Guide to Biological Medicines: A Focus on Biosimilar ... - Europabio

<strong>Biological</strong> <strong>Medicines</strong>
A <strong>Focus</strong> on Biosimilar <strong>Medicines</strong>
Interchangeability
Interchangeability of medicinal
products refers <strong>to</strong> 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 <strong>to</strong> gain a marketing
authorisation in Europe, biosimilar
applicants need <strong>to</strong> demonstrate
similarity <strong>to</strong> the reference
product. Assessments of
interchangeability and
substitutability are not part
of the scientific evaluation by
the European <strong>Medicines</strong> Agency
(EMA) and therefore, no
conclusion on interchangeability
or au<strong>to</strong>matic substitution can be
made based on the grant of a
market authorisation. Decisions
on au<strong>to</strong>matic substitution lie
within the responsibility of the
Member States. Unless products
are designated as substitutable
(see below), the decision as <strong>to</strong>
which product should be used
and whether treatment should
or could be changed <strong>to</strong> another
product lies with the treating
physician.
Substitution
Au<strong>to</strong>matic 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
<strong>to</strong> inform the treating physician.
Some countries make generic
substitution manda<strong>to</strong>ry under
certain conditions, for example
where the doc<strong>to</strong>r prescribes
by INN.
Generic substitution is often
linked <strong>to</strong> reimbursement, as
some health insurance schemes
will only reimburse the patient
for the cost of the generic
version of a product. The result
of this can be that a patient who
refuses the generic version and
insists on the original product
may be liable <strong>to</strong> pay the difference
in cost. Generic versions
of chemical pharmaceuticals
that have demonstrated their
bioequivalence may generally
be substituted with no risk
<strong>to</strong> patient safety.
However, the EMA has
specifically stated that "since
biosimilars and biological
reference products are not
identical, the decision <strong>to</strong> treat a
patient with a reference product
or biosimilar medicine should be
taken following the opinion of a
qualified health professional".
The physician’s 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 au<strong>to</strong>matic
substitution were <strong>to</strong> take place,
it could confound pharmacovigilance
when adverse reactions
occur, especially immune reactions,
as it is more difficult <strong>to</strong>
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 <strong>to</strong> prohibit the
au<strong>to</strong>matic substitution of
biological medicines or have
given regula<strong>to</strong>ry advice on the
use of biologics (including
prescription by brand names).
Based on the above, countries
that currently allow au<strong>to</strong>matic
substitution of biologicals should
take the necessary measures <strong>to</strong>
s<strong>to</strong>p 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 patient’s
consent.
Impact on Healthcare
Budget and Pricing
Generics and biosimilars have an
important role <strong>to</strong> play <strong>to</strong> foster
competition in the marketplace,
contributing thereby <strong>to</strong> the sustainability
of healthcare budgets.
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 <strong>to</strong> produce and develop.
Secondly, the regula<strong>to</strong>ry approval
requirements and post-marketing
surveillance for biosimilars are
more rigorous than for generic
medicines, thus adding a further
layer of cost <strong>to</strong> developing a
biosimilar (e.g. unlike generics,
biosimilars usually require
independent non-clinical and
clinical trials <strong>to</strong> be undertaken).
Therefore, R&D costs required
for the approval of a biosimilar -
ranging on average from USD
75 <strong>to</strong> USD 250 (approximately
€50 <strong>to</strong> €170 million) 2 - are much
higher than those for a generic.
The exact price level of a
biosimilar will depend on a
number of fac<strong>to</strong>rs, namely the
pricing and reimbursement
environment of each country,
competitiveness of the market
and the desire <strong>to</strong> 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 <strong>to</strong> their
lower list prices, are therefore
limited as the products compete
in market segments that only
represent a small portion of <strong>to</strong>tal
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
of the individual EU Member
States or by the "centralised
procedure" for approval carried
out by the European <strong>Medicines</strong>
Agency (EMA). In contrast,
all new biological medicinal
products, including biosimilars,
have <strong>to</strong> follow the centralised
procedure.
Applications submitted <strong>to</strong> 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
regula<strong>to</strong>ry pathway <strong>to</strong> 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 regula<strong>to</strong>ry guidelines
concerning the data required for
the approval of a biosimilar.
The EMA defines biosimilars in "Questions and Answers on biosimilar medicines" as:
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 fac<strong>to</strong>r,
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 <strong>to</strong> approval
"is scientifically not appropriate"
for biosimilars.
2. Industry average source: Sandoz internal
estimates. Conversion in € done in July 2011
"A biosimilar medicine is a medicine which is similar <strong>to</strong> a biological medicine that has
already been authorised (the 'biological reference medicine'). The active substance of
a biosimilar medicine is similar <strong>to</strong> the one of the biological reference medicine.
Biosimilar and biological reference medicines are used in general at the same dose <strong>to</strong>
treat the same disease. Since biosimilar and biological reference medicines are similar
but not identical, the decision <strong>to</strong> 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 <strong>to</strong> those of the
biological reference medicine."
Furthermore, the EMA Questions and Answers document states that the "legislation defines
the studies that need <strong>to</strong> be carried out <strong>to</strong> 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 <strong>to</strong> demonstrate similarity with the reference
product for quality, safety and efficacy. Specifically, the biosimilar must demonstrate that it
has no significant clinical differences <strong>to</strong> the reference product. Biosimilar manufacturers must
provide all of the non-clinical, pre-clinical and clinical data required <strong>to</strong> demonstrate the
similarity of their product <strong>to</strong> the reference product, without the need <strong>to</strong> repeat unnecessary
tests and trials.
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