for biosimilars manufacturers.

Who are the successful biosimilar manufacturers likely to be? Since biosimilars are very
different from traditional generics, it’s an open question. Obtaining approval is expensive
and can be complicated; the costs of setting up manufacturing are high and distribution
may be complex. Once approved, substitution in pharmacies is not permitted and the price
discounts are much lower than for traditional generics. Brand development is important
and direct marketing to small numbers of specialists is required. These are not the skills
traditional generics manufacturers have. This report looks at the early entrants to the
market and others who might follow, and offers an overview of companies in emerging
markets such as India, who have their eye on the European and US markets.

2 October 2010



Introduction
Since the 1976 formation of Genentech—the first biotechnology company—more than 150
biopharmaceutical products have been marketed world-wide 1, which are estimated to
account for around ten percent of the global pharmaceutical market 2. The US Generic
Pharmaceutical Association (GPhA) estimates that by 2012, nearly half the products
approved by the US Food and Drug Administration (FDA) will be biological medicines 3.

Biological medicines treat some of the most devastating diseases; those that are
untreatable by other means, such as genetic disorders, and those for which current
therapies have serious drawbacks, such as cancer and rheumatoid arthritis. However,
these benefits come at huge cost. In a New York Times article, Anthony D. So and Samuel
L. Katz said that biological medicines cost around 20 times as much as standard drugs,
with 28 percent of 2008 sales from the pharmaceutical industry’s top 100 products coming
from biological products. That share is expected to rise to 50 percent by 2014 4, and will no
doubt continue to increase because the diseases they treat are often long-term conditions
associated with the growing ageing population.

Lowering the cost of medicines is seen by governments and the World Health Organization
(WHO) as an economic and healthcare necessity. As with the uninsured in the United
States, much of the developing world’s population is denied access to medicines because
of their cost. In European countries, health technology assessment agencies (such as the
UK’s National Institute for Health and Clinical Excellence [NICE] and Germany’s Institute
for Quality and Efficiency in Healthcare [IQWiG]) restrict access to expensive medicines
such as biological products on cost–benefit grounds. Generic medicines have been the
traditional route to reducing the drugs bill—in the USA generic pharmaceuticals fill
75 percent of the prescriptions dispensed, but consume just 22 percent of total drug
spending 5.

Many first-generation biological medicines—those that copy or closely resemble
endogenous human proteins such as insulin, growth hormone and interferons—have either

1
Misra A. Are biosimilars really generics? Expert Opin Biol Ther 2010;10:489–94.
2
European Generic Medicines Association. Biosimilar Medicines: FAQ. http://www.egagenerics.com/FAQ-
biosimilars.htm
3
Generic Pharmaceutical Association. Biogenerics: GPhA position. http://www.gphaonline.org/issues/biogenerics
4
So AD, Katz SL. Biologics boondoggle. New York Times 2010, March 7.
http://www.nytimes.com/2010/03/08/opinion/08so.html?_r=1
5 Generic Pharmaceutical Association. Press release Jul 26, 2010. http://www.gphaonline.org/media/press-
releases/2010/generic-medicines-saved-us-health-care-system-1396-billion-2009-824-billio

October 2010 3


lost patent protection or soon will do. In theory, the door is open to generic competition.
However, biological medicines are far more complex than traditional generic drugs and
cannot be exactly copied. They cannot therefore be approved via the same abbreviated
procedures as standard generic drugs. The term ‘generics’ has been avoided for this
reason and ‘similar biological products’ (biosimilars) and ‘follow-on biological products’ 6
have been used in the EU and USA, respectively, to describe ‘generic’ biological medicines.

It is therefore essential to examine the issues around biosimilars and the current
regulatory situation around the world-wide, the biological products that are likely to be
targets for biosimilar competition and profile the companies that are in the best position to
take advantage of this new market.

6 The term ‘follow-on biological products’ is often used in the USA to mean improved, next-generation products.
For this report the term ‘biosimilars’ will be used to mean products intended to be as similar as possible to an
existing product, whichever market is being discussed.

4 October 2010



Biosimilars are not generics
Manufacturers of standard generic medicines can seek approval for their products via
abbreviated registration procedures in Europe and the USA. To gain approval in this way, a
generic drug must contain the same active ingredients as the innovator drug; be identical
in strength, dosage form and route of administration; have the same indications; be
bioequivalent (a surrogate marker for therapeutic interchangeability); meet the same
batch requirements for identity, strength, purity and quality; and be manufactured under
the same standards of good manufacturing practice required for innovator products.
Biological medicines cannot meet all these requirements because they are much more
complex than traditional generic drugs. Demonstrating bioequivalence represents
something of a challenge, especially for the more complex biologics. Some of the major
differences between standard generics and biosimilars are presented in Table 1.

Table1. Comparison of generic and biosimilar drugs

Generics Biosimilars
Properties Small (<500Da) Large (5000-300,000Da)
Usually stable Often unstable; may require
specific formulation
Easy to fully characterize
Hard to characterize
Manufacturing Chemical synthesis Fermentation in living cells
Simple Complex isolation and
purification steps
Cheap
Sensitive to manufacturing
changes
Process affects product
Relatively expensive
Development Limited trials required, usually Substantial development work
only Phase I PK/PD studies required – cell lines etc.
Extensive Phase I and III clinical
trials

October 2010 5


Generics Biosimilars
Marketing Large price discounts Smaller price discounts; price
sensitivity is product-specific
No or limited detailing to
physicians Detailing to specialist physicians
required
Key role of wholesalers and
payers Method of delivery can be a key
differentiator
Special delivery device not
usually necessary No automatic substitution
Automatic substitution in possible Specialist distribution often
in some pharmacies required
Simple to distribute
Regulation Must be identical to reference Must be highly similar to
product reference product
Substitutable/interchangeable Not automatically substitutable
Abbreviated procedure is Abbreviated approval
applicable to all drugs requirements vary depending on
the drug

It is fundamental to the approval process for a standard generic drug that it contains the
same active ingredient as the reference product. Achieving identical bioequivalence is
relatively easy to achieve for small, stable molecules that are produced by chemical
synthesis and can easily be characterised but much harder for biological drugs. Biological
drugs have an inherently microheterogeneous structure, which can be affected by changes
to the expression system, culture medium, pH, temperature and so on. The regulatory
authorities therefore address the concept of biosimilarity, which allows a product to be
approvable via an abbreviated pathway while not being completely identical to the
reference product.

Manufacturing
With conventional drugs there is no relationship between the manufacturing process and
the characteristics of the final product. However, for biological drugs the process and the
product are inextricably linked. For example, filgrastim (granulocyte colony-stimulating
factor; G-CSF) produced in Chinese hamster ovary cells (the most commonly used
mammalian manufacturing system for recombinant proteins) is glycosylated (has attached
sugar molecules), unlike that produced in Escherichia coli. A change in glycosylation or
other post-translational modifications can to lead to the protein folding differently. This

6 October 2010


may have no relevant clinical effect, but it may affect the way the protein binds to its
receptor and alter efficacy and safety, particularly immunogenicity. It may also have an
effect on solubility, which could affect the pharmacokinetics and pharmacodynamics of the
protein (i.e. its absorption and tissue distribution). This could also affect the degradation
profile and how quickly the protein is cleared from the body.

