Guidance for Industry
Listed Drugs, 30-Month Stays,
and Approval of ANDAs and
505(b)(2) Applications
Under Hatch-Waxman,
as Amended by the
Medicare Prescription Drug,
Improvement, and Modernization
Act of 2003
Questions and Answers
(PDF
version of this document)
DRAFT
GUIDANCE
This guidance document is being distributed for comment purposes
only.
Comments and suggestions regarding this draft
document should be submitted within 90 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of
availability that publishes in the Federal Register.
For questions regarding this draft document,
contact Martin Shimer, 301-827-5710.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2004
OGD
Additional copies are available from:
Office of Training and Communications
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)
October 2004
OGD
Guidance for Industry
Listed Drugs, 30-Month Stays, and
Approval of ANDAs and 505(b)(2) Applications Under Hatch-Waxman, as
Amended by the Medicare Prescription Drug, Improvement, and
Modernization Act of 2003
Questions and Answers
This
draft guidance, when finalized, will represent the Food and Drug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.
I.
INTRODUCTION
On December 8,
2003, President Bush signed into law the Medicare Prescription Drug,
Improvement, and Modernization Act of 2003 (Public Law 108-173) (MMA).
Title XI of the MMA amends sections 505(b), (c), and (j) of the
Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(b),
(c), and (j)). Among other things, the MMA directs FDA to issue
guidance defining the term listed drug with respect to
amendments and supplements to abbreviated new drug applications (ANDAs).
This guidance is intended to clarify when a change to an ANDA should
reference a listed drug different from the drug
referenced in the original ANDA, thus requiring the change to be
made through an entirely new application.
As directed by the MMA, this
document (in the form of questions and answers) provides guidance on
the definition of listed drug.
Further, as
indicated in our March 3, 2004, Federal
Register notice,
we have been considering what other steps we should take in light of
the MMA. As one such step, this document provides guidance to
industry on certain sections of the MMA that significantly change
provisions of the Act that were originally added by the Drug Price
Competition and Patent Term Restoration Act of 1984 (Public Law
98-417) (Hatch-Waxman).
These changes relate, in substantial part, to 30-month stays and to
the timing of approval of ANDAs and new drug applications (NDAs)
described in section 505(b)(2) of the Act (505(b)(2) applications).
Specifically, this guidance clarifies changes made by the MMA with
respect to (1) the availability and termination of 30-month stays of
approval on ANDAs and 505(b)(2) applications under section
505(j)(5)(B)(iii) and 505(c)(3)(C) of the Act, respectively, and (2)
requirements for notice of patent certifications described in
sections 505(b)(2)(A)(iv) and 505(j)(2)(A)(vii)(IV) of the Act
(paragraph IV certifications). It also clarifies the applicability
of certain changes made by the MMA regarding the period during which
ANDAs that were not the first to challenge a patent on the listed
drug cannot be approved (180-day exclusivity), as described in
section 505(j)(5)(B)(iv) of the Act. Finally, this guidance
explains the various effective dates that apply to the MMA’s
provisions.
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.
1.
Why is a guidance needed on the definition of listed drug?
The MMA, among
other things, generally prohibits an ANDA applicant from amending or
supplementing its application to refer to a listed drug which is
different from that referred to in the application when originally
submitted. Such a change can be made only by the submission of an
entirely new application.
Title XI of the
MMA states in part that the Secretary will issue guidance defining
the term listed drug for purposes of section 1101(a)(1)(B) of
the MMA. That section, which is now section 505(j)(2)(D)(i) of the
Act, provides that “[a]n applicant may not amend or supplement an [ANDA]
to seek approval of a drug referring to a different listed drug from
the listed drug identified in the application as submitted to the
Secretary."
FDA's definition of listed drug is contained in § 314.3 (21
CFR 314.3).
The Agency does not intend to amend that definition.
2. Generally, when should a
separate ANDA be submitted for a different listed drug?
The appropriate
choice of whether to submit a new ANDA for a proposed product — as
opposed to submitting an amendment or supplement to a previously
submitted or already approved ANDA — is governed by a number of
considerations. All changes that would have the effect of seeking
approval for a drug product different from the listed drug cited in
the initial submission (e.g., different active ingredient, dosage
form, route of administration) should be made in a new application.
When the Orange Book identifies as a separate listed drug a product
with the characteristics (e.g., active ingredient, dosage form,
route of administration) for which the applicant is seeking
approval, the applicant should submit a separate ANDA referencing
the corresponding listed drug.
The applicant should not submit a supplement or amendment to its
pending or approved application to seek approval for such a change.
