TM

Biological
Medicines
TM

EuropaBio is the voice of the European biotech Industry.

It represents the interests of the industry towards the European
institutions so that legislation encourages and enables biotechnology
companies in Europe to innovate and provide for our societys
unmet needs.
The European Association for BioIndustries was created in 1996
and represents 62 corporate and 7 associate members operating
worldwide, 2 Bioregions and 19 national biotechnology associations
representing some 1800 small and medium sized enterprises.
Our corporate members are involved in a wide range of activities:
human and animal healthcare, diagnostics, bio-informatics, chemicals,
biofuels, crop production, agriculture, food and environmental
products and services.

Avenue de lArme, 6
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Tel: +32 2 735 03 13
www.europabio.org
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EuropaBio also welcomes associate members such as international

commercial, financial asset management and other service providing
companies, regional biotechnology development organisations
and scientific institutes. The common denominator among all our
members is the use of biotechnology at any stage of research,
development or manufacturing.

A Focus on
Biosimilar
Medicines

EXECUTIVE SUMMARY
Biotechnology has enabled
the discovery of treatments
for a variety of serious diseases.
Worldwide, over 350 million patients have benefited from approved
medicines manufactured through biotechnology. Currently, over 650
new biological medicines and vaccines are be developed to treat
more than 100 diseases. As the exclusive rights for these biological
medicines expire, similar biological medicines, or biosimilars, are
being developed, with some already available on European markets.
Biological medicines are
comprised of proteins and
other substances that are
often naturally produced in
the human body. In healthcare,
biotechnology is being used in
three primary areas: therapeutic
medicines, vaccines and
diagnostics. When compared to
chemical medicines, biological
medicines are generally more
complex and usually much larger
in size than chemical medicines.
The complexity is predominantly
due to the manufacturing
process for biological medicine,
as they are developed in living
system the exact characteristics
and properties are highly
dependent on the manufacturing
process. Chemical medicines
can be approved either by
national medicines authorities or
by the centralised procedure
carried out by the European
Medicines Agency (EMA),
however all biological medicines
products must follow the
centralised procedure
for approval.
Due to the composition and
large molecule size of biological
medicines, they have the inherent
potential to induce (unwanted)

immune reactions. Therefore,

in order to identify unwanted
immune reactions, and for
post regulatory approval
commitments, treating
physicians should state the
brand name and batch
number, as opposed to the
International Non-Proprietary
Name (INN) when prescribing.
Furthermore, due to the unique
nature of biosimilars, there
should not be automatic
substitution of the reference
product, this decision should
be left with the treating
physician.
Generics and Biosimilars have
an important role to play in
fostering competition in the
market place, and thereby
contributing to the sustainability
of healthcare budgets. However,
as the research and development
costs of biosimilars are much
higher than generics, suitable
pricing and reimbursement
environments are needed to
foster the development of
new products. Furthermore,
adequate intellectual property
protection is vital to ensure
that companies are able to fund
research and development

of biological medicines, and

therefore develop and produce
more potential treatments.
Upon expiry of such protection,
biosimilar products (unlike
chemical generics these are
not exact copies, as they are
made in living systems the exact
characteristics are dependent
upon the manufacturing process)
can enter the market to compete
with the original reference
product.
So far the European Union has
approved 7 biosimilars, across
3 product classes. In the United
States, the Biologics Price
Competition and Innovation
Act, signed into law in March
2010, created a statutory
framework for the approval
of biosimilars by the Food and
Drug Administration (FDA).
Over the last two years, the
biosimilar market shares have
steadily increased in most
countries. In several European
countries, biosimilars now have
a higher volume market share
than the reference product,
and this trend appears to be
accelerating.

Biological
Medicines
A Focus on
Biosimilar
Medicines

Biological Medicines
A Focus on Biosimilar Medicines

TABLE OF CONTENTS

INTRODUCTION

02 INTRODUCTION

Biotechnology has enabled the discovery

of treatments for a variety of serious
diseases. Worldwide, more than 350
million patients have already benefited
from approved medicines manufactured
through biotechnology.

