Biological
Medicines
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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)
Biological
Medicines
A Focus on
Biosimilar
Medicines
Biological Medicines
A Focus on Biosimilar Medicines
TABLE OF CONTENTS
INTRODUCTION
02 INTRODUCTION
12 REFERENCES
01
02
Biological Medicines
A Focus on Biosimilar Medicines
HEALTHCARE BIOTECHNOLOGY:
INTRODUCTION TO THE SCIENCE
the complexity of
biological medicines
makes their analytical
characterisation more
challenging than that
of small molecules.
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.
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Biological Medicines
A Focus on Biosimilar Medicines
Biological medicines
made by unrelated
manufacturers after
the expiry of intellectual
property protection are
not exact copies of
the original biological
medicines.
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.
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
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.
The regulation of
biological in Europe,
including biosimilars
Depending on the disease
category, chemical medicines
can be approved either by the
national medicines authorities
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.
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Biological Medicines
A Focus on Biosimilar Medicines
For patients
So far, the European Union has approved 7 biosimilars, across 3 product classes: human growth hormones,
erythropoietins and granulocyte colony stimulating factors.
Active
substance
Abseamed
Binocrit
Biograstim
epoetin alfa
epoetin alfa
filgrastim
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
For healthcare
professionals
the specific
therapeutic needs
of the patient must
always be taken
into account.
Name
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.
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Biological Medicines
A Focus on Biosimilar Medicines
11
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
library/Medicine_QA/2009/12/WC500020062.pdf
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
12