3.
Can an amendment or supplement be submitted for different strengths?
Each strength
of an approved drug is a separate listed drug. Each strength
proposed in an ANDA should reference the corresponding listed drug
(although the reference standard for purposes of bioequivalence may
be only one strength). Generally, a single application can be used
to seek approval for different strengths of the same listed drug.
Also, an applicant may submit an amendment or supplement to seek
approval of a different strength from that for which the application
was initially submitted and is not required to file a separate
application for such a change. This is expressly permitted under
the Act, as amended by the MMA (see section 505(j)(2)(D)(ii) of the
Act, as amended).
1. What court decisions and
other judicial actions are relevant for lifting 30-month stays of
approval on ANDAs and 505(b)(2) applications?
Hatch-Waxman
amended the Act to establish up to a 30-month stay of approval on an
ANDA or 505(b)(2) application if:
·
The application
includes a paragraph IV certification challenging a patent listed in
the Orange Book (a listed patent) that claims the approved drug
(listed drug) on which the ANDA or 505(b)(2) application relies or
claims the use of the listed drug, and
·
The patent owner or
NDA holder for the listed drug sues the ANDA or 505(b)(2) applicant
for patent infringement within 45 days of receiving notice of the
paragraph IV certification.
The 30-month
stay may be shortened or lengthened by the court if “either party to
the action fail[s] to reasonably cooperate in expediting the
action.”
The MMA further amends the Act to
specify what actions by what courts will terminate a 30-month stay
of approval. (The MMA also amends the Act to alter the
circumstances under which a 30-month stay can arise, as discussed
below in questions 1 and 2 in subsection II.D of this document.)
The provisions of the MMA that identify the relevant court actions
apply to any proceeding under section 505 of the Act that is pending
on or after December 8, 2003.
Under the MMA, a 30-month stay will be terminated and approval of an
ANDA or 505(b)(2) application may be made effective, as of any of
the following:
·
The date that
the district court enters judgment
reflecting its decision that the patent at issue is invalid or not
infringed (including any substantive determination that there is no
cause of action for patent infringement or invalidity),
or
·
The date of a
settlement order or consent decree signed and entered by the
district court stating that the
patent that is the subject of the certification is invalid or not
infringed,
or
·
If the district court
decides that the patent has been infringed, and this decision is
reversed on appeal, the date on which the court of appeals
decides that the patent is invalid or not infringed
(including any substantive
determination that there is no cause of action for patent
infringement or invalidity),
or the date of a
settlement order or consent decree signed and entered by the court
of appeals stating that the patent
that is the subject of the certification is invalid or not
infringed.
If the
district court hearing a patent infringement suit resulting from a
paragraph IV certification decides that the patent at issue is
infringed, and this decision is not appealed or is affirmed on
appeal, the ANDA or 505(b)(2) application may be approved based on
the district court’s ruling in accordance with the patent’s
expiration and any extension or exclusivity that remains.
2. What court decisions are
relevant for triggering 180-day exclusivity for ANDAs?
As
established by Hatch-Waxman, if an applicant (or applicants) is the
first to submit a substantially complete ANDA containing a paragraph
IV certification to a listed patent that claims the listed drug on
which the application relies or claims a use of the listed drug (a
paragraph IV ANDA), the applicant (or applicants) can be eligible
for a 180-day period during which no other ANDA with a paragraph IV
certification for the same drug may be approved.
This period is commonly referred to as 180-day exclusivity.
Under Hatch-Waxman before the MMA, the 180-day exclusivity period
was triggered by the earlier of the first commercial marketing of
the drug described in the first applicant’s ANDA, or the first court
decision holding invalid or not infringed the patent that was the
subject of the first applicant’s paragraph IV certification.
The MMA
changes the relevance of court decisions for 180-day exclusivity in
the following ways:
·
For paragraph IV
ANDAs filed after December 8, 2003, for a listed drug for which no
paragraph IV certification was made in any ANDA before that date,
court decisions will no longer trigger the period of 180-day
exclusivity; and
·
For all other ANDAs,
a court decision can still trigger the period of 180-day
exclusivity. However, if the exclusivity was not already triggered
before December 8, 2003, the triggering court decision must be one
from which no appeal has been or can be taken,
other than a petition to the Supreme Court for a writ of
certiorari (generally a decision of an appellate court).
(This is a transitional provision that redefines the court decision
that can begin the 180-day period of exclusivity for any product for
which there was a paragraph IV ANDA before enactment of the MMA.)
