our publication about Biosimilar Medicines - Europabio

EuropaBio
& Biosimilar
Medicines

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
Contents
• Welcome letter from the Secretary General
of EuropaBio
• Healthcare biotechnology and biosimilars
• Glossary of key terms
• References
• Further information
Healthcare biotechnology and biosimilars
I - The Science
1. Healthcare biotechnology – introduction
2. Why do biological medicines differ from chemical medicines?
3. How are biological medicines manufactured?
4. Intellectual property for biotech medicines
II - Biosimilar Medicines – Current Issues
1. Naming
2. Health Economics & Pricing
3. Immunogenicity
4. Interchangeability
5. Substitution
III – The Regulation of Biosimilars
1. In Europe
2. Outside of Europe
IV - The market for biosimilars
1. Which biosimilars are currently available in Europe?
2. When are the next biosimilars coming on to the market?
3. What does the market entry of biosimilars mean for the original innovator products?
V - The impact of biosimilars
1. What do patients need to know?
2. What do healthcare professionals need to know?
3. What do payers need to know?

Welcome letter by EuropaBio
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
Biotechnology has enabled the discovery of
treatments for some of the most serious diseases
known to man – worldwide, the lives of over 325
million people have been transformed by the
availability of a growing number of biotechnology
medicines. Today patients have access to more
than 155 biotechnology drugs and vaccines, and
medical science is working to increase that number
every day. There are more than 418 biotechnology
medicines in development, covering more than 100
diseases i . These include 210 medicines for cancer, 50
for infectious diseases, 44 for autoimmune diseases,
and 22 for AIDS/HIV and related conditions.
As the exclusive rights (patents and other data
protection) for certain biological medicines expire,
similar biological medicines or “biosimilars” are
being developed. Some of these are already on
the market in Europe. This document is intended
to explain the complexities of biotech medicines,
including biosimilar medicines, and to give an
insight into what patients, healthcare professionals
and other interested individuals should know
about biotech and biosimilar medicines.
Willy DeGreef
Secretary General, Europabio
03

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
...patients
have access
to more
than 155
biotechnology
medicines and
vaccines...

I - The Science
1. Healthcare biotechnology – introduction
What are biotechnology medicines*
and how do they work?
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
Biotechnology uses biological systems and living
organisms to make or modify products or processes
for specific use ii . Biotechnology medicines are just
one of the many applications of biotechnology in
healthcare. There are several prominent categories
of biotechnological medicines:
• Recombinant proteins can replace insufficient
or malfunctioning proteins in the human body.
One example of a recombinant protein is insulin,
which is commonly used in the treatment of
diabetes. Other recombinant proteins like
antibodies or vaccines are used in the treatment
or prevention of serious diseases such as cancer.
• Nucleic acids like DNA or RNA are used in
gene-therapy treatments to restore or modulate
specific disease-related genes.
• Tissues and cells are used for tissue repair after
severe injuries e.g., skin transplants.
• Inactivated forms of micro-organisms are used as
vaccines to prevent diseases provoked by these
micro-organisms (mostly viruses). Vaccines work
by stimulating an immune response against a
disease-causing micro-organism.
• Complex chemical molecules like antibiotics,
which are used for the treatment of bacterial
infections, can be either directly obtained from
micro-organisms (e.g. penicillin is produced
by a certain type of fungus), or can be further
modified by chemical processes (e.g. half-synthetic
antibiotics like ampicillin).
Furthermore, many biotechnological healthcare
products are used widely for diagnostic purposes.
*For the purpose of this document, we use the term “biotech medicine” or
“biological medicine” or “biopharmaceutical” for recombinant protein products.
05

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
The history of healthcare biotechnology
06
Although the modern healthcare biotechnology
industry is only 30 years old, the science of
biotechnology has been explored since the 19th
century when eminent scientists such as Louis
Pasteur and Robert Koch first developed the
science of microbiology, the forerunner of today’s
biotechnology. In 1953, James Watson and Francis
Crick discovered DNA and in 1955, Fred Sanger
determined the amino acid sequence of insulin.
In 1972, Paul Berg created the first recombinant
DNA molecule. DNA engineering has become the
basis of modern biotechnology as it allows the
re-arrangement (“recombination”) of so far
unrelated genetic sequences and the use of those
molecules for the production of recombinant
proteins for medical purposes.
The first biotech companies were founded in the
1970s and many more in the early 1980s. Most of
today’s healthcare biotech companies began life
as small start-ups established by a handful of
enthusiastic visionary scientists on a shoe-string
budget. The hard work of the early pioneers has
now come to fruition: today, over 325 million
people have had their lives transformed by
healthcare biotechnology treatments and it is
estimated that by 2010, around 50 percent of
new medicines will be of biological origin iii .