03 HEALTHCARE BIOTECHNOLOGY: INTRODUCTION TO THE SCIENCE

03 What are biological medicines and how do they work?
03 How do biological medicines differ from chemical medicines?
Key differentiating factors.
03 How are biological medicines manufactured?
05 Intellectual property for biotech medicines
06 BIOLOGICAL MEDICINES CURRENT ISSUES
06 Naming, Pharmacovigilance and Risk Management Plans
07 Interchangeability
07 Substitution
08 Impact on healthcare budget and pricing
08 The regulation of biologicals in Europe, including biosimilars
09 THE MARKET FOR BIOSIMILARS
09 Which biosimilars are currently available in Europe?
09 What about the rest of the world?
09 What does the entry of biosimilars in the market mean to originator products?
10 THE POTENTIAL IMPACT OF BIOSIMILARS
10 For patients
10 For healthcare professionals
10 For payers
11 GLOSSARY OF KEY TERMS

12 REFERENCES

These medicines help treat or prevent many rare

and severe diseases including cancers, heart attacks,
stroke, multiple sclerosis, diabetes, rheumatoid
arthritis and autoimmune diseases. In addition,
over 650 new biological medicines and vaccines
are currently being developed to treat more
than 100 diseases 1.
As the exclusive rights (patents and other data
protection) for certain biological medicines expire,
similar biological medicines, or "biosimilars", are
being developed. Several biosimilars are already
available on European markets. This document
is intended to explain the complexities and
specificities of biological medicines, including
biosimilar medicines.

Biological medicines are

comprised of proteins and
other substances that are
often naturally produced
in the human body.

1. "Engaging with the global monoclonal antibody

and biologicals markets" Jean-Claude Muller;
Special Advisor, Innovation and International
Relationships; Formerly Senior Vice President,
R&D Prospective and Strategic Initiatives;
Sanofi-Aventis

01

02

Biological Medicines
A Focus on Biosimilar Medicines

HEALTHCARE BIOTECHNOLOGY:
INTRODUCTION TO THE SCIENCE

Biological medicines are

comprised of proteins (such
as growth hormone, insulin,
erythropoietin, enzymes,
and antibodies) and other
substances that are often
naturally produced in the human
body. Biotechnology uses the
great potential in living systems
(plant or animal cells, bacteria,
viruses and yeasts) and modern
technologies to produce biological medicines to treat diseases
and genetic disorders in humans.
Biotechnology in healthcare is
currently being used in three

primary areas: therapeutic

medicines (also including
advanced therapies such as cell
and gene therapy), vaccines
and diagnostics. In this brochure,
we use the term biological
medicine or biotech medicine
as a synonym for therapeutic
proteins and monoclonal
antibodies.

How are biological

medicines manufactured?
Manufacturing biological
medicines is more complex
than the production of chemical
pharmaceuticals. There are a
number of reasons for this,
including the nature of the
starting material and

How do biological medicines differ from

chemical medicines? Key differentiating factors.
Biological medicines are
generally more complex and
usually much larger in size than
chemical medicines, which are
produced by chemical synthesis.
As biological medicines are made
in living systems, their exact
characteristics and properties
are highly dependent on the
manufacturing process.
Therefore, manufacturing and
precise characterisation tends
to be more difficult when
compared to chemical medicines,
the ingredients of which are
more easily identifiable and
can be exactly reproduced.

Biological medicines may have higher variability.

As biological medicines are produced by living systems, such as cell lines, they
may show a higher variability in their structure and characteristics than traditional
pharmaceuticals produced by chemical synthesis, unless processes are carefully
controlled. This variability is highly dependent on the master cell line selected
and used by each manufacturer, as well as materials and manufacturing conditions
used throughout the production process.

Biological medicines are more complex.

Because biological medicines are generally far more complex than chemical
pharmaceuticals, modifications to their manufacturing process need to be
evaluated carefully, to ensure the drug's efficacy and tolerability are not
compromised. Furthermore, the complexity of biological medicines makes their
analytical characterisation more challenging than that of small molecules
(chemically synthesised). Small changes in the manufacturing processes of
biological medicines can lead to major changes in the products, as these changes
could alter their tri-dimensional structure and their safety and efficacy profile.

Biological medicines have the potential to provoke immune reactions.

