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 Subsequent
Entry Biologics – How They Affect Your Patenting Strategy
Tanya Weston
Health Canada recently released a
draft guidance document, for public comment only, in respect
of a proposed regulatory approval process for Subsequent Entry
Biologics (SEBs).1 This guidance document is the
first step in the development of a comprehensive regulatory
system to address SEBs that will, in all likelihood, also
include regulatory amendments.
Since its release, the guidance
document has been the subject of considerable public
commentary. Key elements are briefly described below:
-
Definition of SEB: Health Canada
describes biologic products as those derived through the
metabolic activity of living organisms. These products are
listed on Schedule D of the Food and Drugs Act (i.e.,
blood products, cells and tissues, gene therapies, vaccines,
etc.). An SEB is defined as a biologic product that would
enter the market subsequent to, and “similar” to, an approved
innovator biologic product. Such products could rely, to some
extent, on the safety and efficacy data of an approved
innovator product where they could demonstrate similarity with
the approved product.
-
Proposed Regulatory Framework:
Health Canada proposes to utilize the existing regulatory
framework for pharmaceuticals and biologics (i.e., Part C,
Division 8 of the Food and Drug Regulations) with some
modification. A manufacturer of an SEB will be required to
submit a New Drug Submission, which may be based on reduced
clinical data where the manufacturer can demonstrate
similarity between the SEB and a chosen reference product.
-
Similarity: The guidance document
indicates that a manufacturer must demonstrate
comparability/similarity through extensive data, including
side-by-side characterizations of the SEB and the reference
product. Manufacturers will be required to demonstrate that
the SEB and reference product are comparable in terms of
quality, safety, and efficacy. It is important to note,
however, that manufacturers will not be required to
demonstrate that the two products are identical. Rather, the
manufacturer will be required to establish that the two
products are similar enough that the existing knowledge of
both products sufficiently indicates that any quality
attribute differences should have no adverse impact on the
safety or efficacy of the SEB.
-
Reference Product: The reference
product should be an approved biologic product marketed in
Canada. The Minister of Health may, however, consider an
approved reference product from another jurisdiction upon
request. The reference product should have “a suitable
duration and volume of marketed use such that a demonstration
of similarity will bring into relevance a substantial body of
acceptable data dealing with safety and efficacy.” An SEB
cannot be used as a reference product for subsequent
submissions since it will not have been authorized on the
basis of a complete quality and clinical data package.
-
Indications: An SEB will not be
readily granted approval for all of the indications of the
reference product. The indications granted will depend on the
data provided by the manufacturer.
-
Product Monograph: A manufacturer
of an SEB cannot rely on the product monograph of the
reference product.
Implications for
Intellectual Property Protection of Biologics in Canada
In Canada, innovators of drug products have three main routes
to prevent (for a limited period of time) “generic” versions
of their drugs from entering the Canadian marketplace: through
a patent infringement suit under the Patent Act;
through the data protection provisions under the Food and
Drug Regulations, or through the Patented Medicines
(Notice of Compliance) Regulations.
Generally speaking, biologic
products tend to have a lengthy patent prosecution and
regulatory approval period thereby providing a shorter period
of exclusivity in the marketplace if relying on the Patent
Act alone for protection. Moreover, patent infringement
suits are often protracted and expensive. Additional market
exclusivity protection through the Food and Drug
Regulations and the Patented Medicines (Notice of
Compliance) Regulations is, therefore, particularly
appealing for innovators of these products.
Under the Food and Drug
Regulations, a drug that meets the definition of an
innovative drug under c.08.004.1 (i.e., a drug that contains a
medicinal ingredient not previously approved in a drug by the
Minister that is not a variation of a previously approved
medicinal ingredient, such as a salt, enantiomer, solvate or
polymorph), is eligible for an 8-year data protection period,
or 8 ½ years for a drug with clinical studies in pediatric
populations. This means that competitors wishing to directly
or indirectly compare their “generic” product to the
innovator’s product are prevented from receiving market
authorization during this period.
The guidance document does not
specifically address the issue of data protection in respect
of biologics. It does, however, state that “all laws, patent
and intellectual property principles outlined within the
Patent Act, Food and Drug Regulations (Data Protection),
and Patented Medicines (Notice of Compliance) Regulations
are applicable to SEBs” thus suggesting that the data
protection restrictions will apply to SEBs.
