bio similar factsheet december 2008
TRANSCRIPT
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EuropaBio&Biosimilar
Medicines
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Contents
Welcome letter rom the Secretary General
o EuropaBio
Healthcare biotechnology and biosimilars
Glossary o key terms
Reerences
Further inormation
Healthcare biotechnology and biosimilars
I - The Science
1. Healthcare biotechnology introduction
2. Why do biological medicines dier rom chemical medicines?
3. How are biological medicines manuactured?
4. Intellectual property or 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 o 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 o biosimilars mean or the original innovator products?
V - The impact of biosimilars
1. What do patients need to know?
2. What do healthcare proessionals need to know?
3. What do payers need to know?
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have accessto more
than 155biotechnologymedicines andvaccines...
...patients
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Biotechnology uses biological systems and living
organisms to make or modiy products or processes
or specic useii. Biotechnology medicines are just
one o the many applications o biotechnology in
healthcare. There are several prominent categorieso biotechnological medicines:
Recombinant proteins can replace insucient
or malunctioning proteins in the human body.
One example o a recombinant protein is insulin,
which is commonly used in the treatment o
diabetes. Other recombinant proteins like
antibodies or vaccines are used in the treatment
or prevention o serious diseases such as cancer.
Nucleic acids like DNA or RNA are used in
gene-therapy treatments to restore or modulate
specic disease-related genes.
Tissues and cells are used or tissue repair ater
severe injuries e.g., skin transplants.
Inactivated orms o 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 or the treatment o bacterial
inections, can be either directly obtained rom
micro-organisms (e.g. penicillin is produced
by a certain type o ungus), or can be urther
modied by chemical processes (e.g. hal-synthetic
antibiotics like ampicillin).
Furthermore, many biotechnological healthcare
products are used widely or diagnostic purposes.
*For the purpose of this document, we use the term biotech medicine or
biological medicine or biopharmaceutical for recombinant protein products.
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I - The Science
1. Healthcare biotechnology introduction
What are biotechnology medicines
and how do they work?
05
*
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The history of healthcare biotechnology
06
Although the modern healthcare biotechnology
industry is only 30 years old, the science o
biotechnology has been explored since the 19th
century when eminent scientists such as Louis
Pasteur and Robert Koch rst developed the
science o microbiology, the orerunner o todays
biotechnology. In 1953, James Watson and FrancisCrick discovered DNA and in 1955, Fred Sanger
determined the amino acid sequence o insulin.
In 1972, Paul Berg created the rst recombinant
DNA molecule. DNA engineering has become the
basis o modern biotechnology as it allows the
re-arrangement (recombination) o so ar
unrelated genetic sequences and the use o those
molecules or the production o recombinant
proteins or medical purposes.
The rst biotech companies were ounded in the
1970s and many more in the early 1980s. Most o
todays healthcare biotech companies began lie
as small start-ups established by a handul o
enthusiastic visionary scientists on a shoe-string
budget. The hard work o the early pioneers has
now come to ruition: today, over 325 million
people have had their lives transormed by
healthcare biotechnology treatments and it is
estimated that by 2010, around 50 percent o
new medicines will be o biological originiii.
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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 o a person; each time
a person (biological) signs something, their
signature will be slightly dierent, whereas a
printed (chemical) signature remains exactly
the same.
2. Biological medicines are more complex.
Proteins consist o one or more chains o
potentially several hundred amino acids with a
complex three-dimensional structure. Their
molecular size is, thereore, bigger than that o
chemical medicines. These large molecules are
diverse and dicult to characterize. In contrast,
the molecular structure o chemical medicines
is relatively simple, which can allow them to beexactly reproduced.
3. Biological medicines have the potential to
provoke immune reactions.
Biological medicines, because o 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
oreign. Small molecule chemical medicines,
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Biological medicines are ar more complex
and usually much bigger in size than chemical
medicines, which are produced by chemical
synthesis. This means that their manuacturing and
precise characterisation tends to be more dicult
than or chemical medicines, the ingredients o
which are more easily identiable and can beexactly reproduced.