Biological medicines have the potential to be recognised by the body as
foreign and therefore have the inherent potential to induce (unwanted)
immune reactions, due to their composition and large molecular size. Chemical
medicines, on the other hand, are usually too small to be recognised by the
immune system and are of a different composition.
The potential to induce an immune reaction in the body (immunogenicity) is a
double-edged sword for biological medicines. Vaccines specifically exploit their
immunogenic potential by provoking an immune response that recognises and
"fights off" an "invader" substance. However, for some medicines based on
03

the very high level of

precision required.
Most biological medicines
are made using a geneticallymodified cell construct or cell
line. Each biotech company
has its own master cell bank
producing unique cell lines
replicated for manufacturing
and develops its own proprietary
(unique) manufacturing processes.
The production of biological
medicines involves processes
such as fermentation and
purification. Even very minor
variations to these manufacturing
processes, for example in
temperature, can result in

significant changes in the

physical and clinical properties
of the biological medicine
produced. It is therefore vital
to control precisely the
manufacturing processes
and the environment inside a
production facility, to obtain
consistent results and to
guarantee the safety and
efficacy of the end product.
Production also requires a high
level of monitoring and quality
testing: typically around 250
in-process tests are conducted
for a biological medicine,
compared to around 50 tests for
a traditional chemical medicine.

proteins, stimulating an immune response is regarded as undesirable (with the

notable exception of vaccines where this immune response is the expected effect).

the complexity of
biological medicines
makes their analytical
characterisation more
challenging than that
of small molecules.

What are biological

medicines and how
do they work?

Most of the immune responses that occur are mild and do not have negative
effects on the patient. However in rare cases, unwanted immune reactions can
lead to severe and detrimental effects on the health of a patient. One example is
the appearance of so-called "neutralising" antibodies that can make the therapeutic
protein in the medicine ineffective. Neutralising antibodies can be of particular
concern for biological medicines that resemble the patient's own proteins (to
replace insufficient substance levels in the patient), as they can trigger the body
to fight off the protein injected in the medicinal product and, in rare cases, any
remaining protein produced by the patient's own body. This immunogenic reaction
can take years to develop and can happen at any time during treatment (after
short-, medium and long-term use). This reaction can persist for years after the
biological medicine has stopped being administered to the patient. Therefore,
immunogenicity assessment through clinical studies plays a major role in the
development of biological medicines.

Biological medicines are typically administered via injections or infusions.

A molecule of a biological medicine is typically a protein made of one or several
chains of several hundred amino acids within a complex three-dimensional
structure. Because proteins are digested when taken orally, typically biological
medicines must be administered by injection. Medicines based on small molecules
(traditional pharmaceuticals) usually come in tablet or capsule form.

Biological medicines usually need special transport and storage conditions.

Biological material generally degrades quickly when handled inappropriately,
particularly if they are subject to high temperature. Therefore, biological medicines
usually need to be stored in a refrigerator and should only be handled under
specific conditions.

04

Biological Medicines
A Focus on Biosimilar Medicines

BIOLOGICAL MEDICINES CURRENT ISSUES

Naming,Pharmacovigilance
and Risk Management Plans

Biological medicines
made by unrelated
manufacturers after
the expiry of intellectual
property protection are
not exact copies of
the original biological
medicines.

Each active ingredient in a

medicine has an International
Non-proprietary Name (INN
for example acetylsalicylic
acid is the INN of the active
ingredient in aspirin) as well
as a brand name.

Intellectual property for

biotech medicines
Innovative medicines benefit
from a certain period of
intellectual property protection,
via patents and other exclusive
rights, such as data protection.
Patent rights give the patent
holder (often, but not always,
the manufacturer) the right
to prevent others from
manufacturing, selling, using
and importing the product
during a limited period of time.
A patent also grants the right
to prevent others from using a
specific process, or selling a
product made by that process,
during a limited period of time.
Patents benefit both companies
and society at large, as they
enable important scientific
information to be made publicly
available, which might otherwise
remain hidden. Patents also make
investments in biotechnology

R&D more attractive, which in

turn leads to more innovation,
and therefore more potential
treatments.
Data exclusivity grants a
period of time after Marketing
Authorisation, during which
competitors are not allowed to
enter the market with a followon product (i.e. generic or biosimilar). The follow-on product
generally uses an abbreviated
regulatory approval procedure.
Intellectual property protection
is vital 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.
As such, the provision of an
adequate intellectual property
protection system is critical to
ensure a steady stream of new
medical advances, to great
public benefit.

Small molecule medicines,

produced by chemical synthesis,
can generally be replicated fairly
easily by unrelated manufacturers
after the expiry of intellectual
property protection. Such copies
of the original chemical medicines
are called "generics". In contrast,
biological medicines made by
unrelated manufacturers after the
expiry of intellectual property
protection are not exact copies of
the original biological medicines
because they are made in
living systems and their exact
characteristics and properties
are highly dependent on the
manufacturing process. These
new versions of biological
medicines are called "similar
biological medicinal products"
or "biosimilars". In both cases,
the originator product is called
the "reference product".

