patent infringement and provides the patentee 30
days in which to defend its patent by suing for
patent infringement. The lawsuit prevents the
FDA from approving the generic drug, pending
resolution of the infringement action.
What is the value to the generics company from
making a Paragraph IV certification, as it will
certainly soon (within 30 days) be a defendant in
a costly lawsuit for patent infringement? It can be
considerable. If it is successful and the patent is
held to be invalid, the generics company is granted
a period of exclusivity for six months to sell its
drug, with competition only from the innovator
company. When the period ends, other generics
companies will undoubtedly enter the market and
the drug’s price will drop to about 10–30% of the
brand drug price. However, during the period of
exclusivity, the price drops to only about 70%, a
handsome reward for invalidating the patent. These
price drops are not dictated by law, just by the
marketplace.
Although Hatch-Waxman is limited to the Uni-
ted States, laws in most other countries have some
things in common with the US system – providing
abbreviated approval processes for generic drugs,
creating safe harbors from infringement to allow
for development and clinical trials of generic drugs
prior to patent expiry and providing patent term
extension and/or data exclusivity periods to ensure
a reasonable period of exclusivity to the innovator
company. The Paragraph IV challenge and pre-
launch patent litigation process, however, is unique
to the United States. Consequently, outside the
United States, the patent owner must usually wait
until the launch of an infringing product to enforce
its patents.
29.2 Seeking generic approval
in the United StatesIn the United States, there are two main routes to
approval of a generic drug.
The more common route isviaan ANDA. An
ANDA requires that the generic product contains
the same active ingredient and has the same dosage
and route of administration as the reference drug. It
must also be for the same indication. The applicant
must show that the generic product is bioequivalent
to the reference product, with respect to its phar-
macokinetic and pharmacodynamic properties.
Bioequivalence can be shown by demonstrating
that the formulations are so similar that no differ-
ence would be expected, or by a small trial in
healthy volunteers, measuring the blood levels of
the active pharmaceutical in patients receiving the
generic formulation compared to the reference
formulation. Measuring blood levels to demon-
strate bioequivalence is usually appropriate for
oral formulations, but may be unsuitable for
drugs that have a primarily local activity, such as
inhaled or topical drugs, or for certain injectable
drugs.
The second route to generic approval in the
United States is the so-called ‘paper NDA’. This
type of application is used when the product or its
use is not the same as the reference drug. Although
an ANDA is reviewed by the Office of Generic
Drugs in the FDA, the paper NDA is treated as a
regular NDA. The trials carried out by the appli-
cant, which may include trials going well beyond
simple bioequivalence in healthy volunteers, are
supplemented by reference to a previously
approved drug product or to published data. The
exact nature of the data and trials required for
approval is determined on a case-by-case basis.
This type of application may be used by the origi-
nator company for line extensions as well as by
generic companies. Drug products approvedvia
this route may or may not be ‘AB-rated’ that is
they may or may not be considered bioequivalent,
and thus fully substitutable for the reference drug.
Generic drugs are subject to quality assurance and
manufacturing requirements similar to branded
drugs, for example for approval, they must meet
batch requirements for identity, strength, purity and
quality, and they must be manufactured in accor-
dance with the FDA’s good manufacturing practice
(GMP) regulations.
Regardless of whether the generic applicant
seeks approvalviathe ANDA route or the paper
NDA route, it must provide the patent certification
as described above. Moreover, approval of generic
drugs is subject to registration data exclusivity
periods. No generic versions of a new chemical
entity can be approved until after five years from29.2 SEEKING GENERIC APPROVAL 383