2. Why do biological medicines differ from
chemical medicines?
What are the differentiating factors?
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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 o the chemical medicinehave decreased in the body, the negative immune
response will, in most cases, disappear and no
longer harm the patient as long as no urther
exposure to the medicine occurs.
The potential to provoke an immune response in
the body (immunogenicity) is a double-edged sword
or all biological medicines. Vaccines specically
exploit this immunogenic potential by provoking an
immune response that recognizes and ghts o an
invader substance. However, or most medicines
based on recombinant proteins, stimulating an
immune response is regarded as undesirable.
Immune responses are complex reactions o the
body and can dier rom patient to patient (due to
genetic actors), as well as rom disease to disease
(depending on the immune status o the patient).
The likelihood o an immune response can also
be infuenced by characteristics o the biological
product itsel, such as its ormulation, stability and
manuacturing process. The individual manuacturing
process has infuence, or example, on the activesubstance and the quality and quantity o impurities.
Most o the immune responses that occur are mild
and do have negative eects on the patient, e.g.
in the majority o cases where transient antibodies
to a therapeutic protein are ound in the blood. In
rare cases, however, unwanted immune reactions
can have severe, detrimental eects on the health
o a patient, e.g. when so-called neutralizing
antibodies appear and make the therapeutic protein
in the biotech medicine ineective.
With biological medicines that resemble the
patients own proteins and are intended to replace
insucient levels o that substance in the patient,
such neutralizing antibodies can even trigger the
body to ght o what remains o the protein
produced by the patients body. This immunogenic
reaction can persist or years ater the biologicalmedicine has stopped being administered to the
patient. This potential to elicit a sustained immune
response to a patients own protein and block
important biochemical pathways or long periods
o time makes immunogenicity o biological
medicines a particular saety concern.
4. Biological medicines are often administered
via injections.
When taken orally, the digestive system breaks
down proteins (o which biotech medecines
are composed), into their building blocks called
amino acids. This progess would prevent the
protein rom reaching the part o the body it
should treat and exerting its therapeutic
unction. Thereore biotech medicines must
generally be administered by injection and
cannot be taken orally in the shape o 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 specic need.
5. Biological medicines need special transport and
storage conditions.
Biological material is generally subject to ast
degradation when handled inappropriately.
Thereore, biological medicines usually need
to be stored in a rerigerator and should be
handled under specic conditions.
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...biotechmedicines
must generally
be administeredby injection...
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3. How are biological medicines manufactured? Manuacturing biological medicines is generally
more complex than the production o traditional
(chemical) pharmaceuticals. Biological medicines
show a higher batch-to-batch variability than
chemical medicines. There are a number o reasons
or this, including the nature o the starting
material and the very high level o precisionrequired in the manuacturing process.
The starting material or most biological medicines
is a genetically modied cell line. Each biotech
company uses unique cell lines and develops its
own proprietary (unique) manuacturing processes
to produce biological medicines.
The production o biological medicines involves
processes such as ermentation and purication.
Even very small changes to these manuacturing
processes such as minor variations during production
e.g. temperature variations, can result in signicant
changes in the clinical properties o the biological
medicine produced. It is thereore vital to precisely
control the manuacturing processes and the
environment inside a production acility, in order to
obtain consistent results and to guarantee the saety
and ecacy o the end product.
The production o biotechnology medicines
requires a high level o monitoring and quality
testing: typically around 250 in-process tests areconducted or a biological, compared with around
50 tests or a traditional (chemical) medicine.
The unique starting material and the complex
manuacturing processes mean that it is not
possible to exactly reproduce a biological in the
same way a pharmaceutical (chemical) generic can
be produced.
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4. Intellectual property for biotech medicines Innovative medicines generally benet rom a
certain period o intellectual property protection
via patents and other exclusive rights such as data
protection and market exclusivity. Patent rights
give the patent holder (oten, but not always, the
manuacturer), the right to prevent others rom
manuacturing, selling, using and importing aproduct, or using a process or selling a product
made by that process during a limited period o
time, e.g. 20 years rom the date o application.