In the case of biological, INN can

be either identical or different
for similar products made by
different manufacturers.
For instance, the INN for
recombinant growth hormone,
is the same (somatropin) for all
growth hormones made by
different originators or biosimilar
companies. By contrast, the
INN for recombinant human
erythropoietin is different for
different originator products
(epoetin alpha, beta or theta)
and can be identical or different
for biosimilar products (epoetin
alpha or zeta).
European Medicine Agency
(EMA) guidance indicates
standard reporting of brand
name, manufacturers name and
batch number for all adverse
events caused by biological
medicines. Therefore, biological
medicines should only be
prescribed by their brand name,

and not by their INN, which

identifies medicines by
their active pharmaceutical
ingredients. Despite the fact
that it may be possible for active
ingredients in different biological
medicines to share the same
INN, patients may experience
different immunogenic reactions
with different products.
Additionally, not all biological
medicinal products have the
same indications, administration
schedules, administration
systems or side effect profiles.
The need for correct and precise
identification is strengthened
by the need to have robust
pharmacovigilance carried out
after marketing authorisation.
Due to the variability of
biologicals, the correct product
identification in case of adverse
events is important.
Biosimilars may be approved
by regulatory authorities on
the basis of demonstrated
comparability to the reference
product, a limited clinical
database and often data on the
main indication only. Holders
of marketing authorisations for
biological medicines, reference
products as well as biosimilars,
may have post-approval
commitments defined in risk

management plans, to
characterise safety profiles more
fully, to establish long-term safety.
As already discussed, biologicals
have the inherent potential to
induce (unwanted) immune
reactions. Immune reactions may
take years to develop, therefore
biologicals are usually treated
differently to chemical medicines
by regulatory authorities. Whilst
much is now known about the
features of biological medicinal
products that cause immune
reactions (for example high
content of host cell proteins and
certain routes of administration),
it is not currently possible to
accurately predict immunogenicity in humans. Immunogenicity
is however assessed through nonclinical assessment in animals,
and in humans within the scope
of clinical trials and thorough
post-marketing surveillance.
At the time of approval (for
both originator and biosimilar
biologicals), information on the
safety of the medicinal product
is relatively limited for several
reasons, including a limited
number of patients in clinical
trials, limited time of exposure
to the medication and, usually,
a rather strictly defined patient
population.

The specific characteristics of biologicals are taken into account

by the European legislator and regulator:
1. The updated European legislation on pharmacovigilance, due to be implemented
mid-2012, establishes that Member States must make sure that all appropriate
measures are taken to identify when biological medicinal products are prescribed,
dispensed, or sold in their territory which is the subject of a suspected adverse
reaction report, with due regard to the name of medicinal product () and the
batch number.
2. All biological medicines, originator and biosimilar products, need to have a
"Risk Management Plan" in place. 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". Assessment of the immunogenicity is
a key measure in the Risk Management Plan of any biological medicine.

05

06

Biological Medicines
A Focus on Biosimilar Medicines

Interchangeability
Interchangeability of medicinal
products refers to the situation
where one product can be
interchanged for another
equivalent product in a clinical
setting, without the risk of a
negative health outcome.
In order to gain a marketing
authorisation in Europe, biosimilar
applicants need to demonstrate
similarity to the reference
product. Assessments of
interchangeability and
substitutability are not part
of the scientific evaluation by
the European Medicines Agency
(EMA) and therefore, no
conclusion on interchangeability
or automatic substitution can be
made based on the grant of a
market authorisation. Decisions
on automatic substitution lie
within the responsibility of the
Member States. Unless products
are designated as substitutable
(see below), the decision as to
which product should be used
and whether treatment should
or could be changed to another
product lies with the treating
physician.

Substitution
Automatic substitution (or
generic substitution) is when a
pharmacist substitutes a generic
medicine for the brand name
version of the same active
ingredient, with no obligation
to inform the treating physician.
Some countries make generic
substitution mandatory under
certain conditions, for example
where the doctor prescribes
by INN.
Generic substitution is often
linked to reimbursement, as
some health insurance schemes
will only reimburse the patient
for the cost of the generic
version of a product. The result
07