The issue is highlighted by Genzyme’s attempt to scale up production of alglucosidase alfa
(Myozyme), an enzyme replacement therapy for Pompe disease. Genzyme wished to move
production to a new plant with greater capacity, but the FDA ruled that the product
manufactured in the larger facility was sufficiently different from the original product as to
require a new Biologics License Application (BLA). This was because of concerns that the
glycosylation of the protein had been altered to such an extent that the product was
materially different from the previous version. The product from the larger facility was
eventually approved in May 2010, as Lumizyme.

Another issue is that the manufacturing process’ complexity means that the originator’s
procedure will be patented and any biosimilar manufacturer will have to work around the
patent or, more likely, patents.

Safety and immunogenicity
The major safety issue with biological drugs is their ability to produce an immune response
(immunogenicity). Biological medicines are produced in living cells and are therefore
recognised as foreign by the human immune system. The resulting immune response may
have no consequences, but could lead to allergic reactions, infusion reactions especially
after the first dose, the induction of neutralising antibodies and loss of effectiveness.
Neutralising antibodies can be important when they act against an essential endogenous
protein. This is demonstrated by the extremely rare occurrence of pure red cell aplasia
(PRCA) after subcutaneous epoetin administration in patients with kidney failure, in which
antibodies are induced to the recombinant epoetin and the patient’s own erythropoietin.
The condition requires transfusions for survival.

The immunogenicity of a product can be changed by any factor that alters its three-
dimensional structure, including changes in glycosylation. Furthermore, any impurities can
be immunogenic in their own right or enhance the immunogenic activity of the product, as
when acting as an adjuvant). Thus any change to the formulation or manufacturing
process, which would have to happen for the production of a biosimilar, could have

October 2010 7


consequences for the safety profile. This was seen when the incidence of PRCA increased
in renal patients receiving Johnson & Johnson’s epoetin alfa subcutaneously. This followed
a minor manufacturing change to replace human serum albumin with polysorbate 80. The
polysorbate 80 caused organic compounds to leach from the rubber stopper of the prefilled
syringe. These compounds were involved in the induction of antibodies to the patients’
own erythropoietin, resulting in PRCA 7.

Automatic substitution and naming

An issue linked to immunogenicity and safety is automatic substitution, which allows and
sometimes requires pharmacists to dispense generic drugs in place of prescribed innovator
products without the knowledge or consent of the treating physician. This is often allowed
with traditional generic medicines on the basis that they are identical to the branded
product. However, it has been argued that if patients receive several biological products
over the course of therapy, depending on whichever is the cheapest at the time of
dispensing, it will be impossible to link an adverse event to a specific product. This will
confound the pharmacovigilance assessment required for approval by the biosimilar
pathway (see ‘Post-marketing surveillance’ in the ‘Regulatory picture’ section).

Moreover, it has been suggested that biosimilars should carry a different international non-
proprietary name (INN) to their reference product to prevent inadvertent substitution.
INNs are issued by the WHO on the advice of an international panel of experts, and
facilitate worldwide pharmacovigilance by ensuring that all adverse event reports are
linked with the correct drug. However, it has been argued that as biosimilars are not
identical to the product for which the name was granted, the INN should not be relied on
as the only method of identifying a biological medicine. The EMA supports this view,
stating in its Guideline on Similar Biological Medicinal Products ‘in order to support
pharmacovigilance monitoring, the specific medicinal product given to the patient should
be clearly identified’ 8.

For example, epoetin zeta is the INN for a recently introduced biosimilar epoetin product.
The name reflects a difference in glycosylation and differentiates it from the original

7
Boven K, Knight J, Bader F, Rossert J, Eckardt KU, Casadevall N. Epoetin-associated pure red cell aplasia in
patients with chronic kidney disease: solving the mystery. Nephrol Dial Transplant 2005;20(Suppl 3):iii33–40.

8 Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol 2008;19:411.

8 October 2010


epoetin alfa. Another suggestion is that biosimilars should always be commercialised with
a brand name or the INN plus the manufacturer’s name 9. The use of unique INNs for
biosimilars would preclude automatic substitution and would probably be supported by the
innovator industry, as it would present a further barrier to substitution.

According to the US Federal Trade Commission (FTC), a lack of automatic substitution will
slow the rate at which a biosimilar can acquire market share and thereby increase its
revenues 10. In the traditional generics market, where automatic substitution is allowed in
some markets, the market share of the incumbent drops dramatically with the first generic
entrant.

Development
Traditional generic drugs do not generally require preclinical or clinical trials to determine
their efficacy and safety. As long as the generic product is bioequivalent to the innovator
product, its safety and efficacy is presumed to be the same. All that is needed to
demonstrate bioequivalence are Phase I pharmacokinetic/pharmacodynamic studies
conducted with healthy volunteers to prove that the generic product delivers the same
amount of drug over the same time period as the reference product. Because biosimilars
cannot be identical to the reference product, they will usually require extensive clinical
trials in addition to Phase I. For more details on the clinical data required by the EU
biosimilar pathway, see ‘EU: Pre-approval trials’ under ‘Regulatory picture’.

The extent to which additional clinical trials are required depends on many factors, not
least the product itself and how well it is characterised. If a clinically-relevant end point
correlated with efficacy is available, trials can be shorter and require fewer patients. Some
examples include glucose levels for insulin, haemoglobin levels for epoetin and neutrophil
levels for filgrastim. A therapeutic marker may not exist at all for some products, such as
monoclonal antibodies; trials for products for diseases such as cancer will need much
longer studies with more patients.

These additional requirements will mean higher development costs for biosimilar medicines
compared with standard generics. Costs are difficult to estimate accurately because
different products require widely differing amounts of development work. However, the

9 Zuñiga L, Calvo B. Biosimilars: pharmacovigilance and risk management. Pharmacoepidemiol Drug Saf
2010;19:661–669.
10 Emerging Health Care Issues: Follow-on Biologic Drug Competition. Federal Trade Commission; June 2009.
http://www.ftc.gov/os/2009/06/P083901biologicsreport.pdf

October 2010 9


FTC estimates that developing a biosimilar will cost $100 to 200 million and take eight to
10 years. This is considerably higher than for a standard generic medicine, which the FTC
estimates costs $1 to $5 million and takes three to five years to develop. This is still
considerably cheaper than the $1 billion widely quoted for developing an innovator drug.
According to David E. Wheadon of the Pharmaceutical Research and Manufacturers of
America (PhRMA), biosimilar manufacturers still have strong incentives to enter the
market, including the ability to support their application with the innovator’s data 11.

Marketing
The business model for a standard generics manufacturer is the regular launch of new
products to maintain growth. In this market, the barriers to entry are few and low. There
are many competitors and price competition is intense, with discounts of 80 to 90 percent.
Standard generic drugs require limited or no detailing to physicians, and wholesalers and
payers have the key role. It will not be possible to follow this business model for
biosimilars, which may be better viewed as specialty generics, at least in highly-regulated
markets. Specialty generics have higher barriers to market entry because they may be
difficult to manufacture, have a complex patent or regulatory environment, or have
specialised marketing requirements. Competition between specialty generic medicines is
not based primarily on price. Products are marketed under separate brand names and also
compete on product differentiation such as delivery systems and promotion like
sponsorship of education 12.