Data and market exclusivity mean that there is a
period o time ater approval beore a competitor
can enter the market with a ollow-on product that
relies wholly or partly on the originators data on
saety and ecacy or its regulatory approval. The
ollow-on product can oten use an abbreviated
regulatory approval procedure.
Such orms o intellectual property protection
are important or companies that develop and
manuacture new medicines, as it enables them to
recoup their investments and urther invest in the
research and development o new medicines.
Follow-on versions o chemical medicines that enter
the market ater expiry o IP protection are
called generics. Follow-on versions o biological
medicines are called similar biological medicinal
products or biosimilars. In both cases, the
originator product is called the reerence product.
Due to certain special eatures that characterise a
biological medicine, the European Union decided
that the name o ollow-on biological medicines
(biosimilars) and their regulatory approval pathway
had to be dierent rom chemical generics.
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II - Biosimilar medicines - current issues
1. Naming
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 o
the originator. Due to the complexity o biologicalmedicinal products, EuropaBio advocates a
revision o 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
manuacturers name.
In some countries, physicians are obliged or
encouraged to prescribe by INN. In such situations
i two biologicals have the same INN, this could
result in products being considered identical
and thus switched, when there might be no
scientic evidence to support that switch. Such a
switch could have negative clinical consequences
or the patient, as typically the two products
are similar but not identical, and the dierences
between them may have a therapeutic impact.
The European Commissions proposal or improving
the EU pharmacovigilanceiv system stresses the
importance o being able to precisely trace a
biological product. Specically, the Commissionsuggests 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 o biological products including
biosimilars, the Commission has proposed that
Member States ensure that biological medicinal
products that are the subject o adverse reaction
reports be identiable 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 o generic medicines or a number
o reasons. Firstly, biological medicines including
biosimilars are generally more complex andcostly 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
or biosimilars are more rigorous than or
generic medicines, thus adding a urther layer to
the cost o producing a biosimilar.
The exact price level o a biosimilar will depend
on the pricing and reimbursement environment
o each country, the competitiveness o the
market and the desire to encourage the uture
development o 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 o
the major reasons why biologicals are generallytreated dierently to chemical medicines by
regulatory authorities.
While a lot is known today about certain
eatures o biological products that make them
more likely to provoke immune reactions e.g.
high content o host cell proteins and certain
routes o administration, it is currently not
possible to accurately predict immunogenicity in
humans only through non-clinical assessment in
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animals. Thereore, immunogenicity assessment
through clinical studies plays a major role in the
development o biological medicines.
At the time a biosimilar receives market approval, a
lot is already known about the saety and ecacy o
the product class and the reerence product, whichat this point has usually been on the market or
years (or even decades). However, the potential to
provoke immune reactions can dier rom product
to product and rare eects can only be detected and
assessed when large numbers o patients have been
treated with a product. At the time o approval,
inormation on the saety o a medicinal product
is relatively limited or several reasons, such as a
limited number o patients in clinical trials, a limited
time o exposure to the medication and, generally, a
rather strictly dened patient population.
Unlike chemical generics, biosimilars need to have a
Risk Management Plan in place. This acknowledges
the special characteristics o biologicals. As with
other new medicines, this Risk Management Plan
denes a set o pharmacovigilance activities and
interventions designed to identiy, characterise,
prevent or minimise risks relating to medicinal
products, and the assessment o the eectiveness o
these interventions.vi
The potential o biologicals to provoke immunereactions has been the major reason or treating
biosimilars in the same way as new (biological)
products with regard to post-marketing surveillance.
4. Interchangeability
Interchangeability o medicinal products reers to
the situation where one product is switched or
another equivalent product in a clinical setting,
without a risk o an adverse health outcome.
Generic medicines, which are considered
bioequivalent, are regarded as therapeutically
equivalent and thereore, interchangeablevii.