2. Why do biological medicines differ from
chemical medicines?
What are the differentiating factors?
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
Biological medicines are far more complex
and usually much bigger in size than chemical
medicines, which are produced by chemical
synthesis. This means that their manufacturing and
precise characterisation tends to be more difficult
than for chemical medicines, the ingredients of
which are more easily identifiable and can be
exactly reproduced.
1. Biological medicines show a higher variability.
As biological medicines are produced by living
systems, such as cell lines, they show a higher
variability than traditional (chemical)
pharmaceuticals. As a consequence, each
biological medicine is unique. This could be
likened to the signature of a person; each time
a person (biological) signs something, their
signature will be slightly different, whereas a
printed (chemical) signature remains exactly
the same.
2. Biological medicines are more complex.
Proteins consist of one or more chains of
potentially several hundred amino acids with a
complex three-dimensional structure. Their
molecular size is, therefore, bigger than that of
chemical medicines. These large molecules are
diverse and difficult to characterize. In contrast,
the molecular structure of chemical medicines
is relatively simple, which can allow them to be
exactly reproduced.
3. Biological medicines have the potential to
provoke immune reactions.
Biological medicines, because of their
composition and large molecular size, have
the ability to stimulate the body to mount an
immune response, i.e. produce antibodies against
a protein that the human body recognizes as
“foreign”. “Small molecule” chemical medicines,
07

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
on the other hand, are too small to be recognized
on their own by the immune system. Chemical
medicines can sometimes provoke rare negative
immune reactions like allergy or hypersensitivity
when they bind to naturally occurring proteins in
the body. However, these reactions are generally
short-lived; once levels of the chemical medicine
have decreased in the body, the negative immune
response will, in most cases, disappear and no
longer harm the patient as long as no further
exposure to the medicine occurs.
The potential to provoke an immune response in
the body (immunogenicity) is a double-edged sword
for all biological medicines. Vaccines specifically
exploit this immunogenic potential by provoking an
immune response that recognizes and “fights off” an
“invader” substance. However, for most medicines
based on recombinant proteins, stimulating an
immune response is regarded as undesirable.
Immune responses are complex reactions of the
body and can differ from patient to patient (due to
genetic factors), as well as from disease to disease
(depending on the immune status of the patient).
The likelihood of an immune response can also
be influenced by characteristics of the biological
product itself, such as its formulation, stability and
manufacturing process. The individual manufacturing
process has influence, for example, on the active
substance and the quality and quantity of impurities.
Most of the immune responses that occur are mild
and do have negative effects on the patient, e.g.
in the majority of cases where transient antibodies
to a therapeutic protein are found in the blood. In
rare cases, however, unwanted immune reactions
can have severe, detrimental effects on the health
of a patient, e.g. when so-called “neutralizing”
antibodies appear and make the therapeutic protein
in the biotech medicine ineffective.
08
With biological medicines that resemble the
patient’s own proteins and are intended to replace
insufficient levels of that substance in the patient,
such neutralizing antibodies can even trigger the
body to fight off what remains of the protein
produced by the patient’s body. This immunogenic
reaction can persist for years after the biological
medicine has stopped being administered to the
patient. This potential to elicit a sustained immune
response to a patient’s own protein and block
important biochemical pathways for long periods
of time makes immunogenicity of biological
medicines a particular safety concern.
4. Biological medicines are often administered
via injections.
When taken orally, the digestive system breaks
down proteins (of which biotech medecines
are composed), into their building blocks called
amino acids. This progess would prevent the
protein from reaching the part of the body it
should treat and exerting its therapeutic
function. Therefore biotech medicines must
generally be administered by injection and
cannot be taken orally in the shape of a pill or
capsule like chemical medicines. Antibiotics,
which are complex structures, but not proteins,
can be taken orally or via injections, depending
on the specific need.
5. Biological medicines need special transport and
storage conditions.
Biological material is generally subject to fast
degradation when handled inappropriately.
Therefore, biological medicines usually need
to be stored in a refrigerator and should be
handled under specific conditions.