of this can be that a patient who

refuses the generic version and
insists on the original product
may be liable to pay the difference in cost. Generic versions
of chemical pharmaceuticals
that have demonstrated their
bioequivalence may generally
be substituted with no risk
to patient safety.
However, the EMA 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".
The physicians involvement is
particularly relevant, as not
all biological medicines will
necessarily have the same
indications, administration
schedules, administration
devices or side effect profiles.
Furthermore, if automatic
substitution were to take place,
it could confound pharmacovigilance when adverse reactions
occur, especially immune reactions, as it is more difficult to
evaluate which product is
responsible for the reaction if
the product has been repeatedly
switched during treatment.
A number of countries have
either established legislative
measures to prohibit the
automatic substitution of
biological medicines or have
given regulatory advice on the
use of biologics (including
prescription by brand names).
Based on the above, countries
that currently allow automatic
substitution of biologicals should
take the necessary measures to
stop this practice in the absence
of data that demonstrate interchangeability. Therefore, any
change of treatment with a

biological medicine should

currently only be made under
close medical supervision by
the physician, with the patients
consent.

Impact on Healthcare
Budget and Pricing
Generics and biosimilars have an
important role to play to foster
competition in the marketplace,
contributing thereby to the sustainability of healthcare budgets.

50 to 170 million) 2 - are much

higher than those for a generic.
The exact price level of a
biosimilar will depend on a
number of factors, namely the
pricing and reimbursement
environment of each country,
competitiveness of the market
and the desire to encourage
the future development of
new products.
Currently the number of
biosimilars is low partly because
only a few biological medicines
have lost their market exclusivity.
Potential savings, due to their
lower list prices, are therefore
limited as the products compete
in market segments that only
represent a small portion of total
healthcare expenditure.

The regulation of
biological in Europe,
including biosimilars
Depending on the disease
category, chemical medicines
can be approved either by the
national medicines authorities

Price reductions for biosimilars

are generally not as those for
generic medicines for a number
of reasons. Firstly, biological
medicines, including biosimilars,
are generally more complex and
costly to produce and develop.
Secondly, the regulatory approval
requirements and post-marketing
surveillance for biosimilars are
more rigorous than for generic
medicines, thus adding a further
layer of cost to developing a
biosimilar (e.g. unlike generics,
biosimilars usually require
independent non-clinical and
clinical trials to be undertaken).
Therefore, R&D costs required
for the approval of a biosimilar ranging on average from USD
75 to USD 250 (approximately

of the individual EU Member

States or by the "centralised
procedure" for approval carried
out by the European Medicines
Agency (EMA). In contrast,
all new biological medicinal
products, including biosimilars,
have to follow the centralised
procedure.
Applications submitted to the
EMA 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 EMA, the
European Commission issues a
marketing authorisation, which is
valid for all EU Member States.
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 and
2004/27/EC created the
legislative route and the EMA
has subsequently developed a
number of regulatory guidelines

concerning the data required for

the approval of a biosimilar.
Besides the "overarching"
general guidelines on biosimilars,
the EMA has also developed
guidelines on quality, non-clinical
and clinical issues, as well as
product-specific guidelines
annexes (for example insulin,
epoetin, somatropin, granulocytestimulating growth factor,
interferon-alfa and low-molecular
weight heparin). At the time of
publication of this document,
further guidelines are being
prepared, including guidelines
on follicle stimulation hormone,
interferon-beta and monoclonal
antibodies.
The EMA's "overarching"
guidelines on biosimilars
specifically state that biosimilar
products are "by definition"
not generics, and that the
generic approach to approval
"is scientifically not appropriate"
for biosimilars.
2. Industry average source: Sandoz internal
estimates. Conversion in done in July 2011

The EMA defines biosimilars in "Questions and Answers on biosimilar medicines" as:

"A biosimilar medicine is a medicine which is similar to a biological medicine that has
already been authorised (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."
Furthermore, the EMA Questions and Answers document 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 the manufacturer to demonstrate similarity with the reference
product for quality, safety and efficacy. Specifically, the biosimilar must demonstrate that it
has no significant clinical differences to the reference product. Biosimilar manufacturers must
provide all of the non-clinical, pre-clinical and clinical data required to demonstrate the
similarity of their product to the reference product, without the need to repeat unnecessary
tests and trials.

08

Biological Medicines
A Focus on Biosimilar Medicines

THE MARKET FOR BIOSIMILARS

THE POTENTIAL IMPACT OF BIOSIMILARS

Which biosimilars are currently available in Europe?

For patients

So far, the European Union has approved 7 biosimilars, across 3 product classes: human growth hormones,
erythropoietins and granulocyte colony stimulating factors.