The current state o scientic knowledge means
that, in general, (chemical) generic medicines
can be deemed interchangeable with their
reerence product. Regulatory agencies such asthe European Medicines Agency (EMEA) do not
assess the interchangeability or substitutability o
a biosimilar when granting a positive opinion or
a marketing authorisation application. In other
words, the granting o approval does not mean
that the biosimilar product can be interchanged or
substituted with the reerence product.
Currently, no clinical studies have been designed
or undertaken to assess the clinical outcome
o repeated switches (changes) o 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 or a generic version o the
same drug. Some countries make generic substitution
mandatory under certain conditions, or example
where the doctor prescribes by INN. Generic
substitution is oten linked to reimbursement; orexample, some health insurance schemes will only
reimburse the patient or the cost o the generic
version o a product. The result o this is that a
patient reusing the generic version and insisting on
the original product must pay the dierence in cost.
Generic versions o chemical pharmaceuticals which
have demonstrated their bioequivalence may be
substituted with no risk to patient saety.
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The EMEA has specically stated that since
biosimilars and biological reerence products are
not identical, the decision to treat a patient with a
reerence product or biosimilar medicine should be
taken ollowing the opinion o a qualied health
proessional*. In addition, there is currently no
convincing scientic data to prove that repeatedproduct switching o 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 o public health.
A number o countries such as France, Italy, Spain,
UK, Netherlands, Germany, Sweden, have either
established legislative measures to prohibit the
automatic substitution o biotech medicines or
have given regulatory advice on the use o biologics
(including prescription by brand). The justication
or such measures is that o patient saety.
EuropaBio rmly believes that other countries that
allow automatic substitution o generic medicines
should take the necessary measures to prevent
automatic substitution o biologics.
*http://www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf
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III - The Regulation of Biosimilars
1. In Europe
Chemical medicines can be approved by the national
medicines authorities o individual EU member states.
In contrast, biological products, including biosimilars,
have to ollow the centralized procedure or
approval carried out by the European MedicinesAgency (EMEA). Applications submitted to the EMEA
are assessed by its Committee or Human Medicinal
Products (CHMP), which can give a positive or negative
opinion. Upon receipt o a positive opinion rom the
EMEA, the European Commission issues a marketing
authorisation which is valid or all EU countries.
Since 2003, the European Union has created
a legal and regulatory pathway to enable the
development and marketing o biosimilar
medicines. Directives 2003/63/ECviii and 2004/27/
ECix, created a legislative route and the EMEA has
subsequently developed a number o regulatory
guidelines concerning the required data needed or
approval o a biosimilar. Besides the overarching,
general guideline on biosimilars, the EMEA has
developed guidelines on quality, on non-clinical
and clinical issues, and product-specic annexes
to those on e.g., insulin, epoetin, somatropin and
granulocyte-stimulating growth actor. At the time
o publication o this document, urther guidelines
were close to being nalised, including guidelines
on intereron-ala and low-molecular heparinx
.
EMEAs overarching guideline on biosimilarsxi
specically states that biosimilar products are
by denition not generics, and that the
generic approach to approval is scientically not
appropriate or biosimilars.
In its document Questions and Answers on
biosimilar medicines, the EMEA denes biosimilars
as ollowsxii:
A biosimilar medicine is a medicine which is
similar to a biological medicine that has already
been authorized (the biological reerence
medicine). The active substance o a biosimilar
medicine is similar to the one o the biological
reerence medicine. Biosimilar and biologicalreerence medicines are used in general at
the same dose to treat the same disease. Since
biosimilar and biological reerence medicines
are similar but not identical, the decision to
treat a patient with a reerence or a biosimilar
medicine should be taken ollowing the
opinion o a qualied healthcare proessional.
The name, appearance and packaging o a
biosimilar medicine dier to those o the
biological reerence medicine.
The EMEA Q&A document urther states that
the legislation denes the studies that need
to be carried out to show that the biosimilar
medicine is similar and as sae and eective as the
biological reerence medicine. To this end, the
biosimilar approval pathway requires a biosimilar
manuacturer to demonstrate similarity with the
reerence product or quality, saety and ecacy.