3. An ANDA was submitted on
September 6, 2003, and was the first substantially complete ANDA to
be submitted with a paragraph IV certification to the only listed
patent for the listed drug. The ANDA applicant is sued for patent
infringement. After December 8, 2003, the district court issues a
decision finding the patent at issue invalid. This decision is
appealed. Can the ANDA be approved? Does the applicant’s 180-day
exclusivity start to run on the date of the district court’s
decision?
As explained
in the response to question 1 in subsection II.B of this document,
for any proceeding under section 505 of the Act pending on or after
December 8, 2003, the district court’s decision that the patent at
issue is invalid or not infringed terminates the 30-month stay of
approval. Thus, if it is otherwise ready for approval, the ANDA in
this question can be approved at the time of the district court’s
decision. However, as explained in response to question 2 in
subsection II.B, as a result of the MMA, 180-day exclusivity for
ANDAs filed before December 8, 2003, can now be triggered by a court
decision only if it is a decision that has not been, or cannot be,
appealed. Therefore, the district court’s decision does not trigger
180-day exclusivity in the scenario described in this question
because that decision has been appealed. Note that this result is a
departure from prior law. Before enactment of the MMA, a district
court decision finding a listed patent invalid or not infringed
would have both terminated a 30-month stay and, in the case of an
ANDA that qualified for 180-day exclusivity, triggered the start of
such exclusivity as to that patent (if the exclusivity was not
already triggered by commercial marketing).
4. What is the status of
FDA’s guidance for industry entitled Court Decisions, ANDA
Approvals, and 180-Day Exclusivity Under the Hatch-Waxman Amendments
to the Federal Food, Drug, and Cosmetic Act?
That
guidance addresses the types of court decisions relevant for ANDA
approvals and 180-day exclusivity under Hatch-Waxman before
enactment of the MMA. The MMA supersedes relevant provisions of
Hatch-Waxman in effect at the time that guidance was published and
thus supersedes the guidance.
1. Are ANDA and 505(b)(2) applicants required to give notice
for paragraph IV certifications made between August 18, 2003, and
December 8, 2003?
Yes. The
MMA requires ANDA and 505(b)(2) applicants to provide notice for
all paragraph IV
certifications submitted to FDA on or after August 18, 2003.
Notice is to be provided:
·
If the certification
is included in the original application, not later than 20 days
after the date of the postmark on the notice from FDA informing the
applicant that the application has been filed, or
·
If the certification
is in an amendment or supplement, at the time the applicant submits
the amendment or supplement, regardless of whether the applicant has
already given notice of a prior paragraph IV certification contained
in the application or an amendment or supplement to the application.
We recognize
that our final rule which became effective on August 18, 2003 (Final
Rule),
stated that notice was not required for a paragraph IV certification
made by an ANDA or 505(b)(2) applicant if the applicant had already
provided notice of another paragraph IV certification in its
application or an amendment or supplement to the application.
However, as discussed above, the MMA’s provisions regarding notice
are retroactive to August 18, 2003, and supersede the Final Rule’s
provisions concerning this subject. On March 10, 2004, FDA revoked
the Final Rule’s notice-related provisions.
We are also
aware that compliance with the MMA’s time frame for providing notice
of a paragraph IV certification made in an amendment to an ANDA or
505(b)(2) application is not possible for ANDA and 505(b)(2)
applicants who submitted paragraph IV certifications in amendments
between August 18, 2003, and December 8, 2003, for which no notice
was required under the Final Rule, and who have not yet provided
notice of these certifications. We emphasize, however, that the
MMA’s requirement for notice is now in effect for all paragraph IV
certifications made on or after August 18, 2003,
including those paragraph IV certifications previously
excluded from notice requirements by the recently revoked provisions
of the Final Rule. Accordingly, all applicants with pending ANDAs
or 505(b)(2) applications that include paragraph IV certifications
made on or after August 18, 2003, but before December 8, 2003,
should have provided notice to NDA holders and patent owners in a
timely manner.
2. If, between August 18, 2003, and December 8, 2003, an
ANDA or 505(b)(2) applicant provided voluntary notice with respect
to a paragraph IV certification for which notice was not required
under the Final Rule, is the applicant considered to have satisfied
the MMA’s notice requirement?
The
applicant will have satisfied the MMA’s notice requirement if the
notice it gave complies with all applicable provisions of the MMA
(e.g., provisions specifying to whom notice must be given and the
notice’s required contents).
1. Does the MMA preclude ANDAs and 505(b)(2) applications
from being subject to more than one 30-month stay of approval?