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
...biotech
medicines
must generally
be administered
by injection...

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
3. How are biological medicines manufactured? Manufacturing biological medicines is generally
10
more complex than the production of traditional
(chemical) pharmaceuticals. Biological medicines
show a higher batch-to-batch variability than
chemical medicines. There are a number of reasons
for this, including the nature of the starting
material and the very high level of precision
required in the manufacturing process.
The starting material for most biological medicines
is a genetically modified cell line. Each biotech
company uses unique cell lines and develops its
own proprietary (unique) manufacturing processes
to produce biological medicines.
The production of biological medicines involves
processes such as fermentation and purification.
Even very small changes to these manufacturing
processes such as minor variations during production
e.g. temperature variations, can result in significant
changes in the clinical properties of the biological
medicine produced. It is therefore vital to precisely
control the manufacturing processes and the
environment inside a production facility, in order to
obtain consistent results and to guarantee the safety
and efficacy of the end product.
The production of biotechnology medicines
requires a high level of monitoring and quality
testing: typically around 250 in-process tests are
conducted for a biological, compared with around
50 tests for a traditional (chemical) medicine.
The unique starting material and the complex
manufacturing processes mean that it is not
possible to exactly reproduce a biological in the
same way a pharmaceutical (chemical) generic can
be produced.

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
4. Intellectual property for biotech medicines Innovative medicines generally benefit from a
certain period of intellectual property protection
via patents and other exclusive rights such as data
protection and market exclusivity. Patent rights
give the patent holder (often, but not always, the
manufacturer), the right to prevent others from
manufacturing, selling, using and importing a
product, or using a process or selling a product
made by that process during a limited period of
time, e.g. 20 years from the date of application.
Data and market exclusivity mean that there is a
period of time after approval before a competitor
can enter the market with a follow-on product that
relies wholly or partly on the originator’s data on
safety and efficacy for its regulatory approval. The
follow-on product can often use an abbreviated
regulatory approval procedure.
Such forms of intellectual property protection
are important for companies that develop and
manufacture new medicines, as it enables them to
recoup their investments and further invest in the
research and development of new medicines.
Follow-on versions of chemical medicines that enter
the market after expiry of IP protection are
called “generics”. Follow-on versions of biological
medicines are called “similar biological medicinal
products” or “biosimilars”. In both cases, the
originator product is called the “reference product”.
Due to certain special features that characterise a
biological medicine, the European Union decided
that the name of follow-on biological medicines
(“biosimilars”) and their regulatory approval pathway
had to be different from chemical “generics”.
11

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
II - Biosimilar medicines - current issues
1. Naming
12
All medicines have an International Non-proprietary
Name (INN) and most have a brand name, too.
Chemical pharmaceuticals have the same INN as
the originator product as they are exact copies of
the originator. Due to the complexity of biological
medicinal products, EuropaBio advocates a
revision of the INN nomenclature system so that
each biotechnology-derived medicine is assigned
a distinct INN. Another alternative would be to
ensure that biologicals are always commercialised
with a brand name or the INN plus the
manufacturer’s name.
In some countries, physicians are obliged or
encouraged to prescribe by INN. In such situations
if two biologicals have the same INN, this could
result in products being considered identical
and thus “switched”, when there might be no
scientific evidence to support that switch. Such a
switch could have negative clinical consequences
for the patient, as typically the two products
are similar but not identical, and the differences
between them may have a therapeutic impact.
The European Commission’s proposal for improving
the EU pharmacovigilance iv system stresses the
importance of being able to precisely trace a
biological product. Specifically, the Commission
suggests that marketing authorisation holders
should advise those completing adverse event
reports to provide “the (invented) name and the
batch number”. Also, in order to improve the
pharmacovigilance of biological products including
biosimilars, the Commission has proposed that
Member States ensure that biological medicinal
products that are the subject of adverse reaction
reports be identifiable i.e. traceable. v
2. Health Economics and Pricing
Biosimilars are unlikely to result in the same
price competition as has occurred with the
introduction of generic medicines for a number
of reasons. Firstly, biological medicines including
biosimilars are generally more complex and
costly to produce, e.g. unlike generic medicines,
biosimilars require independent clinical trials to
be undertaken.
Furthermore, the pre-approval regulatory
requirements and post-marketing surveillance
for biosimilars are more rigorous than for
generic medicines, thus adding a further layer to
the cost of producing a biosimilar.
The exact price level of a biosimilar will depend
on the pricing and reimbursement environment
of each country, the competitiveness of the
market and the desire to encourage the future
development of new products.
3. Immunogenicity –
what is it and why does it matter?
Biologicals have the inherent potential to
provoke (unwanted) immune reactions (see
chapter I part 2 above). This potential is one of
the major reasons why biologicals are generally
treated differently to chemical medicines by
regulatory authorities.
While a lot is known today about certain
features of biological products that make them
more likely to provoke immune reactions e.g.
high content of host cell proteins and certain
routes of administration, it is currently not
possible to accurately predict immunogenicity in
humans only through non-clinical assessment in