Specically, the biosimilar must demonstrate,
through clinical studies, that it has no signicant
clinical dierences with the reerence product.Biosimilar manuacturers must provide all o
the pre-clinical and clinical data required to
demonstrate the similarity o their product with
the reerence product, without the need to repeat
unnecessary tests and trials.
The EMEA assesses the level o data required or a
biosimilar marketing authorisation application on a
case-by-case basis, but the level o data required is
still less than or an original biological.
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A biosimilar manuacturer must undertake
pre-clinical and clinical studies in order to submit
relevant data that establishes the quality, saety and
ecacy o the product, as well as its similarity with the
reerence product. The biosimilar must demonstrate
the similarity o its active substance in molecular
and biological terms, to the active substance inthe reerence product. In addition, the biosimilars
similarity with the reerence product should extend
to the pharmaceutical orm, strength and route
o administration. The data required can include
pre-clinical data rom in-vitro and in-vivo (animal)
testing and data generated by clinical trials in healthy
individuals and the target patient population.
When the reerence product has more than one
therapeutic indication, i.e. treats more than one
disease,the ecacy and saety o the biosimilar
medicine may also have to be assessed using
specic tests or studies or each disease.xiii
Under certain circumstances, the EMEA allows
extrapolation o indication, i.e. a biosimilar that
has demonstrated comparable saety and ecacy
in the most sensitive indication can be assumed
to be able to extrapolate that saety and ecacy
to other indications o the reerence product.
However, this extrapolation is only allowed i the
indications share the same mode o action and i
it is appropriately justied by current scientic
knowledgexiv
, without conducting specic clinicalstudies or each o those indications.
As with all biopharmaceuticals, the EMEA requires
biosimilar manuacturers to prepare a risk
management programme (RMP), which comprises
a saety specication, a pharmacovigilance plan,
an evaluation o the need or risk minimisation
activities and (i deemed necessary), a plan or risk
minimisation activities. The pre-clinical and clinical
testing required as part o the abridged biosimilar
approval procedure may not reveal all possible
immunogenicity.
This means that preparing a marketing
authorisation application or a biosimilar is more
costly and complex than or a generic medicine.
Generic manuacturers do not usually have to carryout non-clinical (i.e., animal) studies or clinical
trials when requesting authorisation. Instead, they
need only demonstrate the bioequivalence o their
product with the reerence product. For (chemical)
generic pharmaceuticals, this is normally done by
showing that the blood levels o the two products
are the same when given to a small number o
healthy volunteers.
2. Outside of Europe
At the time o publication, the European Union
is the only region that has established a specic
approval pathway or biosimilar medicines. The
US congress is still in the process o 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 drat guidelines on biosimilar medicines.
Regulators in Japan and Korea, amongst other
countries, are currently examining the issue o
biosimiliars.
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IV - The Market for Biosimilars
1. Which biosimilars are currently available in Europe?
The ollowing table shows the biosimilar medicines that have been approved by the EMEAxv :
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 Intereron ala-2a BioPartners Roeron-A Reject 28/06/2006
Abseamed1 epoetin ala Medice Eprex Approve 28/082007
Binocrit1 epoetin ala Sandoz Eprex Approve 28/08/2007
epoetin ala Hexal1 epoetin ala Hexal Eprex Approve 28/08/2007
Retacrit2 epoetin ala Hospira Eprex Approve 18/12/2007
Silapo2 epoetin ala STADA Eprex Approve 18/12/2007
Insulin Rapid Marvel, Long Marvel
30/70 Mix MarvelInsulin 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
expected 01/2009)
2. When are the next biosimilars coming onto
the market?
The EMEAs Committee or Human MedicinalProducts (CHMP) is currently assessing several
applications or biosimilars and it is expected that
these products will be approved during the course
o 2008. The CHMP gave a positive opinion on
three biosimilar versions o lgrastim (reerence
product: Amgens Neupogen) in February 2008
and a revised opinion in July 2008. These three
biosimilars then received a marketing authorisation
rom the European Commission in September 2008.
3. What does the market entry of biosimilars mean
for the original innovator products?
