U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2003
OGD
Guidance for Industry
180-Day Exclusivity When Multiple ANDAs Are Submitted on the
Same Day
Additional copies are
available from:
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2003
OGD
Guidance for Industry
180-Day Exclusivity When Multiple ANDAs are
Submitted on the Same Day
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of
this guidance.
This guidance is intended to provide
information on how the Food and Drug Administration (FDA) intends
to determine eligibility for 180-day generic drug exclusivity
when, on the same day, more than one applicant submits an
abbreviated new drug application (ANDA) for the same drug under
section 505(j) of the Federal Food, Drug, and Cosmetic Act (Act)
containing a paragraph IV certification to a listed patent, and no
paragraph IV certification to the patent was submitted on any
previous day. To date, FDA's exclusivity decisions have involved
applications or amendments submitted on different days. This
guidance explains why and how the Agency intends to apply a
multiple first applicant approach.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
The Drug Price
Competition and Patent Term Restoration Act of 1984 (Pub. L. No.
98-417) (the Hatch-Waxman Amendments) amended the Federal Food,
Drug, and Cosmetic Act (the Act). The Hatch-Waxman Amendments
created section 505(j) of the Act (21 U.S.C. 355(j)). Section
505(j) established the ANDA approval process, which allows
lower-priced generic versions of previously approved innovator
drugs to be approved and brought on the market.
An innovator drug applicant must include in
its new drug application (NDA) information about any patents that
claim the drug product that is the subject of the NDA, or the use
of such drug product (21 U.S.C. 355(b)(1) and (c)(2)). The FDA
publishes this patent information upon approval of the NDA or a
supplemental NDA in Approved Drug Products with Therapeutic
Equivalence Evaluations, which is generally known as the
Orange Book.
An ANDA applicant must include in its ANDA a
patent certification as described in section 505(j)(2)(A)(vii) of
the Act. The certification must make one of the following
statements: (1) such patent information has not been filed; (2)
such patent has expired; (3) the date on which such patent
expires; or (4) such patent is invalid or will not be infringed by
the manufacture, use, or sale of the drug product for which the
ANDA is submitted. The fourth certification is known as a
paragraph IV certification. The ANDA applicant must provide
appropriate notice of a paragraph IV certification to each owner
of the patent that is the subject of the certification and to the
holder of the approved NDA to which the ANDA
refers (21 U.S.C. 505(j)(2)(B)(i),
21 CFR 314.95). Section 505(j)(5)(B)(iv) of the Act
established an incentive for generic manufacturers to file
paragraph IV certifications and to challenge listed patents as
invalid, or not infringed, by providing for a 180-day period of
marketing exclusivity:
If
the [ANDA] contains a [paragraph IV certification] and is for a
drug for which a previous application has been submitted under
this subsection continuing [sic] such a certification, the
application shall be made effective not earlier than one hundred
and eighty days after—
(I)
the date the Secretary receives notice from the applicant
under the previous [ANDA] of the first commercial marketing of the
drug under the previous [ANDA], or
(II) the
date of a decision of a court in [a patent infringement action]
holding the patent which is the subject of the certification to be
invalid or not infringed, [the
font size of this paragraph needs to be 11]
whichever is earlier.
This means that, in certain circumstances, an
applicant who submits the ANDA containing the first paragraph IV
certification to a patent is protected from competition
from other generic versions of the same drug product for 180 days
after the earliest of either the initial marketing of the first
applicant’s drug or a court decision that holds that the patent
that is the subject of the paragraph IV certification is invalid
or not infringed. This marketing protection is commonly known as
180-day exclusivity.
The 180-day period of generic drug
exclusivity provides a very strong financial incentive for an ANDA
applicant to challenge a patent that it believes it does not
infringe or that it believes is invalid or unenforceable. The
Congressional Budget Office (CBO) issued a report in July 1998
entitled How Increased Competition from Generic Drugs has
Affected Prices in the Pharmaceutical Industry. This report
indicated that the price of a generic drug decreases with the
entry of multiple manufacturers selling generic duplicates of a
given innovator drug (see CBO report page 33). With less
competition, an ANDA holder is able to derive higher profits.
Thus, the opportunity to be the sole competitor to the innovator
for up to 6 months is aggressively pursued.