animals. Therefore, immunogenicity assessment
through clinical studies plays a major role in the
development of biological medicines.
At the time a biosimilar receives market approval, a
lot is already known about the safety and efficacy of
the product class and the reference product, which
at this point has usually been on the market for
years (or even decades). However, the potential to
provoke immune reactions can differ from product
to product and rare effects can only be detected and
assessed when large numbers of patients have been
treated with a product. At the time of approval,
information on the safety of a medicinal product
is relatively limited for several reasons, such as a
limited number of patients in clinical trials, a limited
time of exposure to the medication and, generally, a
rather strictly defined patient population.
Unlike chemical generics, biosimilars need to have a
“Risk Management Plan” in place. This acknowledges
the special characteristics of biologicals. As with
other new medicines, this Risk Management Plan
defines a set of “pharmacovigilance activities and
interventions designed to identify, characterise,
prevent or minimise risks relating to medicinal
products, and the assessment of the effectiveness of
these interventions”. vi
The potential of biologicals to provoke immune
reactions has been the major reason for treating
biosimilars in the same way as new (biological)
products with regard to post-marketing surveillance.
4. Interchangeability
Interchangeability of medicinal products refers to
the situation where one product is “switched” for
another equivalent product in a clinical setting,
without a risk of an adverse health outcome.
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
Generic medicines, which are considered
bioequivalent, are regarded as “therapeutically
equivalent and therefore, interchangeable” vii .
The current state of scientific knowledge means
that, in general, (chemical) generic medicines
can be deemed interchangeable with their
reference product. Regulatory agencies such as
the European Medicines Agency (EMEA) do not
assess the interchangeability or substitutability of
a biosimilar when granting a positive opinion for
a marketing authorisation application. In other
words, the granting of approval does not mean
that the biosimilar product can be interchanged or
substituted with the reference product.
Currently, no clinical studies have been designed
or undertaken to assess the clinical outcome
of repeated switches (changes) of a biological
medicine, whether using two original biological
medicines or an original and a biosimilar.
5. Substitution
Automatic substitution (or generic substitution) is
where the pharmacist substitutes a brand name
(chemical) medicine for a generic version of the
same drug. Some countries make generic substitution
mandatory under certain conditions, for example
where the doctor prescribes by INN. Generic
substitution is often linked to reimbursement; for
example, some health insurance schemes will only
reimburse the patient for the cost of the generic
version of a product. The result of this is that a
patient refusing the generic version and insisting on
the original product must pay the difference in cost.
Generic versions of chemical pharmaceuticals which
have demonstrated their bioequivalence may be
substituted with no risk to patient safety.
13

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
The EMEA has specifically stated that “since
biosimilars and biological reference products are
not identical, the decision to treat a patient with a
reference product or biosimilar medicine should be
taken following the opinion of a qualified health
professional”*. In addition, there is currently no
convincing scientific data to prove that repeated
product switching of biological medicines
(whether biosimilar versions or not) does not
lead to negative clinical consequences. Moreover,
regulators need to remain prudent in matters
relating to the protection of public health.
A number of countries such as France, Italy, Spain,
UK, Netherlands, Germany, Sweden, have either
established legislative measures to prohibit the
automatic substitution of biotech medicines or
have given regulatory advice on the use of biologics
(including prescription by brand). The justification
for such measures is that of patient safety.
EuropaBio firmly believes that other countries that
allow automatic substitution of generic medicines
should take the necessary measures to prevent
automatic substitution of biologics.
*http://www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf
14