The MMA
generally precludes multiple 30-month stays for those applications
to which it applies. The relevant provisions of the MMA apply to
patents submitted to FDA on or after August 18, 2003.
For ANDAs and 505(b)(2) applications with paragraph IV
certifications to a patent submitted to FDA on or after August 18,
2003, the MMA provides that a 30-month stay may be available for
litigation related to that patent only if the patent was submitted
to FDA before the date that the ANDA or 505(b)(2) application
(excluding an amendment or supplement) was submitted.
In other words, the MMA precludes 30-month stays for later listed
patents, that is, those patents submitted to FDA on or after the
date the ANDA or 505(b)(2) application was submitted. Because of
this limitation, in most cases, ANDAs and 505(b)(2) applications
will be subject to no more than one 30-month stay.
Multiple
30-month stays, however, still may be possible in certain cases.
For instance, an ANDA or 505(b)(2) application may contain a
paragraph IV certification to a patent at the time of first
submission that gives rise to one 30-month stay. If the same
application also contains a paragraph III certification to a
different patent that was submitted to FDA (1) on or after August
18, 2003, and (2) before the ANDA or 505(b)(2) application was
submitted, and the applicant subsequently converts this
certification to a paragraph IV certification, a second 30-month
stay could be possible. This is because the new paragraph IV
certification is subject to the MMA and references a patent
submitted to FDA before the applicant’s ANDA was submitted.
2. Does the MMA ensure that a patent owner or NDA holder can
obtain one 30-month stay of approval on an ANDA or 505(b)(2)
application containing a paragraph IV certification to a listed
patent when the patent owner or NDA holder sues the ANDA or
505(b)(2) applicant for patent infringement?
No. The MMA
does not guarantee that any patent owner or NDA holder will receive
a 30-month stay, even if it sues for patent infringement. Rather,
the MMA provides the opportunity to obtain a stay only in certain
situations. As noted in response to question 1 in subsection II.D
of this document, the amendments made by the MMA with respect to the
availability of 30-month stays apply to patents submitted to FDA on
or after August 18, 2003. With respect
to such patents, a 30-month stay of approval on an ANDA or 505(b)(2)
application containing a paragraph IV certification to the patent
will ensue if:
·
The patent was
submitted before the date that the ANDA or 505(b)(2) application
(excluding an amendment or supplement) was submitted to FDA,
and
·
The patent owner or
NDA holder initiates a patent infringement action on the patent
within 45 days of the date that it receives notice of the
certification.
No 30-month
stay of approval will result from a patent subject to the MMA, even
if litigation is initiated based on a paragraph IV certification to
the patent, if either of the conditions described above is not
satisfied. That is, no 30-month stay of approval will apply if the
patent was submitted to FDA on or after the date the
ANDA or 505(b)(2) application with a paragraph IV certification to
the patent was submitted. (Note that this is the case even if the
later-submitted patent is the first listed patent to claim the drug
described in the ANDA or 505(b)(2) application.) In addition, a
30-month stay will not ensue if litigation is initiated more than 45
days after the date that the patent owner or NDA holder receives
notice of the certification.
3. An ANDA was submitted to FDA in November 2003 with
multiple patent certifications, including a paragraph IV
certification to at least one patent. No patent infringement
lawsuit was initiated, but a new patent was submitted to FDA on
December 27, 2003. What are the ANDA applicant’s certification and
notification obligations? Is a 30-month stay of approval possible
based on the December 27 patent?
Under
section 505(j)(2)(A)(vii) of the Act (which was not amended by the
MMA), the ANDA applicant would be required to provide a
certification with respect to the December 27, 2003, patent. With
regard to notice, as discussed in response to question 1 in
subsection II.C of this document, the MMA amends section 505 of the
Act to make clear that ANDA and 505(b)(2) applicants must provide
notice of all paragraph IV certifications.
Accordingly, if the applicant amends its ANDA to include a paragraph
IV certification to the December 27, 2003, patent, it would be
required by the MMA to notify the patent owner and NDA holder of its
certification at the time its amendment is submitted.
As
previously discussed, the MMA provides that a 30-month stay cannot
arise from a patent submitted on or after August 18, 2003, unless
the patent was also submitted to FDA before the ANDA or 505(b)(2)
application was submitted.
Accordingly, no 30-month stay of approval would be possible based on
the December 27, 2003, patent in this question.
4.
Is a 30-month stay based on a patent possible if the patent
(1) is submitted to FDA on or after August 18, 2003, and before an
ANDA or 505(b)(2) application with a paragraph IV certification to
the patent is submitted, and (2) is not published in the Orange Book
before the application’s submission?