Several issues, however, may
arise in respect of the application of the data protection
provisions to biologics. Complex biologics may contain large
molecules that differ from a previously approved product by
just a few amino acids or nucleotides, but have significantly
different effects. It is unclear whether these “slight”
differences in the sequence of the product will be viewed by
Health Canada as “variations” or as a distinctly different
“innovative” product. In effect, the question arises as to
whether biologics should be defined by their physico-chemical
properties, biologic function, or both. These issues have
never been meaningfully addressed since no regulatory approval
process for SEBs currently exists; however, with many
biologics approaching the end of their patent exclusivity
period and work currently underway by Health Canada to develop
a regulatory process for SEBs, the application of the data
protection provisions in the context of biologic products will
no doubt be further debated and clarified by Health Canada
and/or the Federal Court.
The guidance document also
suggests that manufacturers of SEBs will be subject to the
requirements under the Patented Medicines (Notice of
Compliance) Regulations. Currently, when an innovator
files a new drug submission, or a supplemental new drug
submission, it may list patents on the Patent Register in
respect of the product to which the submission pertains if the
patent claims: a medicinal ingredient, a formulation or change
in a formulation that contains a medicinal ingredient; a
dosage form or change in the dosage form; and a use of the
medicinal ingredient or change in the use. The claim for the
medicinal ingredient may be chemical or biological in nature.
Any subsequent submission seeking regulatory approval based on
a direct or indirect comparison to the innovator’s product
must address each patent listed on the Patent Register in
respect of the innovator’s product before regulatory approval
will be granted.
The guidance document implies
that manufacturers of SEBs will be required to address patents
listed on the Patent Register in respect of their chosen
reference product. There is, however, some uncertainty as to
how the provisions of the Patented Medicines (Notice of
Compliance) Regulations will accommodate the unique
characteristics of most biologics. For example, how will a
medicinal ingredient be defined or viewed in the context of
biologic products? Will a biologic product used to create
another substance in vivo, which then carries out a
therapeutic function be considered a medicinal ingredient?
Once again, these issues will need to be clarified, either
through Health Canada, legislative amendments and/or by the
Federal Court.
Lastly, the current scheme under
the Patented Medicines (Notice of Compliance) Regulations
excludes process patents. In the context of biologic products,
however, manufacturing processes are often critical to
biologic production. Accordingly, in order to protect and
foster innovation in this area, any proposed regulatory
pathway for SEBs must ensure adequate protection for biologics
utilizing these processes for the purposes of developing
innovative medical treatments. This issue will likely have to
be addressed through legislative amendments rather than
through guidance for industry if protection beyond what may be
available under the Patent Act is to be afforded.
Strategies for Innovators
of Biologic Products:
The draft guidance document is the first step in the
development of a regulatory pathway for SEBs in Canada. With
an increasing number of biologics coming off patent in the
near future, the interest in the development and regulatory
approval of SEBs is likely to increase.
In comparison to chemically
synthesized drugs, there are relatively few patents listed on
the Patent Register in relation to approved biologics.
Innovators have not yet had to deal with competition in
relation to “similar” products, nor have they had to deal with
the intense judicial scrutiny in relation to eligibility for
patent listing under the Patented Medicines (Notice of
Compliance) Regulations as have innovators of chemically
synthesized drugs. With the real possibility of SEBs entering
the marketplace, innovators of biologic products may, however,
wish to leverage the various regimes available to them in
order to strategically maximize opportunities for protection
of their products in the future.
Innovators have a prime
opportunity to consider their patenting strategies in
conjunction with opportunities for data protection early on in
the development of their biologic products to maximize the
period of exclusivity available in the marketplace. Patent
filing and claim drafting strategies that are layered in
multiple applications, and over time, generally afford greater
flexibility in this regard. The objective is to ensure that if
eligibility for data protection exists, patents can also be
eligible for listing on the Patent Register in such a way so
as to not preclude downstream products from eligibility for
data protection and patent listing.
Given that reservations exist as
to the extent of protection the Food and Drug Regulations
and Patented Medicines (Notice of Compliance) Regulations,
as they are currently drafted, will afford innovators of
biologics, innovators need to advocate their interests,
particularly in the context of legislative or policy debate,
through participation in Health Canada’s consultation
processes.
____________________________
1 Draft
Guidance for Sponsors: Information and Submission Requirements
for Subsequent Entry Biologics (SEBs), available at
http://www.hc-sc.gc.ca/dhp-mps/brgtherap/activit/consultation/seb-pbu/2008-tc-tm-eng.php
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