III - The Regulation of Biosimilars
1. In Europe
Chemical medicines can be approved by the national
medicines authorities of individual EU member states.
In contrast, biological products, including biosimilars,
have to follow the “centralized procedure” for
approval carried out by the European Medicines
Agency (EMEA). Applications submitted to the EMEA
are assessed by its Committee for Human Medicinal
Products (CHMP), which can give a positive or negative
opinion. Upon receipt of a positive opinion from the
EMEA, the European Commission issues a marketing
authorisation which is valid for all EU countries.
Since 2003, the European Union has created
a legal and regulatory pathway to enable the
development and marketing of biosimilar
medicines. Directives 2003/63/EC viii and 2004/27/
EC ix , created a legislative route and the EMEA has
subsequently developed a number of regulatory
guidelines concerning the required data needed for
approval of a biosimilar. Besides the “overarching”,
general guideline on biosimilars, the EMEA has
developed guidelines on quality, on non-clinical
and clinical issues, and product-specific annexes
to those on e.g., insulin, epoetin, somatropin and
granulocyte-stimulating growth factor. At the time
of publication of this document, further guidelines
were close to being finalised, including guidelines
on interferon-alfa and low-molecular heparin x .
EMEA’s “overarching” guideline on biosimilars xi
specifically states that biosimilar products are
“by definition” not generics, and that the
generic approach to approval “is scientifically not
appropriate” for biosimilars.
In its document “Questions and Answers on
biosimilar medicines”, the EMEA defines biosimilars
as follows xii :
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
“A biosimilar medicine is a medicine which is
similar to a biological medicine that has already
been authorized (the ‘biological reference
medicine’). The active substance of a biosimilar
medicine is similar to the one of the biological
reference medicine. Biosimilar and biological
reference medicines are used in general at
the same dose to treat the same disease. Since
biosimilar and biological reference medicines
are similar but not identical, the decision to
treat a patient with a reference or a biosimilar
medicine should be taken following the
opinion of a qualified healthcare professional.
The name, appearance and packaging of a
biosimilar medicine differ to those of the
biological reference medicine.”
The EMEA Q&A document further states that
the “legislation defines the studies that need
to be carried out to show that the biosimilar
medicine is similar and as safe and effective as the
biological reference medicine”. To this end, the
biosimilar approval pathway requires a biosimilar
manufacturer to demonstrate similarity with the
reference product for quality, safety and efficacy.
Specifically, the biosimilar must demonstrate,
through clinical studies, that it has no significant
clinical differences with the reference product.
Biosimilar manufacturers must provide all of
the pre-clinical and clinical data required to
demonstrate the similarity of their product with
the reference product, without the need to repeat
unnecessary tests and trials.
The EMEA assesses the level of data required for a
biosimilar marketing authorisation application on a
case-by-case basis, but the level of data required is
still less than for an original biological.
15

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
A biosimilar manufacturer must undertake
pre-clinical and clinical studies in order to submit
relevant data that establishes the quality, safety and
efficacy of the product, as well as its similarity with the
reference product. The biosimilar must demonstrate
the similarity of its active substance in molecular
and biological terms, to the active substance in
the reference product. In addition, the biosimilar’s
similarity with the reference product should extend
to the pharmaceutical form, strength and route
of administration. The data required can include
pre-clinical data from in-vitro and in-vivo (animal)
testing and data generated by clinical trials in healthy
individuals and the target patient population.
When the reference product has more than one
therapeutic indication, i.e. treats more than one
disease,“the efficacy and safety of the biosimilar
medicine may also have to be assessed using
specific tests or studies for each disease”. xiii
Under certain circumstances, the EMEA allows
extrapolation of indication, i.e. a biosimilar that
has demonstrated comparable safety and efficacy
in the “most sensitive” indication can be assumed
to be able to extrapolate that safety and efficacy
to other indications of the reference product.
However, this extrapolation is only allowed if the
indications share the same mode of action and if
it is “appropriately justified by current scientific
knowledge” xiv , without conducting specific clinical
studies for each of those indications.
As with all biopharmaceuticals, the EMEA requires
biosimilar manufacturers to prepare a risk
management programme (RMP), which comprises
a safety specification, a pharmacovigilance plan,
an evaluation of the need for risk minimisation
activities and (if deemed necessary), a plan for risk
minimisation activities. The pre-clinical and clinical
testing required as part of the abridged biosimilar
16
approval procedure may not reveal all possible
immunogenicity.
This means that preparing a marketing
authorisation application for a biosimilar is more
costly and complex than for a generic medicine.
Generic manufacturers do not usually have to carry
out non-clinical (i.e., animal) studies or clinical
trials when requesting authorisation. Instead, they
need only demonstrate the bioequivalence of their
product with the reference product. For (chemical)
generic pharmaceuticals, this is normally done by
showing that the blood levels of the two products
are the same when given to a small number of
healthy volunteers.
2. Outside of Europe
At the time of publication, the European Union
is the only region that has established a specific
approval pathway for biosimilar medicines. The
US congress is still in the process of developing
legislation that would lead to an approval pathway.
The World Health Organisation and numerous
countries around the world such as Argentina,
Canada, Malaysia, Turkey and Saudi Arabia have
produced draft guidelines on biosimilar medicines.
Regulators in Japan and Korea, amongst other
countries, are currently examining the issue of
biosimiliars.

