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Biopharmaceuticals
are drugs derived from living organisms. They are usually
complex molecules and are therefore more difficult to consistently
manufacture, quantify and purify.
Over the next few years, a number
of first-generation biopharmaceuticals will come off patent
or lose marketing exclusivity (first in Europe, then the
USA), including alpha-interferon, erythropoietin, human
growth hormone, human insulin, granulocyte-macrophage colony-stimulating
factor and some interleukins. This will open the door for
the manufacture of generic biopharmaceuticals (biogenerics).
Some biopharmaceuticals
nearing generic exposure
|
Brand
name(s)
|
Generic
name
|
Originator
|
|
Epogen/Procrit
|
Erythropoietin alpha
|
Amgen
|
|
Neupogen
|
Filgrastim
|
Amgen
|
|
Intron A
|
Interferon alpha-2b
|
Biogen
|
|
Avonex
|
Interferon beta-1a
|
Biogen
|
|
Engerix-B
|
Hepatitis B vaccine
|
SmithKline Beecham (now
GSK)
|
|
Genotropin
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Somatropin
|
Genentech/Pharmacia
|
|
Betaseron
|
Interferon beta-1b
|
Chiron
|
Source: Generic Planning/LifeCycle Assuming that biogenerics have
a penetration rate comparable with that of traditional drugs,
the potential global biogeneric market is worth about $2
billion. There is an increasing demand from consumers for
access to lower cost biopharmaceuticals and, because drug
costs continue to receive increased scrutiny, the timing
for generic biopharmaceuticals is excellent.
For any generic to be successful
several factors have to be met. There must be a large market
for the original product, the original product must be at
a high price and it must be in a simple non-proprietary
formulation. Many biopharmaceuticals adhere to all of these
factors. There are, however, some factors that biopharmaceuticals
lack that may hinder the production of generics:
- Availability of the active
substance produced through non-infringing rights
- Well characterized activity
with easy to match specifications
- Manageable costs for demonstrating
bioequivalence
The complex and unclear nature
of biotech patents also represents a major hurdle for biogenerics.
Comparability problems
Generic manufacturers have to
submit abbreviated registration documents to regulatory
bodies for approval to market a generic product. The abbreviated
processes do not require firms to replicate extensive clinical
trials with generics, but instead, they must conduct tests
to prove a generic is bioequivalent to the brandname
drug.
Unlike drugs made of purified
small molecules, biopharmaceuticals are difficult to characterize
chemically. In certain cases, a product is defined by its
manufacturing process, and a product can be process specific.
For these reasons, it is challenging, both in scientific
and regulatory terms, to determine if complex drug substances
are comparable before and after manufacturing changes, or
to decide if they are therapeutically equivalent when made
by different companies.
Proof of comparability is more
difficult in situations where a new manufacturer is seeking
marketing approval for a biotechnology-derived drug produced
by another manufacturer and already authorized, as in the
case of generic biopharmaceuticals.
Comparison can be made against
published data, such as in a pharmacopeial monograph, with
respect to gross physicochemical or biochemical characteristics
of the molecule. However, this is not sufficient to establish
all aspects pertinent to the evaluation of quality, safety
and efficacy for a biotechnology-derived drug.
The generic manufacturer does
not have access to all the necessary information for comparison
in terms of the quality with the original drug. Indeed,
the expression/vector system, production and purification
process, facility/equipment, analytical techniques etc.
will probably be different from those of the brand manufacturer,
and the extent of these differences cannot be evaluated
by the second manufacturer.
Specific regulations lacking
There are no clear, specific
regulations established for dealing with generic biopharmaceuticals.
Without these, it is unclear whether a generic biopharmaceutical
market will be allowed to exist.
In the US, the Complex Drug Substances
Coordinating Committee (CDS CC) in the Center for Drug Evaluation
and Research (CDER) has been tasked with producing guidance.
The CDER has indicated that generic
companies will need to provide sufficient characterization
of their product to show both chemical and biological comparability
with the previously licensed biopharmaceutical, as well
as sufficient clinical data to assure their product’s safety
and efficacy.
Meanwhile in Europe, the Committee
for Proprietary Medicinal Products (CPMP) at the EMEA (European
Medicines Evaluation Agency) has put forward guidance on
the comparability of medicinal products containing biotechnology-derived
proteins as active substance.
European guidelines
The first draft of the European
guidelines on comparability of biotechnology-derived proteins,
drawn up in 2000, leaves substantial room for interpretation:
there are no ‘universally’ applicable guidelines – each
product having to be reviewed on a case by case basis. It
states, as in the US, that "an extensive comparability
exercise" may be required. For each proposed generic
biopharmaceutical, appropriate preclinical and clinical
studies should be considered, taking into account:
- the nature of the drug substance
and the complexity of its molecular structure
- knowledge of in vivo behaviour
- the extent of the clinical
experience for a given drug substance and whether the
molecular entity under consideration has already been
marketed by one or several producers
- established relationship between
known side effects (essential immunogenicity) and molecular
features
No life-long monopoly
There is no reason to think that
biopharmaceuticals will enjoy indefinite monopolies just
because they are difficult to make and regulatory processes
are lacking. As health costs continue to rise, biogenerics
could offer an attractive source of savings for governments
and consumers alike.
Companies already working on
generic biopharmaceuticals include Cangene (Canada), GeneMedix
(UK), IVAX (USA), Microbix (Canada), Rhein Biotech (Germany)
and Teva (Israel). Some of the generic manufacturers are
preparing to sell copycat biopharmaceutical products, which
are due to be off patent soon in major markets, in markets
without stringent intellectual property rights.
Many countries are encouraging
their health systems to make greater use of generic drugs,
which offer equivalent pharmaceutical care at a substantially
lower cost. With healthcare budgets coming under increasing
pressure, many governments have introduced a range of measures
designed to encourage broader generic prescribing. These
include:
- Mandatory generic substitution
requirements
- Pricing restrictions
- Formularies
- Prescribing guidelines
- Positive or negative lists
Most advances in terms of generic
market development are in the US, where the generic market
is worth over $10 billion, and is expected to double by
2006.
Sales values
of molecules coming off patent in the USA
(2001 to 2011)
Source: Generic Planning
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