In Europe, where a mechanism for approving biosimilar products has been in place since
2006, price reductions have mostly been a modest 25 to 30 percent. However, price
sensitivity appears to be product- and market-specific. In Germany for example, where the
generics market is well established, biosimilar somatropin is more heavily discounted.
Although the price discounts may be smaller compared with traditional generic drugs, the
high price of treatment with many biological drugs—Roche’s Herceptin (trastuzumab)
costs $48 000 per year 13—means that payers will see reasonably large savings.

11 Wheadon DE. N Engl J Med 2009;362:661.

12
Specialty Generics: Climbing the pharmaceutical value chain. FirstWord; July 2010.
13
Emerging Health Care Issues: Follow-on Biologic Drug Competition. Federal Trade Commission; June 2009.

10 October 2010


The FTC believes that the specialty pharmaceutical characteristics of biosimilars are likely
to limit market share. Specialty drugs, including biologicals, are commonly used to treat
patients with severe, chronic diseases and terminal conditions. The drugs are primarily
injected or infused and are combined with ancillary medical services and products that
require training for proper handling and administration. Because most biological products
are delivered to patients in clinics, hospitals, doctors’ offices or other medically supervised
settings, shifting to another product is typically more costly because it requires restocking
inventory and retraining nurses and healthcare providers 14. As a result, the FTC suggests
that only two or three companies will try to compete with each biological drug, in which
case price competition will be limited. However, once a medical facility has been
persuaded to switch, there will be an advantage for the biosimilar manufacturer as all the
patients at that facility will follow.

Market acceptance

In the EU, the initial acceptance of biosimilars has generally been low but this varies
greatly from country to country. “[Biosimilar] epoetin penetration in Germany, for
example, has now reached around 60% of the market (by volume), Suzette Kox, Senior
Director Scientific Affairs for the European Generic Medicines Association (EGA) told
FirstWord. Kox believes that “the situation is now rapidly changing. The adoption rate is
expected to increase significantly in the future as the experience and confidence in this
new category of products grows day by day.”

Difficulty gaining market share is likely to be common because of concerns about
differences in safety and efficacy between the innovator product and the biosimilar.
Physicians may be reluctant to switch their patients from an innovator product to a
biosimilar because of the risk that they will react differently to the biosimilar. Convenience
will be an issue for patient—receiving a second-generation product are unlikely to want to
switch to a first-generation product with a less convenient dosing regimen. This may limit
biosimilar market opportunities to newly-diagnosed patients. Careful marketing to
prescribers will therefore be important to ensure adequate market penetration. The
reputation of the manufacturer is likely to carry significant weight. Those with an existing
reputation in the field such as a supplier of other specialty medicines may prosper.

14

October 2010 11


The perspectives of organised patient groups in therapeutic areas with high usage of
biological drugs will also be important in driving or limiting demand for biosimilars. For
example, those denied access to anticancer monoclonal antibodies on cost–benefit grounds
by health technology assessment agencies, such as the UK’s NICE, may welcome the
availability of cheaper versions.

Patents
The innovator pharmaceutical industry has suggested that, as biological drugs are so
complex, it is relatively easy to ‘design around’ their patents. However, the FTC believes
there is no evidence that biological drug patents have been designed around more
frequently than those claiming small-molecule drugs 15. For example, Amgen controls the
US epoetin market and on the basis of its patents has successfully challenged competitors
attempting to enter the market with novel epoetin variants, notably Roche’s Mircera.

Innovator biological products are covered by suites of patents protecting not only the
product (if it is not naturally occurring) but the production process (the technology,
vectors and cell lines) and the formulation or delivery system. These are often more
numerous and varied than for small-molecule branded products. A major issue for
biosimilars manufacturers will be how to balance the need to assure the regulator that
their product is highly similar to the reference product, yet make a product that is different
enough so as not to infringe any patents covering the reference product. This is a
particular problem in the US, where drug patent infringement suits are commonplace. For
those patents that cannot be worked around, biosimilars manufacturers will have to pay
licensing fees to the originators.

The large number of patents covering a biological drug makes it difficult to determine
when it is no longer protected. The potential for litigation against biosimilars
manufacturers may therefore be greater than for traditional generics manufacturers.

Regulatory picture
The balancing act to be managed by the regulatory agencies weighs safety and
effectiveness against economics. The regulatory system needs to ensure that biosimilars

15

12 October 2010


are as safe and effective as the reference product. But is this even possible? Economically,
a balance must be struck between the incentive to innovate and ensure a steady supply of
novel therapies with the need for lower prices and greater access.

In Europe, an abbreviated approval pathway for biosimilars exists. Even the simplest of
the biological medicines have seen competition for several years. In the USA where there
is the largest potential market, legislation allowing the creation of a pathway for
abbreviated approval was created in March 2010.

EU
In October 2005, a legal framework for the development of biosimilars in the EU was
enacted, with the first biosimilar medicines gaining approval in April 2006. Since then, 14
products have been approved under the pathway: two somatropins, five epoetins and
seven filgrastims. Only five have been rejected or withdrawn: one interferon alfa-2a, one
interferon beta-1a and three insulin products. The system is deemed to be working well.
According to Suzette Kox of the EGA, “from our standpoint, the pathway for the first
biosimilar molecules is well established, works well and delivers. It is broadly believed
within the industry and amongst regulators to be a success.”

EU approvals are dealt with on a case-by-case basis. In other words, the degree of
similarity required is flexible, depending on the product. For example, Lilly’s Humatrope
(somatropin) is produced in Escherichia coli. The biosimilar product Valtropin
(Biopartners/LG Life Sciences) is produced in yeast and so must be different in at least
some respects. It has been approved by the EU as biosimilar, although it is not yet
marketed due to problems sourcing the delivery device. Another example is epoetin. All
available epoetins vary in their glycosylation pattern, but are accepted by the EU as
biosimilar, as the differences are deemed to be within the range seen in the natural
product.

October 2010 13



Guidelines

EU guidelines require biosimilar drugs to have a reference biological drug that is approved
in the EU for the intended indication and for which the data protection period has expired.
Clinical testing must be carried out to support the approval. Tailored post-marketing
pharmacovigilance or risk management must be carried out to monitor the potential
emergence of immunogenicity issues. The aim is to ensure a product is similar to the
reference product in terms of quality, safety and efficacy.

All biological drugs, including biosimilars, are assessed by the EMA’s Committee for
Medicinal Products for Human Use (CHMP), which has developed both overarching and
product-specific guidelines. The first general guideline 16, issued by the CHMP in October
2005, introduces the concept of similar biological products and the basic principles applied
to gaining approval. Among other things, it states that for a product to be considered a
biosimilar, it must have the same amino acid sequence as the reference product. The
second guideline 17, which came into effect in June 2006, specifies the quality requirements
regarding manufacturing processes, the analytical methods to assess comparability,
factors to consider when choosing a reference product and physicochemical and biological
characterisation of the biosimilar. The third guideline 18 was also issued in June 2006. The
non-clinical section covers the pharmacotoxicological assessment, while the clinical section
addresses the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety
studies, with emphasis on the evaluation of immunogenicity.