IV - The Market for Biosimilars
1. Which biosimilars are currently available in Europe?
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
The following table shows the biosimilar medicines that have been approved by the EMEA xv :
TRADE NAME INN SPONSOR REFERENCE
PRODUCT
DECISION DATE
Omnitrope ® somatropin Sandoz Genotropin Approve 12/04/2006
Valtropin ® somatropin BioPartners Humatrope Approve 24/04/2006
Alpheon ® Interferon alfa-2a BioPartners Roferon-A Reject 28/06/2006
Abseamed ®1 epoetin alfa Medice Eprex Approve 28/082007
Binocrit ®1 epoetin alfa Sandoz Eprex Approve 28/08/2007
epoetin alfa Hexal ®1 epoetin alfa Hexal Eprex Approve 28/08/2007
Retacrit ®2 epoetin alfa Hospira Eprex Approve 18/12/2007
Silapo ®2 epoetin alfa STADA Eprex Approve 18/12/2007
Insulin Rapid Marvel ® , Long Marvel
30/70 Mix Marvel ®
Insulin Marvel Humulin Withdraw 16/01/2008
Ratiograstim ® Filgrastim Ratiopharm Neupogen Approve 16/09/2008
Biograstim ® Filgrastim CT Arzneimittel Neupogen Approve 16/09/2008
Tevagrastim ® Filgrastim Teva Neupogen Approve 16/09/2008
Zarzio ® Filgrastim Sandoz Neupogen Positive opinion 20/11/2008 (MA
expected 01/2009)
Filgrastim Hexal4 ® Filgrastim Hexal Neupogen Positive opinion 20/11/2008 (MA
2. When are the next biosimilars coming onto
the market?
The EMEA’s Committee for Human Medicinal
Products (CHMP) is currently assessing several
applications for biosimilars and it is expected that
these products will be approved during the course
of 2008. The CHMP gave a positive opinion on
three biosimilar versions of filgrastim (reference
product: Amgen’s Neupogen) in February 2008
and a revised opinion in July 2008. These three
biosimilars then received a marketing authorisation
from the European Commission in September 2008.
expected 01/2009)
3. What does the market entry of biosimilars mean
for the original innovator products?
Biosimilar products will compete with originator
biologicals, many of which already compete with
other originator products made by different biotech
companies. However, in many cases, biosimilars
are copies of older biological medicines, for which
second-generation biological medicines are already
available. This means that the biosimilar products will
mainly compete with the older biological medicines,
rather than with the most recent treatments
developed by originator companies, which can offer
increased therapeutic benefit to patients.
1 The EMEA approved three licenses for the same EPO made by Sandoz, with two additional licenses being granted to marketing partners Hexal and Medice Arzneimittel.
2 The EMEA approved two licenses for the same EPO made by Hosp /STADA
3 The EMEA approved three licenses for the same Filgrastim made by Ratiopharm/Teva/CT Artzneimittel
4 The EMEA approved two licenses for the same Filgrastim made by Sandoz/Hexal

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
...physicians
must be
allowed
to exercise
appropriate
clinical
judgement...