Patients need and deserve to be

fully informed about any medical
treatment that they are receiving.
If a physician chooses to prescribe
a medicine to a patient, the
patient should be involved in
that decision, meaning that the
patient understands why the
choice has been made as well

Active
substance

Abseamed
Binocrit
Biograstim

epoetin alfa
epoetin alfa
filgrastim

Epoetin alfa Hexal

Filgrastim Hexal

epoetin alfa
filgrastim

Filgrastim
ratiopharm
Nivestim

filgrastim

Omnitrope

somatropin

Ratiograstim

filgrastim

Retacrit

epoetin zeta

Silapo

epoetin zeta

Tevagrastim

filgrastim

Valtropin
Zarzio

somatropin
filgrastim

filgrastim

Therapeutic area
Kidney Failure, Chronic Anemia Cancer
Kidney Failure, Chronic Anemia
Hematopoietic Stem Cell Transplantation
Neutropenia Cancer
Kidney Failure, Chronic Anemia Cancer
Neutropenia Cancer Hematopoietic Stem
Cell Transplantation
Neutropenia Hematopoietic Stem Cell
Transplantation Cancer
Hematopoietic Stem Cell Transplantation
Cancer Neutropenia
Turner Syndrome Dwarfism, Pituitary PraderWilli Syndrome
Neutropenia Cancer Hematopoietic Stem
Cell Transplantation
Cancer Anemia Kidney Failure, Chronic
Blood Transfusion, Autologous
Anemia Blood Transfusion, Autologous
Cancer Kidney Failure, Chronic
Neutropenia Cancer Hematopoietic Stem
Cell Transplantation
Dwarfism, Pituitary Turner Syndrome
Cancer Hematopoietic Stem Cell
Transplantation Neutropenia

Date of
authorisation

Status

28/08/2007
28/08/2007
15/09/2008

Authorised
Authorised
Authorised

28/08/2007
06/02/2009

Authorised
Authorised

15/09/2008

Authorised

08/06/2010

Authorised

12/04/2006

Authorised

15/09/2008

Authorised

18/12/2007

Authorised

18/12/2007

Authorised

15/09/2008

Authorised

24/04/2006
06/02/2009

Authorised
Authorised

Source: European Medicines Agency (June 2011)

What about the rest

of the world?
In the United States, the
Biologics Price Competition and
Innovation Act, signed into law in
March 2010, created a statutory
framework for the approval of
biosimilars by the Food and Drug
Administration (FDA). Almost all
guidelines that have either been
passed or are being discussed in
other parts of the world (for
example Australia, Japan, Korea,
Malaysia, Mexico, Switzerland,
South Africa, Taiwan and Turkey)
largely correspond to the
European body of regulations for
biosimilars. Lastly, the World
Health Organisations guideline
for biosimilars fundamentally
follows the EU principles and is
meant to serve as a basis for
countries to develop their own
biosimilar legislation.
09

What does the entry of

biosimilars in the market
mean to originator
products?
Market success for all medicines,
including biological medicines
and biosimilars, in the EU
depends upon a number of
factors, including pricing and
reimbursement and physician
and patient expectations.
Biosimilar products compete
with originator biologicals, which
already compete with other
originator products made by
different biopharmaceutical
companies. Experience so far
indicates that biosimilar uptake
varies by product class and
country. Naturally, biosimilars
are versions of older biological
medicines that have lost IP
protection. Continued innovation

has often led to secondgeneration biological medicines

providing increased therapeutic
benefits to patients. This means
that the biosimilar products
mainly compete with older
biological medicines, with which
they are comparable, rather than
with the most recent innovative
treatments.
Over the last 2 years, the
biosimilar market shares have
steadily increased in most
countries. In several European
countries, biosimilars now have a
higher volume market share than
the reference products, and this
trend appears to be accelerating.

Cost and the potential to

increase access to biological
treatments;
Safety and efficacy;
Patient information and
decision-making;
Regulatory process; and
Interchangeability.
Therefore, it is very important
that the label and other product
information relating to the
biosimilar reflect the specific
characteristics (such as
reference product, potential
side effects etc).

For healthcare
professionals

the specific
therapeutic needs
of the patient must
always be taken
into account.

Name

According to a survey by the

International Alliance of Patients'
Organizations (IAPO), the key
interests of patients with regards
to biosimilars are:

as 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. This includes the potential
of different products to provoke
different immunogenic reactions
in the patient. It is important
that patients are not obliged to
"switch" their treatment from
one biological to another purely
on cost grounds, the specific
therapeutic needs of the patient
must always be taken into
account.