Biosimilar products will compete with originatorbiologicals, many o which already compete with
other originator products made by dierent biotech
companies. However, in many cases, biosimilars
are copies o older biological medicines, or 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 oer
increased therapeutic benet 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 /STADA3 The EMEA approved three licenses for the same Filgrastim made by Ratiopharm/Teva/CT Artzneimittel4 The EMEA approved two licenses for the same Filgrastim made by Sandoz/Hexal
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must beallowed
to exerciseappropriateclinicaljudgement...
...physicians
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1. What do patients need to know? Patients need and deserve to be ully inormed
about any medical treatment they are receiving.
I 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 or his or her
treatment.
Patients may not be completely aware o the
complexities o biologicals, including biosimilars,
and the implications o using them. These
implications include the potential o dierent
products provoking dierent immunogenic
reactions in individual patients. It is important
that patients are not obliged to switch their
treatment rom an originator to a biosimilar purely
on cost grounds, but that the specic therapeutic
needs o the patient are always taken into account.
According to a survey by the International Alliance
o Patients Organizations (IAPO), the key concerns
o patients with regard to biosimilars arexvi:
Cost and the potential to increase access to
biological treatments
Saety and ecacy
Patient inormation and decision-making
Regulatory process
Interchangeability
For these reasons it is very important that the label
and other product inormation relating to the
biosimilar refect the specic characteristics (clinical
data, reerence product, switching advice etc) o
the biosimilar in question.
V - The Impact of Biosimilars
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2. What do healthcare professionals need to know? Healthcare proessionals need to understand the
EMEA approval process or biosimilars, in particular
the abridged clinical data requirements, which can
allow the extrapolation o indication or biosimilars
in certain circumstances.
Furthermore, in relation to interchangeability andsubstitution, healthcare proessionals should be
aware that the two dierent products may provoke
dierent immune reactions in dierent patients.
Physicians should not eel obliged to prescribe a
certain medication purely on the grounds o cost,
but should be allowed to exercise appropriate
clinical judgement.
For these reasons it is very important that the label
and other product inormation o the biosimilar
refect the specic characteristics (clinical data,
reerence product, switching advice, etc.) o the
biosimilar in question.
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3. What do payers need to know? Payers, such as national health systems and health
insurance unds, may be interested in cost-saving
potential. Biological medicines tend to be more
expensive than traditional pharmaceuticals or
a number o reasons. These reasons include the
high costs involved in researching, developing,
producing and marketing biological medicines.It is important or payers to understand the
cost structure o biological medicines, including
biosimilars, with regard to complex manuacturing
procedures and regulatory requirements, which can
require enhanced post-marketing surveillance.
Evidence so ar shows that biosimilars will not
result in the same cost savings that generic
medicines have brought. Due to the act that
biosimilars have been on the market or a relatively
short period o 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 ar 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
o patient saety, automatic substitution or
biologics should not occur and the choice to use
any biological product should remain in the handso the treating physician. The physician must be
allowed to exercise appropriate clinical judgement
to select the best available treatment or the
individual patient. Treatment choice should not be
mandated purely or reasons o cost.
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Glossary of key terms
Adverse event: The occurrence o an undesirable,
unpleasant or lie-threatening reaction to a
medicinal product.
Allergy: A disorder o the immune system that
causes reactions such as itching, swollen or
infamed skin or eyes, runny nose. More extremeallergic reactions such as anaphylactic shock, which
can be lie threatening.
Amino acid: One o several molecules that join
together to orm proteins. There are 20 common
amino acids ound in proteins.
Antibody (pl: antibodies): Antibodies (also known as
immunoglobulins, abbreviated to Ig) are proteins that
are ound in blood or other bodily fuids. Antibodies
are used by the immune system to identiy and
neutralize oreign objects, such as bacteria and viruses.
Biological/biotech medicine: A substance made rom
a living organism or its products. Biologicals/biotech
medicines may be used to prevent, diagnose, treat
or relieve the symptoms o a disease. For example,
antibodies, interleukins, and vaccines are biologicals.