V - The Impact of Biosimilars
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
1. What do patients need to know? Patients need and deserve to be fully informed
about any medical treatment they are receiving.
If a physician chooses to prescribe a medicine
to a patient, the patient should be involved in
that decision, understand why that choice has
been made, and what it will mean for his or her
treatment.
Patients may not be completely aware of the
complexities of biologicals, including biosimilars,
and the implications of using them. These
implications include the potential of different
products provoking different immunogenic
reactions in individual patients. It is important
that patients are not obliged to “switch” their
treatment from an originator to a biosimilar purely
on cost grounds, but that the specific therapeutic
needs of the patient are always taken into account.
According to a survey by the International Alliance
of Patients’ Organizations (IAPO), the key concerns
of patients with regard to biosimilars are xvi :
• Cost and the potential to increase access to
biological treatments
• Safety and efficacy
• Patient information and decision-making
• Regulatory process
• Interchangeability
For these reasons it is very important that the label
and other product information relating to the
biosimilar reflect the specific characteristics (clinical
data, reference product, switching advice etc) of
the biosimilar in question.
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E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
2. What do healthcare professionals need to know? Healthcare professionals need to understand the
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EMEA approval process for biosimilars, in particular
the abridged clinical data requirements, which can
allow the extrapolation of indication for biosimilars
in certain circumstances.
Furthermore, in relation to interchangeability and
substitution, healthcare professionals should be
aware that the two different products may provoke
different immune reactions in different patients.
Physicians should not feel obliged to prescribe a
certain medication purely on the grounds of cost,
but should be allowed to exercise appropriate
clinical judgement.
For these reasons it is very important that the label
and other product information of the biosimilar
reflect the specific characteristics (clinical data,
reference product, switching advice, etc.) of the
biosimilar in question.

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
3. What do payers need to know? Payers, such as national health systems and health
insurance funds, may be interested in cost-saving
potential. Biological medicines tend to be more
expensive than traditional pharmaceuticals for
a number of reasons. These reasons include the
high costs involved in researching, developing,
producing and marketing biological medicines.
It is important for payers to understand the
cost structure of biological medicines, including
biosimilars, with regard to complex manufacturing
procedures and regulatory requirements, which can
require enhanced post-marketing surveillance.
Evidence so far shows that biosimilars will not
result in the same cost savings that generic
medicines have brought. Due to the fact that
biosimilars have been on the market for a relatively
short period of time, it is not possible to accurately
estimate the average price discount compared to
the originator products. In Germany, the biosimilars
that have been launched so far are available at a
price that is around 25% lower than the originator.
However, it is also true that some biosimilars have
the same price as the originator product.
In addition, it is important that payers understand
that, due to the need to remain prudent in matters
of patient safety, automatic substitution for
biologics should not occur and the choice to use
any biological product should remain in the hands
of the treating physician. The physician must be
allowed to exercise appropriate clinical judgement
to select the best available treatment for the
individual patient. Treatment choice should not be
mandated purely for reasons of cost.
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E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
Glossary of key terms
Adverse event: The occurrence of an undesirable,
unpleasant or life-threatening reaction to a
medicinal product.
Allergy: A disorder of the immune system that
causes reactions such as itching, swollen or
inflamed skin or eyes, runny nose. More extreme
allergic reactions such as anaphylactic shock, which
can be life threatening.
Amino acid: One of several molecules that join
together to form proteins. There are 20 common
amino acids found in proteins.
Antibody (pl: antibodies): Antibodies (also known as
immunoglobulins, abbreviated to Ig) are proteins that
are found in blood or other bodily fluids. Antibodies
are used by the immune system to identify and
neutralize foreign objects, such as bacteria and viruses.
Biological/biotech medicine: A substance made from
a living organism or its products. Biologicals/biotech
medicines may be used to prevent, diagnose, treat
or relieve the symptoms of a disease. For example,
antibodies, interleukins, and vaccines are biologicals.
Biosimilar: A similar but not identical version of an
existing biological made following patent expiry by
a different manufacturer than the producer of the
original product.
Biotechnology: Any technological application
that uses biological systems, living organisms, or
derivatives thereof, to make or modify products or
processes for specific use.
DNA: Deoxyribonucleic acid (DNA) is a nucleic acid
that contains the genetic instructions used in the
development and functioning of all known living
organisms and some viruses.
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Generic (medicine): A copy of an existing (chemical)
medicine, which is bioequivalent to the original
medicine, but is made by a different firm.
Gene therapy: The practice inserting of genes into
an individual’s cells and tissues in order to treat a
disease or correct a generic deficiency.
Genetics: The science of heredity and variation in
living organisms.
Hypersensitivity: The occurrence of undesirable
(damaging, discomfort-producing and sometimes
fatal) reactions produced by the immune system.
Immune system: The collection of mechanisms
within the body that protect against disease by
identifying and killing pathogens and tumour cells.
Immunogenic: The potential to cause immune
reactions.
Indication: A valid reason to use a certain test,
medication, procedure, or surgery, which is often
subject to official (regulatory) approval.
Insulin: A hormone that affects metabolism and
causes the body’s cells to take up glucose (sugar)
from the blood and store it as glycogen in the liver
and muscles.
INN: International non-proprietary name.
In-vitro: In the laboratory (outside the body).
In-vivo: In the body (the opposite of in-vitro).