Several product-specific guidelines 19 have subsequently been issued for granulocyte
colony-stimulating factor (filgrastim), human growth hormone (somatropin) and human
insulin. All were adopted in April 2006. Recombinant epoetin was adopted in July 2006,
low-molecular-weight heparin in October 2009 and interferon alfa in Apr 2009. Concept

16
European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on similar biological
medicinal products. CHMP/437/04. London: EMEA; 2005.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf
17
medicinal products containing biotechnology-derived proteins as active substance: quality issues.
EMEA/CHMP/BWP/49348/2005. London: EMEA; 2006.
18
medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues.
EMEA/CHMP/BMWP/42832/2005. London: EMEA; 2006.
19 All the product-specific guidelines, plus consultation documents and guidelines relevant to all biological
medicines can be found at:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC
0b01ac058002958c&murl=menus/regulations/regulations.jsp&jsenabled=true

14 October 2010


papers on monoclonal antibodies were released Oct 2009, follicle-stimulating hormone and
recombinant interferon beta were both released March 2010. The first draft monoclonal
antibodies guideline is expected by the end of 2010.

Substitution

The EMA does not assess the interchangeability or substitutability of a biosimilar.
Substitution practice varies by country. For example, all biological medicines are excluded
from substitution in Spain, while in France biosimilars will not be registered in the
Directory of Generics, which is a requirement to authorise substitution by pharmacists. At
least 15 European countries now prevent the automatic substitution of biological drugs
with biosimilars.

Data exclusivity

The other side of the generic coin is fostering innovation. Innovator companies need to
have sufficient time before generic competition starts to make a return on their
investment. This is achieved in the EU (and the USA, see below) by a period of data
exclusivity, during which companies making generic drugs cannot rely on the originator’s
data to support their application, as they must do to prove similarity. The period of data
exclusivity was enacted with EU Directive 2004/27/EC. For generic or biosimilar products
that reference products with marketing applications submitted before late 2005, this
period is ten years or six years in some cases. In the case of generics or biosimilars that
reference products with marketing applications submitted after late 2005, there is an
eight-year data exclusivity period during which a marketing application for a biosimilar
cannot be submitted, followed by a two-year period of market exclusivity when no generic
applications are approvable. The ten-year period may be extended for an additional year,
for a total of 11 years of data exclusivity, with respect to a new indication that constitutes
a significant clinical benefit.

Pre-approval trials

The philosophy of biosimilar approval ensures that the product is comparable to an
approved reference biological product in terms of quality, efficacy and tolerability. This
requires comparative quality studies and non-clinical and clinical efficacy and tolerability
studies.

October 2010 15


Because of the differences between biopharmaceutical products, the approval process
varies according to the product. The comparability programme is clearly defined and
agreed upon in advance with the EMA, which defines the set of non-clinical and clinical
data necessary to demonstrate comparability. The extent of the data required varies
according to the type and complexity of the medicine involved, and each biosimilar
medicine is assessed on a case-by-case basis. In particular, the amount of clinical data
available may depend on the inherent variability of efficacy end points and the availability
of validated surrogate markers 20. Typically, one study in a single population during a
limited time interval or 12 months will be deemed sufficient to demonstrate comparable
efficacy and tolerability.

Comparative non-clinical pharmacokinetics, safety pharmacology, reproduction toxicology,
mutagenicity and carcinogenicity studies are not required as these will have been done for
the reference product and, if approved, the biosimilar will be demonstrably comparable to
the reference product.

Because biopharmaceuticals have been associated with serious adverse events, EMA
guidelines 21 require all biological drugs to undergo immunogenicity testing. Biosimilars are
not exempt from this requirement as the relatively minor alterations that will necessarily
occur from the reference product can have a major effect on the product’s
immunogenicity.

Post-marketing surveillance (pharmacovigilance)

Although pre-authorization clinical studies can demonstrate that a biosimilar drug has
comparable efficacy and tolerability to the reference drug, this could be established by
only one study in a single population during a 12-month limited time interval, and may
even allow extrapolation to all other approved indications of the reference product. This
may not be sufficient to identify the full safety profile of the biosimilar, which may differ
from the reference drug in nature, seriousness or incidence of adverse reactions. The
potential for immunogenicity may not occur until several months after treatment has
started. As a result, biosimilar manufacturers must develop a risk management system
and submit a risk management plan (EU-RMP) with their application.

20
Surrogate marker – a laboratory measurement or a physical sign used as a substitute for a clinically
meaningful end point that directly measures how a patient feels, functions or survives.
21
European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on immunogenicity
assessment of biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006. London: EMA; 2007.

16 October 2010


A risk management system is defined in the relevant guideline as ‘a set of
pharmacovigilance 22 activities and interventions designed to identify, characterise, prevent
or minimise risks relating to medicinal products, and the assessment of the effectiveness
of those interventions’ 23. An EU-RMP is not specific to biosimilars and is required by the
EMA with the marketing authorisation for any product containing a new active substance,
and in several other situations. However, they are not generally required for traditional
generic drugs.

An example of the problem is the pure red cell aplasia (PRCA), which can occur in patients
receiving subcutaneous epoetin alfa (see ‘Safety and Immunogenicity’ above). PRCA is a
very rare event taking months to years of epoetin treatment to develop. In the limited
clinical trials required for the approval of biosimilar epoetin with a minimum of 300
patients, PRCA may not be detected as too few patients are likely to be included to detect
such a rare event. The EMA guideline for the approval of biosimilar epoetin 24 requires 12-
month immunogenicity testing.

Professor Paul Declerck of the Katholieke Universiteit Leuven questions whether the
current criteria for comparability of biosimilars and their reference products are valid. He
calls for long-term clinical investigations and systematic monitoring of the efficacy and
tolerability of biosimilars 25. “The minimum number of required patients in clinical studies
for approval of biosimilars is exclusively based upon statistical grounds to be able to prove
that the product is as effective as the reference. This (small) number is, however, not
sufficient to draw any conclusion with respect to possible adverse events (which occur at a
much lower frequency). Therefore, to my opinion, the RMP for biosimilars should not be
considered as a classical RMP but should really be considered as an active, 'post-approval'
commitment.” He also believes that the mere fact that there is an RMP is often used to
conclude erroneously that safety is virtually fully proven and that the RMP is only a rather
routine commitment.

22
Pharmacovigilance describes the detection, assessment, understanding and prevention of adverse effects after
the launch of a product onto the market.
23
European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on risk management
systems for medicinal products for human use. EMEA/CHMP/96268/2005. London: EMA; November 2005.
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC50
0004888.pdf
24
European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on non-clinical and
clinical development of similar biological medicinal products containing recombinant erythropoietins (Revision).
EMEA/CHMP/BMWP/301636/2008 London: EMA; March 2010.
25
Declerck PJ, Darendeliler F, Góth M, Kolouskova S, Micle I, Noordam C, et al. Curr Med Res Opin
2010;26:1219–29.

October 2010 17


Prof. Declerck also expressed concern that although the RMP is imposed by the EMA, the
specific details of the RMP are discussed and eventually approved at a national level. This
could result in a heterogeneous approach between member states and may compromise
the strength of the pharmacovigilance.