Healthcare professionals need

to understand the EMA approval
process for biosimilars and be
aware of the scientific data
underlying their approval (in
particular the abridged clinical
data requirements, which can
allow the extrapolation of
indications).
For physicians too, it is very
important that the label and
other product information
relating to the biosimilar reflect
the specific characteristics (such
as reference product, potential
side effects, etc). The summary
of product information on
biosimilars should also list the
available data in order to
show which applications were
substantiated by studies and
which were derived from the
biological medicine of the
original manufacturer without
separate data via extrapolation.
Furthermore, healthcare
professionals must be aware that
the interchangeability between
the biosimilar and its reference

product has not been evaluated

by the regulatory authority.
Physicians should not be obliged
to prescribe a certain medication
purely on the grounds of cost, but
should be allowed to exercise
appropriate clinical judgment.
With regards to patients, it is
very important for healthcare
professionals that the label and
other product information of
the biosimilar reflect its specific
characteristics (clinical data,
reference product, etc.).

For payers
Payers, such as national health
systems and health insurance
funds, are interested in the costsaving potential of biosimilars.
Biological medicines have
brought great benefit to patients,
often treating so far untreatable
or insufficiently treatable, severe
diseases. Biosimilars offer opportunities for savings upon loss of
IP protection for the originator
products. Biosimilars have
brought enhanced competition
to prices of biological medicines,
which in turn have resulted in
significant price decreases in the
majority of markets. It is important however that physicians and
patients retain the flexibility to
make informed decisions about
the different treatment options.
It is important that payers
understand that, due to the
precautionary principle,
automatic substitution for
biologics should not occur and
the choice to use any biological
product should remain in the
hands of the treating physician.
Any future decisions need to be
based on appropriate data. The
physician must be allowed to
exercise appropriate clinical
judgment to select the best available treatment for the individual
patient, and such choices should
never be mandated purely on
the basis of product prices.
10

Biological Medicines
A Focus on Biosimilar Medicines

GLOSSARY OF KEY TERMS

Advanced therapies: New and
emerging therapies, including cell,
gene and tissue therapies

medicine made following the patent

expiry of the original product (must be
made by a different manufacturer)

Adverse event: The occurrence of

an undesirable, unpleasant or lifethreatening reaction to a medicinal
product

Biotechnology: Any technological

application that uses biological systems,
living organisms, or derivatives thereof,
to make or modify products or
processes for specific use

Amino acid: Building block of

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 neutralise foreign
objects, such as bacteria and viruses
Autoimmune disease: A disease
caused by the body producing an
excessive immune response against
its own tissues. Thereby, the immune
system ceases to recognise one or
more of the body's normal constituents
as "self" and will create auto-antibodies
that attack its own cells, tissues,
and/or organs. Inflammation and tissue
damage are common symptoms of
autoimmune diseases
Automatic substitution: The practice
by which a product other than the
one specified on the prescription is
dispensed to the patient, without the
prior informed consent of the treating
physician. A variation of substitution is
practiced in some countries, where, if
the physician prescribes by International
Non-proprietary Name (INN), the
pharmacist may decide to dispense any
product with the same active ingredient
Biological/biotech medicine:
A medicinal product or a vaccine that
consists of, or has been produced by
the use of, living organisms. Often
recombinant DNA (a form of DNA that
does not exist naturally and which
combines DNA sequences that would
not normally occur together in order
to establish new functions) forms
the basis for biotechnologically
manufactured products. Examples
include therapeutic proteins such as
antibodies, insulins or interleukins; but
also vaccines, nucleic acid or tissues
and cells. For the purpose of this
document, the term biological/biotech
medicine refers to therapeutic proteins
Biosimilar: A similar, but not identical,
version of an existing biological

11

Cell line (including master cell line):

A well-established, living system of
cultured (grown in a laboratory) cells
that will continue to grow and produce
new cells indefinitely, so long as the
cells receive nourishment and have
space to propagate
Extrapolation: Extending the findings
from one set of conditions to another,
such as extending and applying the
data from clinical studies regarding
one medical condition to another
medical condition or extending data
from clinical studies in adults to children
Generic (medicine): A copy of an
existing (chemical) medicine, which is
bioequivalent to the original medicine,
but which may be made by a different
firm after patent expiry of the originator
product
Immune system: The collection of
mechanisms within the body that
protect against disease by identifying
and killing pathogens (e.g. viruses
and bacteria) and tumour cells
Immunogenic: The potential to cause
immune reactions
Indication: The medical condition,
disorder or disease for which a certain
test, medication, procedure, or surgery
is used. Such tests and medications
are often subject to official (regulatory)
approval. Most countries and jurisdictions have a licensing body whose
duty it is to determine whether to
approve a drug for a specific indication,
based on the relative safety of the
drug and its efficacy for the particular
indication (use) being investigated
INN: International Non-proprietary
Name
Interchangeability: Where two
products can be exchanged one with
another without a significant risk of
an adverse health outcome