Since the decisions in Mova
Pharmaceuticals, Inc. v. Shalala, 140 F.3d 1060 (D.C.Cir.
1998) and Granutec, Inc. v. Shalala, 46 U.S.P.Q.2d 1398
(4th Cir. 1998), the first applicant who submits a substantially
complete ANDA containing a paragraph IV certification to a listed
patent is eligible for 180-day generic drug exclusivity.
As noted in a 1999 citizen petition response,
many of the current regulations were adopted prior to the Mova
decision, when the Agency interpreted the statute to require that
an ANDA applicant had to be sued and win its patent litigation to
qualify for exclusivity. FDA's pre-Mova
interpretation limited
the number of times 180-day exclusivity was granted because an
ANDA applicant had to be first to challenge a patent and win the
patent litigation to be eligible for 180-day exclusivity.
The chance of having
multiple ANDA applicants qualify for 180-day exclusivity was
extremely low as evidenced by the
number of times that 180-day exclusivity was granted.
By contrast, after the Mova decision, it is now easier to
qualify for 180-day exclusivity. As a result, FDA has had to
address a number of new issues, including eligibility for
exclusivity when multiple paragraph IV certifications are filed on
the same day.
Congress did not address, in the 180-day
exclusivity provisions of the Act, the possibility that multiple
applicants would submit patent challenges to FDA on the same day,
when no applicant had submitted a challenge to the patent on a
previous day. Similarly, FDA regulations now in effect do not
address this specific situation. In August 1999,
FDA proposed a multiple first
applicant approach in a proposed rule addressing 180-day generic
drug exclusivity (64 FR 42873; August 6, 1999). FDA received
comments both for and against this approach (see Docket
85N-0214). The proposed rule was withdrawn in 2002 for reasons
unrelated to the merits of the multiple first applicant approach
(67 FR 66593; November 1, 2002). When the proposed rule was
withdrawn, the Agency noted that it would continue to regulate
directly from the statute and any applicable regulations, and make
decisions on an issue-by-issue basis. The Agency continues to
believe that the approach described in the proposed rule is a
reasonable and appropriate interpretation of the statute. Two
citizen petitions have specifically asked the Agency to follow the
approach described in the proposed rule when addressing 180-day
exclusivity in cases where there are multiple ANDAs containing
challenges to the same patent submitted on the same day (see
Dockets 00P-1445 and 03P-0217).
Same day patent challenges generally occur
when the expiration of 4 years of a 5-year exclusivity period
under section 505(j)(5)(D)(ii) permits submission of ANDAs
containing a paragraph IV certification as of a specific date, and
multiple applicants vie to be first to make such a submission.
Multiple submissions on the same day may also occur when a new
patent is issued by the Patent and Trademark Office and submitted
to FDA by the NDA sponsor after ANDAs have been submitted.
Because new patents must be submitted to FDA within 30 days of
issuance, ANDA applicants position themselves to be the first to
submit a paragraph IV certification as soon as the patent is
submitted to FDA – often exactly 30 days after patent issuance.
Recently,
there have been a number of cases in which multiple ANDA
applicants or their representatives have sought to be the first to
submit a patent challenge by lining up outside, and literally
camping out adjacent to, an FDA building for periods ranging from
1 day to more than 3 weeks. Concerns about liability, security,
and safety led the property owners to prohibit lines of applicants
before the date submissions may be made. This has lent an urgency
to the question of how the Agency deals with multiple ANDA
applicants submitting paragraph IV certifications on the same
day. There are other periods of exclusivity expiring soon, and
FDA believes it is possible there will be multiple ANDA
submissions referencing the same listed drug. Because of the
seriousness of these issues, it has been necessary to promptly
provide information to the industry on how patent challenges may
be made to FDA and how FDA will apply the 180-day exclusivity
provisions of the statute to these submission.