Extrapolation

Data extrapolation—the approval of a drug for indications or situations in which it has not
been evaluated in clinical trials—is permitted for biosimilars if an ‘adequate’ scientific
explanation is provided and the mechanism of action in the new indication is the same as
the original indication, but usually only for same route of administration. For example, the
EMA’s revised biosimilar epoetin guideline says: “Since the mechanism of action of epoetin
is the same for all currently approved indications and there is only one known epoetin
receptor, demonstration of efficacy and safety in renal anaemia will allow extrapolation to
other indications of the reference medicinal product with the same route of
administration.”

Thus, biosimilar epoetins are approved not only for the primary indication—the treatment
of anaemia associated with renal failure—but also for chemotherapy-induced anaemia and
to increase the yield of autologous blood from patients before they undergo major elective
orthopaedic surgery. The dosages required to achieve the desired response may vary
considerably between indications and are highest in the oncology indications. The lack of a
clinical trial in each indication may well lead to reluctance by physicians to prescribe for
the extrapolated indications or for a patient population in which there has been
extrapolation, such as in children. It is notable that the converse route—approval for the
oncology indication being extended to renal—has not been implemented, and undoubtedly
reflects the fears that risk of PRCA would not be picked up in the immune-compromised
oncology patient population.

Epoetin can be administered intravenously or subcutaneously. The pharmacokinetics and
dose requirements usually differ for each route. Furthermore, subcutaneous administration
in renal failure is associated with PRCA (see ‘Safety and immunogenicity’ above). The EMA
guideline requires that similar efficacy between the test and reference products be ensured
for both routes of administration. This can be achieved either by performing separate
clinical trials for each route or by performing a clinical trial for one route and providing
adequate bridging data for the other. Adequate bridging data could be comparative single-

18 October 2010


dose and multiple-dose PK/PD data in an epoetin-sensitive population of healthy
volunteers. The guideline suggests that since comparative immunogenicity data will always
be required for subcutaneous use, if applied for, the most reasonable approach would be
to perform a clinical trial using subcutaneous epoetin and to provide PK/PD bridging data
for the intravenous route. The biosimilar epoetins approved to date are for intravenous
administration. The biosimilar epoetins approved to date are for intravenous
administration, and at least one instance of immunogenicity occurred during a trial in
which the biosimilar was administered subcutaneously 26.

To extend the approval of currently approved epoetin biosimilars to the subcutaneous
route in the renal indication; manufacturers must conduct a full clinical trial demonstrating
comparable efficacy and safety to the reference product, as products were initially
approved only for intravenous use in this indication. (Comparative immunogenicity trials
could not be performed because subcutaneous use of the reference product was
contraindicated at the time of the studies 27).

Monoclonal antibodies

Monoclonal antibodies (mAbs) are far more complex than first-generation biological
products. The first-generation drugs are comparatively simple molecules resembling
endogenous human proteins (e.g. somatropin or epoetin) whose modes of action are well
understood. Monoclonal antibodies are around three times heavier and often consist of
four protein chains rather than one. Furthermore they are novel constructs that do not
substitute for endogenous proteins. Their mechanism of action is often incompletely
understood. It has therefore been asked whether the development of biosimilar mAbs is
possible. In theory, the biosimilar approval process is applicable to more complex
molecules; the EMA guidelines state as much.

EMA guidance on quality for manufacturers of mAbs already exists 28, but it was thought
there was insufficient guidance on non-clinical and clinical issues. Before establishing a
biosimilar guideline, the Biosimilar Medicinal Products Working Party (BMWP) issued a

26
GaBi Online (October 2009) Safety study for subcutaneous epoetin alfa biosimilar Binocrit/Epoetin alfa
Hexal/Abseamed suspended http://www.gabionline.net/Biosimilars/News/Safety-study-for-subcutaneous-
epoetin-alfa-biosimilar-Binocrit-Epoetin-alfa-Hexal-Abseamed-suspended
27
Schellekens H. Clin J Am Soc Nephrol 2008;3:174–8.
28
European Medicines Agency. Guideline on development, production, characterization and specifications for
monoclonal antibodies and related products. London: EMA; 2008. CHMP/BWP/157653/07.

October 2010 19


concept paper aimed at gathering opinions 29. The discussion period ended in January
2010, and an EMA spokeswoman told FirstWord that a draft guideline will be released for
external consultation by the end of 2010. The guideline is eagerly awaited. At the 8th EGA
International Symposium on Biosimilar Medicines held in London in early September 2010,
Greg Perry, Director General of the EGA, said that “if healthcare systems are to continue
to function long-term, we must address the importance of biosimilar monoclonal antibodies
next. Science for monoclonal antibodies is already here today and our industry is
expecting a workable guideline.”

The concept paper indicates that the approach to establishing biosimilarity might be
different for mAbs with different modes of action. The paper draws a distinction between
immunomodulators (e.g. anti-TNF-alpha mAbs such as etanercept and infliximab);
cytotoxic mAbs with or without receptor modulation (e.g. anti-CD20, anti-EGFR or anti-
Her2 mAbs such as rituximab and trastuzumab) and others that do not fall into these
categories, such as antimicrobial mAbs such as palivizumab, which targets respiratory
syncytial virus. The often incomplete understanding of mAbs`mechanism further
complicates the picture, exemplified by the TNF-alpha antagonists etanercept and
infliximab. Etanercept is a fusion protein consisting of the p75 binding unit of the TNF-
alpha receptor and the Fc portion of human IgG1, whereas infliximab is a chimaeric anti-
TNF-alpha IgG1 antibody. Although they are both TNF antagonists, infliximab is effective in
Crohn’s disease, whereas etanercept is not. This would suggest that extrapolation of
efficacy from one indication to another will have to be on a case-by-case basis.

There are many other issues to be resolved, among them whether or not such complex
molecules can be replicated, if the structure of two monoclonal antibodies can be rapidly
and reliable proved to be the same, if there are differences are they significant and to
what extent of clinical trials are required? Considering the first issue, it is fundamental to
the EU biosimilars pathway that a protein will only be considered as a biosimilar, if it has
the identical amino acid sequence to the reference product. However, not all parts of the
mAb molecule are necessary for mediating the mechanism of action—there are regions
that act as a framework—and it has been asked whether minor structural differences be

29
European Medicines Agency. Concept paper on the development of a guideline on similar biological medicinal
products containing monoclonal antibodies. London: EMA; 2009.
EMEA/CHMP/BMWP/632613/2009.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/11/WC500014438.pdf

20 October 2010


acceptable, if adequately justified 30. The EMA was not in a position to make a statement
on this, other than to say that the issue of an identical amino acid sequence is an
important one that may evolve in future in the light of experience.

With respect to clinical trials, mAbs are used in different ways from first-generation
biological drugs.Although used in patients with cancer, epoetin and filgrastim do not treat
the cancer itself but the symptoms anaemia and neutropenia.. Because of this, there are
clinically relevant surrogate end points that can be measured in clinical trials, such as
haemoglobin and neutrophil levels. The availability of sensitive and rapidly measurable
surrogate end points is less likely for mAbs used in cancer and rheumatoid arthritis.
Although clinical trials will need to be larger and longer, the issue is how large and how
long they will be. According to the Generics and Biosimilars Initiative, it is one thing to
require a trial for efficacy in a particular clinical indication. But if equivalence/non-
inferiority studies were required against a reference product, they might require many
more patients than stand-alone trials showing efficacy. This would depend on the attitude
of regulators toward the specific biosimilar product 31.