REFERENCES
the conditions described in the label,
following the company's submission
of required documentation and data
relating to testing and clinical trials of
the product
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,
can be made up of many thousands
of atoms
Molecular: Of a molecule
Nucleic acid: A macromolecule
(i.e. a very large molecule) composed
of chains of monomeric (having a single
component) nucleotides, which are
molecules that, when joined together,
make up the structural units of RNA
and DNA. 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 (national
government) to an inventor or their
assignee for a limited period of time
in exchange for public disclosure of an
invention. Typically, however, a patent
application must include one or more
claims defining the invention which
must be new, non-obvious, and
useful or industrially applicable
Pharmacovigilance: Safety control
procedures to which medicines are
subject before, during and after their
approval by regulatory authorities
Protein: Large organic compounds
made of amino acids. Proteins are
essential parts of organisms and
participate in virtually every process
within cells

Directive 2001/83/EC of the European Parliament and of

the Council of 6 November 2001 on the Community code
relating to medicinal products for human use. Article 10.

Guidelines on Similar biological medicinal product

containing recombinant interferon beta; Mar 2010;
European Medicines Agency

Available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=

CELEX:32001L0083:en:NOT

Brochure - Biosimilar medicinal products; 2001;

European Medicines Agency.
Available at: http://www.ema.europa.eu/docs/en_GB/document_
library/Brochure/2011/03/WC500104228.pdf

Questions and Answers on biosimilar medicines

(similar biological medicinal products); Oct 2008;
European Medicines Agency.
Available at: http://www.ema.europa.eu/docs/en_GB/document_

Concept Paper on Guidelines on Similar biological medicinal

products containing monoclonal antibodies; Nov 2010;
European Medicines Agency
Guidelines on Similar biological medicinal products
containing recombinant Erythropoietins; Sep 2010;
European Medicines Agency
Guidelines on Similar biological medicinal products
containing low-molecular-weight-heparins; Oct 2009;
European Medicines Agency

library/Medicine_QA/2009/12/WC500020062.pdf

All the following European Medicines Agencys

guidelines are available at:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/
special_topics/document_listing/document_listing_000318.jsp
&murl=menus/special_topics/special_topics.jsp&mid=WC0b01
ac0580281bf0
Guidelines on Similar Biological Medicinal Products containing
Biotechnology-Derived Proteins as Active Substance:
Non-Clinical and Clinical Issues; Feb 2006; European
Medicines Agency
Concept paper on the Revision of the guideline on similar
biological medicinal products containing biotechnologyderived proteins as active substance: quality Issues; Feb 2011;
European Medicines Agency
Guidelines on Similar Biological Medicinal Products Containing
Biotechnology-Derived Proteins as Active Substance: Quality
Issues; Feb 2006; European Medicines Agency

Guidelines on Non-clinical and clinical development of

similar medicinal products containing recombinant interferon
alpha; Apr 2009; European Medicines Agency
Guidelines on Evaluation of Similar Biotherapeutic Products
(SBPs); Oct 2009; World Health Organization (WHO).
Available at: http://www.who.int/biologicals/areas/biological_
therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf
CPME Position on Access to Medicines Biosimilars;
Mar 2011; Comit Permanent des Mdecins Europens.
Available at: http://cpme.dyndns.org:591/database/
2011/cpme.2011-027.Position.Biosimilars.pdf

Biosimilar Medicines; International Alliance of Patients

Organizations; May 2006.
Available at: http://www.patientsorganizations.org/
showarticle. pl?id=727;n=37120

Guidelines on Similar Biological Medicinal Product;

Sep 2005; European Medicines Agency
Guidelines on Similar biological medicinal products containing
recombinant follicle stimulation hormone; Mar 2010;
European Medicines Agency

Reference product: The original

product to which a biosimilar or
generic drug refers in its application
for marketing approval
Vaccine: A biological preparation
which is used to establish or improve
immunity to a particular disease

Marketing authorisation: The

permission granted by a regulatory
authority to a company to market a
medicinal product in accordance with

12