The patent
described in this question could provide the basis for a 30-month
stay if the other conditions for a stay, as discussed above, are
satisfied. As previously noted, under the MMA, a patent that is
submitted to FDA on or after August 18, 2003, could potentially
trigger a 30-month stay if it is also “submitted . . . before the
date on which the [ANDA] application (excluding an amendment or
supplement to the application) is submitted.”
Eligibility for a 30-month stay thus turns on when the patent is
submitted to FDA, as opposed to when it is published in the
Orange Book. Because the patent in this question meets the time
frames for submission specified in the MMA, it can result in a
30-month stay, regardless of when it is published in the Orange
Book.
What ANDAs are subject to the MMA’s new
180-day exclusivity provisions?
With two
exceptions, the new provisions relating to 180-day exclusivity
govern only ANDAs filed after the date of the MMA’s enactment
(December 8, 2003) that reference a listed drug for which no
paragraph IV certification was made in any ANDA before that date.
The two exceptions concern the forfeiture of 180-day exclusivity by
entering into a collusive agreement and the triggering of the
exclusivity period by judicial action.
All other ANDAs remain subject to the 180-day exclusivity provisions
in effect before the MMA’s enactment. Thus, for example, FDA’s
guidance for industry, 180-Day Exclusivity When Multiple ANDAs
Are Submitted on the Same Day, still applies to ANDAs submitted
before, on, or after December 8, 2003, that reference a listed drug
for which a paragraph IV certification had been made in any ANDA
before December 8, 2003. FDA will further interpret provisions of
the MMA relating to 180-day exclusivity in future regulations and/or
guidances.
What are the effective dates of the
various provisions of the MMA?
MMA Section
|
Amended or Added Sections of the Act |
Effective Date
or Scope of Applicability
|
1101(a)(1) and (b)(1)
(Amending or supplementing an application)
|
505(j)(2)(D) and 505(b)(4) |
A change
in listed drug or proposed drug made on or after December 8,
2003 |
1101(a)(1) and (b)(1)
(Notice
provisions) |
505(j)(2)(B) and 505(b)(3) |
Any
paragraph IV certification submitted on or after August 18, 2003
in an application, amendment, or supplement
|
1101(a)(2)(A)(ii)(I) and (b)(2)(B)(i)
(30-month stay provisions)
|
505(j)(5)(B)(iii) and 505(c)(3)(C) |
Retroactive to patent information submitted to FDA on or after
August 18, 2003 |
1101(a)(2)(A)(ii)(II) and (b)(2)(B)(ii)
(Court
decision provisions for approval)
|
505(j)(5)(B)(iii) and 505(c)(3)(C) |
Any
proceeding pending on or after
December 8, 2003, regardless
of the date on which the proceeding was or is commenced |
1101(a)(2)(C) and (b)(2)(D)
(Civil
action to obtain patent certainty)
|
505(j)(5)(C) and 505(c)(3)(D) |
Any
proceeding pending on or after
December 8, 2003, regardless
of the date on which the proceeding was or is commenced
|
1102(a)
(180-day
exclusivity period) |
505(j)(5)(B)(iv) and 505(j)(5)(D) |
ANDAs
filed after December 8, 2003 for a listed drug for which no
paragraph IV certification had been made in any ANDA before
December 8, 2003, except as provided in the box immediately
following
|
1102(a)(2)
(Collusive agreement forfeiture provision)
|
New
505(j)(5)(D)(i)(V) |
ANDAs
filed after December 8, 2003, regardless of when the first
paragraph IV certification was made for the listed drug
referenced in any ANDA
|
1102(b)(3)
(Meaning
of decision of a court that will trigger the beginning of
180-day exclusivity for certain ANDAs) |
505(j)(5)(B)(iv) |
ANDAs
for a listed drug for which a paragraph IV certification was
made in any ANDA before December 8, 2003, and for which there
was no court decision or commercial marketing that triggered
180-day exclusivity (under the Act pre-MMA) on or before
December 8, 2003
|
1103(a)
(Bioavailability/
bioequivalence) |
505(j)(8) |
December
8, 2003
|
See MMA Title XI section
1101(c)(3). The effective date for this provision means that
the MMA supersedes FDA’s Final Rule with respect to the
availability of 30-month stays. As noted earlier in response to
question 1 in subsection II.C of this document, on March 10,
2004, FDA revoked provisions of the Final Rule superseded by the
MMA (see footnote 20, supra).
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Date created: November 2, 2004 |