USA
Until March 2010, there was no US legislation allowing the FDA to provide a mechanism for
the approval of biosimilars, known there as follow-on protein products. And although the
legislation has now been passed, the FDA has not yet issued guidance.

The marketing of biological products in the USA usually requires a biologics licence issued
under the Public Health Service (PHS) Act, whereas small-molecule pharmaceuticals are
handled under the Food, Drug and Cosmetic (FDC) Act. In 1984, Congress passed the
Drug Price Competition and Patent Term Restoration Act or the Hatch–Waxman Act. The
Act amended the FDC Act to create a simple, inexpensive pathway for FDA approval of
bioequivalent generic drugs (the abbreviated new drug application; ANDA). The Hatch–
Waxman Act made no amendments to the PHS Act and there has been no abbreviated
approval process for competitors to the original version of a biological product. The PHS
Act has now been amended by part of the 2010 healthcare reform legislation to provide

30
GaBIonline: Generics and Biosimilars Initiative. How far does similarity go?
http://www.gabionline.net/Biosimilars/Research/How-far-does-similarity-go
31
GaBIonline: Generics and Biosimilars Initiative. What clinical trials will be required for biosimilar mAbs?
http://www.gabionline.net/Biosimilars/Research/What-clinical-trials-will-be-required-for-biosimilar-mAbs

October 2010 21


provisions analogous to, but different from, those for small molecules under the Hatch–
Waxman Act.

Legislation

Made law in March 2010 by the Obama administration, the Patient Protection and
Affordable Care Act (PPAC Act) amends the PHS Act to establish an abbreviated approval
pathway for biological products that are demonstrated to be highly similar (biosimilar) to
or interchangeable with an FDA-approved biological product. These new provisions may
also be referred to as the Biologics Price Competition and Innovation Act of 2009 (BPCI
Act), which is included as a subtitle to the PPAC Act.

According to the FDA 32, under the BPCI Act, a sponsor may seek approval of a biosimilar
product under new section 351(k) of the PHS Act. A biological product may be
demonstrated to be biosimilar if data shows that the product is highly similar to the
reference product, notwithstanding minor differences in clinically inactive components.
There must also be no clinically meaningful differences between the biological product and
the reference product in terms of safety, purity and potency.

In May 2010, the FDA instituted the role of Acting Associate Director for Biosimilars within
the Office of New Drugs (OND), and established the Biosimilars Review Committee (BRC).
The BRC will advise the OND as it considers sponsor requests for advice about how to
develop a biosimilar product and as it reviews biosimilar BLAs. The FDA also stated its
intention to hold public meetings in order to receive information and comments from a
broad group of stakeholders, such as healthcare professionals, healthcare institutions,
manufacturers of biomedical products, interested industry and professional associations,
patients and patient associations, third-party payers and the public regarding
implementation of the BPCI Act. The first of these will be on November 2 and 3, 2010 and
will cover the issues of biosimilarity, interchangeability, patient safety and
pharmacovigilance, exclusivity and user fees, among others 33.

It is not mandatory for guidance to have been issued for the FDA to consider biosimilars
applications. But how the FDA will interpret the legislation is a matter for conjecture.Key

32
US Food and Drug Administration. Implementation of the Biologics Price Competition and Innovation Act of
2009. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm
33
Department of Health and Human Services, Food and Drug Administration. Approval Pathway for Biosimilar and
Interchangeable Biological Products; Public Hearing; Request for Comments.
http://thehill.com/images/stories/blogs/biosimilars.pdf

22 October 2010


questions are how ‘highly similar’ the FDA will require a biosimilar to be, and what ‘minor
differences in clinically active components’ will taken to mean. Companies may therefore
be reluctant to make a biosimilar product application until the discussion period is over and
guidance has been issued.

Substitution/interchangeability

Once approved, standard generic drugs can be automatically substituted by a pharmacist
for the reference product without the intervention of the prescribing healthcare provider in
many states. This is a key plank in the business model of generics manufacturers in the
USA. However, biosimilars are not automatically interchangeable under the PPAC Act,
which has effectively created a second category of biosimilars—those that are
interchangeable.

In its commentary on the PPAC Act, the FDA states that “in order to meet the higher
standard of interchangeability, a sponsor must demonstrate that the biosimilar product
can be expected to produce the same clinical result as the reference product in any given
patient and, for a biological product that is administered more than once, that the risk of
alternating or switching between use of the biosimilar product and the reference product is
not greater than the risk of maintaining the patient on the reference product.” This is
much more difficult to prove. In the short term, it may be impossible as considerable
pharmacovigilance data collection will be required before a biosimilars manufacturer may
be able to make a claim for interchangeability status.

The first biosimilar to be granted interchangeability status will receive one year of
marketing exclusivity. Other non-interchangeable products can still be approved.

Data exclusivity

The PPAC Act provides four years of data exclusivity from the date on which the reference
product was first licensed During that period, a biosimilar application may not be made.
There is also provision for a further eight years of marketing exclusivity when a biosimilar
product may not be sold, and six months paediatric exclusivity. This exclusivity runs
concurrently with the patents.

October 2010 23


The total 12-year market exclusivity period granted by the legislation, and which is
additional to any existing patent rights, is contentious. In June 2009, an FTC Report 34
concluded that innovative products should not receive additional market exclusivity beyond
the term of their patents because the original products would keep 70 to 90 percent of
their market share. Manufacturers have disagreed, arguing that 12 years of exclusivity are
essential because it is easier to design around patents for biological drugs than those for
small-molecule drugs. This claim has been refuted by the FTC (see ‘Patents’ under
‘Biosimilars are not generics’).

Perhaps good news for potential biosimilars manufacturers is that because the biosimilar
application can be filed as soon as four years after approval of the reference product, any
patent litigation may be resolved well before the 12-year period of regulatory exclusivity
has expired 35. However, it has been suggested that manufacturers of potential biosimilars
may prefer to ignore the new pathway and opt to file a standard Biologics License
Application (BLA), which would not be subject to the 12-year delay. Any higher cost would
be offset by the greater profit opportunity available to early market entrants 36. Teva opted
for this route for its filgrastim (Neutroval) when they submitted a full BLA in December
2009. In November 2009, they had sought to have declared invalid two of Amgen’s
Neupogen patents that expire in 2013.

Extrapolation to other indications

The PPAC Act does not give specific guidance on whether a biosimilar tested in one patient
population will receive approval for all the indications that the reference product is
approved for.

Patent information exchange

There is no equivalent of the ‘Orange Book’, created by Hatch–Waxman, for BLA holders.
This requires each NDA holder to identify any patent, in existence at the time of filing or
issued subsequently, that claims the drug or a method of using the drug and for which an
action of infringement can reasonably be asserted. The biosimilars legislation therefore

34
35
Fairchild BA. Updated patent strategy for biosimilar era. Genetic Engineering and Biotechnology News.
http://genengnews.com/gen-articles/updated-patent-strategy-for-biosimilar-era/3343/?page=1
36
Engelberg AB, Kesselheim AS, Avorn J. Balancing innovation, access, and profits—market exclusivity for
biologics. N Engl J Med 2009;361:1917–19.