Biosimilar: A similar but not identical version o an
existing biological made ollowing patent expiry by
a dierent manuacturer than the producer o the
original product.
Biotechnology: Any technological application
that uses biological systems, living organisms, or
derivatives thereo, to make or modiy products or
processes or specic use.
DNA: Deoxyribonucleic acid (DNA) is a nucleic acid
that contains the genetic instructions used in the
development and unctioning o all known living
organisms and some viruses.
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Generic (medicine): A copy o an existing (chemical)
medicine, which is bioequivalent to the original
medicine, but is made by a dierent rm.
Gene therapy: The practice inserting o genes into
an individuals cells and tissues in order to treat a
disease or correct a generic deciency.
Genetics: The science o heredity and variation in
living organisms.
Hypersensitivity: The occurrence o undesirable
(damaging, discomort-producing and sometimes
atal) reactions produced by the immune system.
Immune system: The collection o mechanisms
within the body that protect against disease by
identiying 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 oten
subject to ocial (regulatory) approval.
Insulin: A hormone that aects metabolism and
causes the bodys cells to take up glucose (sugar)
rom 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 o in-vitro).
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Marketing authorisation: The permission granted
by a regulatory authority to a company to market
a medicinal product ollowing the companys
submission o required documentation and data
relating to testing and clinical trials o the product.
Medical biotechnology: The production o saeand eective versions o biological substances
that occur naturally in the human body, in a
scientically controlled environment in order to
make medicinal products.
Microbiology: The science o 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 o a substance that
has all o the physical and chemical properties o
that substance. Molecules are made up o one or
more atoms. I they contain more than one atom,
the atoms can be the same (an oxygen molecule
has two oxygen atoms) or dierent (a water
molecule has two hydrogen atoms and one oxygen
atom). Biological molecules, such as proteins and
DNA, can be made up o many thousands o atoms.
Molecular: O a molecule
Nucleic acid: A macromolecule composed o chains
o monomeric nucleotides. In biochemistry these
molecules carry genetic inormation or orm
structures within cells.
Patent: A patent is a set o exclusive rights granted
by a state to an inventor or his assignee or a xed
period o time in exchange or a disclosure o an
invention.
Pharmacovigilance: Saety control procedures
which medicines are subject to both beore, during
and ater their approval by regulatory authorities.
Protein: Large organic compounds made o
amino acids arranged in a linear chain and joined
together by peptide bonds between the carboxyland amino groups o adjacent amino acid residues.
Recombinant: In genetics, recombinant means
DNA, proteins, cells, or organisms that are made
by combining genetic material rom two dierent
sources. Recombinant substances are made in the
laboratory and are being studied in the treatment
o cancer and or many other uses.
Reference product: The original product on which a
biosimilar or generic drug bases its application or
marketing approval.
RNA: Ribonucleic acid is a nucleic acid which is
central to the synthesis o 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/pds/human/biosimilar/043704en.pd (overarching guideline on biosimilars)
http://www.emea.europa.eu/pds/human/biosimilar/17073408en.pd (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 rom Convention on Biological Diversity (1992)
iii Add PhRMA reerence.
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.pd
v http://ec.europa.eu/enterprise/pharmaceuticals/pharmacovigilance/docs/public-consultation_12-2007.pd
vi EMEA Guideline on Risk Management Systems or Medicinal Products or Human Use
vii US, Orange Book
viii In case the originally authorized medicinal product has more than one indication, the ecacy and saety o the medicinal
product claimed to be similar has to be justied or, i necessary, demonstrated separately or each o the claimed indications
(part II, 4 o Directive 2003/63/EC).
ix Where a biological medicinal product which is similar to a reerence medicinal product does not meet the condition in
the denition o generic medicinal products, owing to, in particular, dierences relating to raw materials or dierences in
manuacturing processes o the biological medicinal product and the reerence biological medicinal product, the results o
appropriate pre-clinical tests or clinical trials relating to these conditions must be provided (article 10 o 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 EMEAs Questions and Answers on biosimilars (similar biological medicinal products)
xiii EMEAs 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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