Marketing authorisation: The permission granted
by a regulatory authority to a company to market
a medicinal product following the company’s
submission of required documentation and data
relating to testing and clinical trials of the product.
Medical biotechnology: The production of safe
and effective versions of biological substances
that occur naturally in the human body, in a
scientifically controlled environment in order to
make medicinal products.
Microbiology: The science of studying micro
organisms or microscopic organisms.
Micro-organism: An organism that is so small it
cannot be seen by the human eye.
Molecule: The smallest particle of a substance that
has all of the physical and chemical properties of
that substance. Molecules are made up of one or
more atoms. If they contain more than one atom,
the atoms can be the same (an oxygen molecule
has two oxygen atoms) or different (a water
molecule has two hydrogen atoms and one oxygen
atom). Biological molecules, such as proteins and
DNA, can be made up of many thousands of atoms.
Molecular: Of a molecule
Nucleic acid: A macromolecule composed of chains
of monomeric nucleotides. In biochemistry these
molecules carry genetic information or form
structures within cells.
Patent: A patent is a set of exclusive rights granted
by a state to an inventor or his assignee for a fixed
period of time in exchange for a disclosure of an
invention.
E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S
Pharmacovigilance: Safety control procedures
which medicines are subject to both before, during
and after their approval by regulatory authorities.
Protein: Large organic compounds made of
amino acids arranged in a linear chain and joined
together by peptide bonds between the carboxyl
and amino groups of adjacent amino acid residues.
Recombinant: In genetics, recombinant means
DNA, proteins, cells, or organisms that are made
by combining genetic material from two different
sources. Recombinant substances are made in the
laboratory and are being studied in the treatment
of cancer and for many other uses.
Reference product: The original product on which a
biosimilar or generic drug bases its application for
marketing approval.
RNA: Ribonucleic acid is a nucleic acid which is
central to the synthesis of proteins.
Vaccine: A biological preparation which is used
to establish or improve immunity to a particular
disease.
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Further information
• EMEA working group on biosimilars:
http://www.emea.europa.eu/htms/general/contacts/CHMP/CHMP_BMWP.html
• EMEA guidelines on biosimilar medicines:
http://www.emea.europa.eu/pdfs/human/biosimilar/043704en.pdf (overarching guideline on biosimilars)
http://www.emea.europa.eu/pdfs/human/biosimilar/17073408en.pdf (Erythropoietin products)
• IAPO view on biosimilars:
http://www.patientsorganizations.org/showarticle.pl?id=767
• Wikipedia entry on biosimilars:
http://en.wikipedia.org/wiki/Biosimilars
References
i PhRMA Report, 14 August 2006
ii Adapted from Convention on Biological Diversity (1992)
iii Add PhRMA reference.
iv European Commission proposals to revise EudraLex Volume 9A. For more details please see:
http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/docs/doc2008/2008_03/pc_vol9_03-2008.pdf
v http://ec.europa.eu/enterprise/pharmaceuticals/pharmacovigilance/docs/public-consultation_12-2007.pdf
vi EMEA “Guideline on Risk Management Systems for Medicinal Products for Human Use”
vii US, Orange Book
viii “In case the originally authorized medicinal product has more than one indication, the efficacy and safety of the medicinal
product claimed to be similar has to be justified or, if necessary, demonstrated separately for each of the claimed indications”
(part II, 4 of Directive 2003/63/EC).
ix “Where a biological medicinal product which is similar to a reference medicinal product does not meet the condition in
the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in
manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of
appropriate pre-clinical tests or clinical trials relating to these conditions must be provided” (article 10 of Directive 2004/27/EC).
x For guidelines on biosimilars see: http://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm
xi EMEA “Guideline on Similar Biological Medicinal Products” (CHMP/437/04)
xii EMEA’s “Questions and Answers on biosimilars (similar biological medicinal products)”
xiii EMEA’s “Questions and Answers on biosimilars (similar biological medicinal products)”
xiv “Guidance on Biosimilar Medicinal Products Containing Erythropoietins”; EMEA/CHMP/94526/2005
xvi See: http://www.patientsorganizations.org/
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