24 October 2010


created a unique scheme for the confidential exchange of information regarding patent
rights relevant to the biosimilar, and the reference product so that issues of patent validity
or infringement can be resolved before approval of the biosimilar. The scheme is complex
and includes penalties for non-compliance. Yet it represents a default which originators
and biosimilar companies can find alternatives to.

Biological products approved as drugs

Although a specific biosimilar approval pathway has only recently been approved, some
biological products have seen competition in the USA for some years. Some early
biological drugs, such as somatropin and insulin, were approved as drugs under the FDC
Act. ‘Biosimilar’ versions cannot be approved as generics under 505(j) (ANDA) regulations,
as these require a drug to be identical in active ingredient, form, route of administration
etc. Instead, they have received approval for New Drug Applications (NDAs) under section
505(b)(2) of the FDC Act.

Examples of biopharmaceuticals approved under these provisions are Sandoz’ Omnitrope
(somatropin), LG Life Sciences’ Valtropin (somatropin), several versions of hyaluronidase,
Fortical (salmon calcitonin) and GlucaGen (glucagon). More recently, Sandoz /Momenta’s
version of enoxaparin was granted an ANDA. (See ‘Low-molecular-weight heparins’ under
‘Target biopharmaceutical products’)

October 2010 25



Other markets
Following the EU’s lead, biosimilar approval guidelines have been implemented or
proposed in several markets, including some emerging markets that have adopted the EU
guidelines or used them as a basis for their own (Table 1).

Table 1. Countries outside the EU and the USA in which guidelines for an abbreviated
regulatory pathway for biosimilars exist

Country Regulatory body/Guideline title Date of
implementation

Japan Ministry of Health, Labor and Wealth Mar 2009
Based on similar scientific principles to the EMA
approval pathway

S. Korea Jun 2009

Malaysia Ministry of Health Malaysia July 2008
Guidance document and guidelines for registration
of biosimilars in Malaysia
Based on EMA guidelines

Singapore Health Sciences Authority Aug 2009
Guidance on registration of similar biological
products in Singapore

Australia Therapeutic Goods Administration Aug 2008
Adopted EMA guidelines

Canada Health Canada Mar 2010
Draft guideline on subsequent entry biologicals

Turkey General Directorate of Pharmaceuticals and Aug 2008
Pharmacy
Instruction manual on biosimilar medical products

Middle Expert panel recommended the implementation of Recommendation 2008
East the EMA guidelines 37

Saudi Drug master file requirements for the registration Draft Aug 2008
Arabia of biosimilars

37
Curr Med Res Opin 2008;24:2897–903.

26 October 2010



Country Regulatory body/Guideline title Date of
implementation

WHO Guidelines on evaluation of similar biotherapeutic 2009
products (SBPs)

Reproduced with permission from Ingrid Schwarzenberger, Head of Global Regulatory
Affairs Biopharmaceuticals, Sandoz GmbH.
Japan published draft guidelines in September 2008. In November of that year, Kissei
Pharmaceutical filed Japan’s first biosimilar application, for its epoetin kappa, which was
launched in May 2010. However, the first biosimilar to be approved in Japan was Sandoz’
Omnitrope (somatropin) in June 2009, three months after the approval guideline was
adopted.

‘Biosimilar’ versions of biological medicines have been available in both India and China for
several years. However, their regulatory systems are less stringent and the products
would not be approvable as biosimilars in the major markets. Furthermore, these countries
have underdeveloped pharmacovigilance systems and provide few adverse drug reaction
reports to the WHO International Programme on Drug Monitoring database, managed by
the Uppsala Monitoring Centre 38.

“Biosimilars are only those products which have been approved in Europe according to the
very stringent European guidelines for the approval of biosimilars,`explains Dr Ingrid
Schwarzenberger, Head of Global Regulatory Affairs Biopharmaceuticals at Sandoz, told
FirstWord. Those approved in Canada or Japan could also be called biosimilars and soon,
hopefully, also those approved in the USA. But all the other copy products of biologics
which are approved and available in India, China, Korea, Latin America must not be called
biosimilars. These products have been approved nationally with very little data and have
not been subject to a comprehensive comparability exercise as it is required for the EU,
Japan, Canada or the USA.”

According to the Generics and Biosimilars Initiative, India has the greatest acceptance of
‘biosimilars’. Around 50 biopharmaceutical products have been approved for marketing in
India in recent years, with more than half of them being ‘biosimilars’. Until 2005, Indian
law allowed companies to manufacture generic versions of products including biologicals,
as long as the process used was different from the originator’s. However, India joined the

38
WHO Drug Information 2009;23:87–94.

October 2010 27


World Trade Organization (WTO) in 1995 and in 2005 started the process of becoming
compliant with the TRIPS agreement (WTO’s Trade-Related Intellectual Property Rights)
and recognizing product patents. This may well lead to fewer biogenerics being sold.

India has no specific approval pathway for biosimilars. Approval is on a case-by-case
basis. However, in 2010, the Indian government began the process of streamlining the
biosimilars approval process and it has been suggested that the WHO biosimilars
guidelines (see below) could help 39. Currently, responsibility for regulating the
development and approval of all biological drugs is shared between the Review Committee
on Genetic Manipulation (RCGM; Department of Biotechnology) and the Drugs Controller
General of India (DCGI). The RCGM gives permission to either develop a recombinant
clone or, if a clone is imported, to perform toxicology studies. The preclinical protocol is
also submitted to the RCGM and once preclinical studies are completed, the sponsor
applies to the DCGI to conduct clinical trials; for a biosimilar, this typically includes a non-
inferiority study but not extensive clinical trials. The DCGI also gives final marketing
approval 40.

Jill Deviprasad of Biocon believes that a stringent regulatory framework in India could
deny less well-off Indians access to biological drugs. There is no managed care programme
in India, no health insurance and patients have to pay for drugs themselves. However, an
Indian pharmaceutical industry commentator believes that the lack of a specific regulatory
framework for biological drugs might allow poor-quality products to be sold, which could
ruin the reputation of the Indian industry.

Global biosimilars strategy

The WHO seeks to promote improved access to biological drugs at a reduced price; in
2007, the body formally recognised the need for additional global regulatory guidelines for
the evaluation and regulation of biosimilars. Since then, WHO has been working with
regulators from many countries on a draft document to provide a base standard for the
development and evaluation of biological products by abbreviated licensing pathways. The
document was finalised in 2010 41 and, according to WHO, “can be adopted as a whole, or

39
Som N. Bionomics of biosimilars. Biospectrum Asia 2010, Feb 04.
http://www.biospectrumasia.com/content/040210IND11983.asp
40
Iyer H. MAbs 2009;1:411–16.
41
WHO. Guidelines on evaluation of similar biotherapeutic products (SBPs). Geneva: World Health Organization;
2009.
http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf

28 October 2010


partially, by national regulatory authorities worldwide or used as a basis for establishing
national regulatory frameworks for licensure of these products.” At the 8th EGA Biosimilars
Symposium in September 2010, EGA Director General Greg Perry noted: “This is an
important step towards a global, harmonised, regulatory approach”.