FDA intends to apply a multiple first
applicant approach to eligibility for 180-day exclusivity by
considering all substantially complete ANDAs, amendments, and
supplements containing a paragraph IV certification to a listed
patent that are submitted to the OGD document room on the same day
as being first applicants, when no paragraph IV
certification to the patent has been submitted on any previous
day, as long as the applications comply with the applicable
requirements for submission. FDA considers this approach to be an
appropriate interpretation of the statutory language and
consistent with the goals of the Hatch-Waxman Amendments. This
approach will provide all applicants submitting patent challenges
on the same day an opportunity to share in exclusivity; it permits
submission by U.S. mail or courier or delivery service; it
permits, but does not require, submission in person; it avoids the
random aspect of a lottery or mail room date stamp approach; it
will prevent disputes over who's first, which rely on video
and other evidence; and it will preserve the safety and security
of the applicants and FDA property and staff.
Under the approach described in this
guidance, FDA intends to treat all ANDAs containing a paragraph IV
certification to a listed patent that are submitted on the same
day as being submitted at the same time for purposes of 180-day
exclusivity when no ANDA for the same drug product containing a
paragraph IV certification to the same patent has been submitted
on a previous day. Thus, none of those same-day submissions would
be considered "previous[ly] . . . submitted" to another patent
challenge submitted on that same day for purposes of section
505(j)(5)(B)(iv), and all applicants who fulfill the requirements
for submission would be considered first applicants. The
Agency intends to approve a first applicant's ANDA whenever it is
ready for approval. Whether and when the Agency will be able to
approve a first applicant's ANDA will depend upon a number of
factors, including, for example, the status of its scientific
submissions to the Agency. Exclusivity begins to run, independent
of the approval, with the commercial marketing of that drug
product or with a court decision on the patent, whichever comes
first. Exclusivity will be triggered for all of the first
applicants for a specific listed patent by the earlier of
commercial marketing by one of the first applicants or by a court
decision (regarding the patent as to which the applicant is a
first applicant) finding the patent invalid, unenforceable, or not
infringed. The commercial marketing trigger will begin
exclusivity as to all of the listed patents; a court decision will
only begin the running of exclusivity as to the patents addressed
in the decision.
During the exclusivity period, FDA may
approve any other first applicant's ANDA, but no other ANDAs. Any
first applicant whose ANDA is approved after the exclusivity has
been triggered will share in the remaining period of exclusivity.
Once the 180-day exclusivity period has run, FDA may approve all
subsequent ANDAs.
Obviously, this approach may deprive any one
applicant of the chance to be the sole competitor to the NDA
holder. But exclusivity is already structured in such a way that
eligibility for exclusivity does not guarantee 180 days as the
sole marketed generic drug (i.e., the court decision trigger could
start exclusivity before an ANDA is approved, or uncertainty over
the patent could result in no marketing of an approved product
until an affirmation in the Federal Circuit of a district court
win). A multiple first applicant approach to 180-day
exclusivity will limit the number of ANDAs approved during the
exclusivity period to the number of first applicants. Moreover,
making multiple applicants eligible for exclusivity may give each
first applicant some part of the benefit from the early challenge
to the listed patent.
The approach to 180-day exclusivity described
in this guidance will apply only in cases in which multiple ANDA
applicants submit paragraph IV certifications challenging the same
listed patent or patents on the same first day. The Agency
recognizes the highly competitive nature of the generic drug
approval process and the possibility of substantial profits for
the recipient of 180-day exclusivity. There is no public health
reason to encourage and reward competition over being the first
to submit a paragraph IV certification within minutes or
seconds of another such applicant. The Agency believes that,
where there are multiple filings on the same first day, the
multiple first applicant approach is consistent with
language of section 505(j)(5)(B)(iv) and with the intent of both
the 180-day exclusivity provision and the Hatch-Waxman Amendments.
This guidance is
being issued as a level 1 guidance for immediate implementation,
consistent with FDA’s good guidance practices regulation (21 CFR
10.115). The Agency believes that given the need for public
guidance on this pressing issue and existing liability, safety,
and security concerns, public comment is neither feasible nor
appropriate before implementing this guidance. FDA intends to
apply the approach described in this guidance to all 180-day
exclusivity determinations made by FDA on or after the date of
publication of the notice announcing the availability of this
guidance involving situations in which the first paragraph IV
certifications to a specific patent are submitted on the same day
(including patent certifications that were submitted prior to the
date of the notice where the exclusivity determination has not yet
been made). The approach described in this guidance will remain
in effect until superseded.