If worldwide development programmes are to become a reality, the generic and
biotechnology industries need to persuade the regulatory authorities to work together to
develop harmonised regulations. A key issue is the source of the reference product. The
EU regulations, the Japanese guideline and the US legislation require the use of a
reference product authorised in their jurisdiction. This means that new clinical trials must
be conducted in each region, a situation described by Ingrid Schwarzenberger at the 7th
EGA Symposium on Biosimilars in April 2009 as “unnecessary, unethical… and
uneconomical” 42. Dr Schwarzenberger told FirstWord that it will take several more years to
persuade the regulatory authorities to accept that duplication of preclinical/clinical studies
in each region is not necessary. She also commented that the resulting ‘global data
package’ used for the successful approval in the EU, USA and Japan could then be used for
approval in all other countries in the world, without any further local study requirements.

The recent passage of US biosimilars legislation may move the situation forward. “One
immediate consequence [of the legislation] is that the environment is now ripe for FDA
and EMA to increase their dialogue on biosimilar medicines, which we fully support,” says
Suzette Kox of the EGA.

42
Schwarzenberger I. Global development, the way forward: the EGA’s perspective. 7th EGA Annual Symposium
on Biosimilars; London, 23–24 April 2009.
http://www.egagenerics.com/doc/ega_biosimilars_Schwarzenberger_090424.pdf

October 2010 29



Target biopharmaceutical products
In the market for traditional drugs, relatively few compounds account for a
disproportionate share of sales and profits. It is these that will attract the most interest
from biosimilars manufacturers, as in the market for traditional generic drugs. There,
several studies have established that the number of entrants is strongly related to the size
of the branded product’s sales before entry 43. Teva, the world’s largest generic drug
manufacturer and a leader in the biosimilars market, projected in 2010 that about
$53 billion in sales of branded biological drugs will be exposed to biosimilar competition by
2015 through patent expirations alone.

Biopharmaceuticals fall into several categories depending on their complexity (Table 3).
Some of the simpler ones have already been the subject of biosimilar competition in
Europe, while the more complex promising products—the monoclonal antibodies and
fusion proteins—remain remain are subjected to competition. This section of the report will
look at the biosimilar competition that exists and discuss the potential for the next wave of
products.

43
Grabowski H, Cockburn I, Long G. Health Aff (Millwood) 2006;25:1291–1301.

30 October 2010


Table 3. The major classes of biological drugs

Product class Definition

EU biosimilars guidelines exist

Somatropin (growth Non-glycosylated protein of 191 amino acids
hormone) Used for growth failure, growth hormone
deficiency, short bowel syndrome and HIV-related
weight loss or wasting

Epoetin Heavily glycosylated protein hormone of 165
amino acids that stimulates red blood cell
production
Used for treating anaemia in patients with chronic
kidney disease or patients with cancer who are
receiving chemotherapy

Filgrastim (G-CSF) Minimally glycosylated protein of 174 amino acids
that stimulates the production of white blood cells
Used to restore white blood cell levels and prevent
infections in patients with cancer or who have had
a bone marrow transplant

Insulin Peptide of 51 amino acids
Used in Type I and Type II diabetes

Interferon alfa Protein of 165 amino acids secreted in response to
infection
Used for chronic hepatitis B or C virus infection
and cancers

Heparins Glycosaminoglycans (mucopolysaccharides) –
long, unbranched polysaccharides used to prevent
blood coagulation

EU biosimilars guidelines in preparation

Monoclonal antibodies and Based on the antibodies (immunoglobulins) the
fusion proteins body uses to fight infection and cancer and which
are involved in the development of immune
conditions such as rheumatoid arthritis and
psoriasis

Interferon beta Glycoprotein of 166 amino acids secreted in
response to infection
Used in multiple sclerosis

October 2010 31



Product class Definition

Follitropin (follicle- Glycoprotein consisting of two polypeptide chains
stimulating hormone; FSH) that regulates growth, development and
reproduction
Used in fertilization medicine for women, and for
men to induce and maintain spermatogenesis

Biosimilars guidelines not available or planned

Vaccines Live, weakened or killed microorganisms, or
recombinant subunits of the infecting organism

Enzymes Replacement for enzymes deficient owing to a
genetic disorder such as Gaucher’s disease
ThrombolyticsImiglucerase

Blood coagulation factors Naturally occurring or recombinant coagulation
factors for the treatment of haemophilia
Factor VIII
Factor IX

Fourteen biological products have been approved in the EU under the biosimilars pathway:
two somatropins, five epoetins and seven filgrastims. A further five products had been
submitted for approval by December 2009, but the CHMP either declined to recommend
approval or the products were withdrawn from the authorisation process. These were one
interferon alfa-2a, one interferon beta-1a and three insulin products (see relevant sections
below).

32 October 2010



Somatropin (growth hormone)
Several somatropin products are available that have been developed as new products (see
Table 5). There are no second-generation products. However superior branded versions
exist with improved delivery systems. Biopartners says it is on track to be the first
company to submit a sustained-release somatropin formulation that will cut the number of
self-administered injections from one per day to one per week.

Table 5. Original somatropin products

Brand Distributor Manufacturer

Genotropin Pfizer/Pharmacia Genentech

Nutropin/Nutropin AQ Genentech/Ipsen Genentech

Humatrope Lilly Lilly

Norditropin Novo Nordisk Novo Nordisk

Saizen/Serostim/Zorbtive Merck Serono Merck Serono

Zomacton Ferring Ferring

Two biosimilar somatropins have been approved in the EU (Table 6), one of which is
Sandoz’ Omnitrope 44, the first biosimilar to be approved in a highly regulated market. This
has been subject to relatively few competitors compared with epoetins and filgrastims, for
several reasons. The somatropin market is low-value, saturated and device-driven;
manufacturers engage in aggressive pricing tactics to maintain market share. Moreover,
the patient population is predominantly paediatric, with treatment typically lasting six
years, and biosimilars will almost certainly be restricted to new patients. There are also
superior formulations available that would out-compete basic lyophilized biosimilar growth
hormone.

44
Stanhope R, Sörgel F, Gravel P, Pannatier Schuetz YB, Zabransky M, Muenzberg M. Bioequivalence studies of
Omnitrope, the first biosimilar/rHGH follow-on protein: two comparative phase 1 randomized studies and
population pharmacokinetic analysis. J Clin Pharmacol 2010 Feb 19. [Epub ahead of print].

October 2010 33


Table 6. Biosimilar somatropins approved in the EU

Brand Distributor Manufacturer Reference product EU approval
date

Omnitrope Sandoz Sandoz Genotropin (Pfizer) Apr 2006

Valtropin* Biopartners LG Life Sciences Humatrope (Lilly) Apr 2006

* Not yet marketed.

In May 2010 the UK’s National Institute for Health and Clinical Excellence (NICE) reviewed
and reappraised its guidance on the use of somatropin in children with growth failure. It
noted that Omnitrope was approved via the biosimilar route but was satisfied that it could
consider it for the treatment of growth failure alongside the other six somatropin products.
This was the first time that NICE had recommended the use of a biosimilar.

Epoetin (erythropoietin)
The market-leading epoetins are shown in Table 7. The different INNs of the various
products reflect differences in glycosylation, which are significant because glycosylation is
extensive and can influence the pharmacokinetics of the product, which may influence
efficacy and safety, especially immunogenicity.

34 October 2010


Biosimilars report

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