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

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes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notice announcing the availability of the draft guidance.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**

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

*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**

TABLE OF CONTENTS

I. INTRODUCTION [1](#i.-introduction)

II\. QUESTIONS AND ANSWERS [2](#questions-and-answers-2)

A. Listed Drug [2](#a.-listed-drug)

B. Role of Court Decisions and Other Judicial Action
[3](#b.-role-of-court-decisions-and-other-judicial-action)

C. Notice of Paragraph IV Certifications
[6](#c.-notice-of-paragraph-iv-certifications)

D. Multiple 30-Month Stays [8](#d.-multiple-30-month-stays)

E. 180-Day Exclusivity [10](#e.-180-day-exclusivity)

F. Applicability and Effective Dates
[11](#applicability-and-effective-dates)

#####  {#section .TOC-5}

Guidance for Industry[^1]

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,[^2] 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.

# QUESTIONS AND ANSWERS

## A. Listed Drug

**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.\"[^3] FDA\'s definition of
*listed drug* is contained in § 314.3 (21 CFR 314.3).[^4] 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.[^5] 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).

## B. Role of Court Decisions and Other Judicial Action

**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."[^6]

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.[^7] 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), [^8] or

```{=html}
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```
-   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, [^9] 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),[^10] 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.[^11]

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.[^12]

**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.[^13] This period is commonly referred to
as *180-day exclusivity*.[^14] 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.[^15]

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).[^16]
        (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.

## C. Notice of Paragraph IV Certifications

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.[^17] 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.[^18]

We recognize that our final rule which became effective on August 18,
2003 (Final Rule),[^19] 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.[^20]

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, [^21] 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). [^22]

## D. Multiple 30-Month Stays

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.[^23] 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.[^24] 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. [^25]

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

```{=html}
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```
-   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.[^26]

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.[^27] 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.[^28]

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.[^29] 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."[^30] 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.

## E. 180-Day Exclusivity

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.[^31] 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.[^32] 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.

## Applicability and Effective Dates

## 

**What are the effective dates of the various provisions of the MMA?**

+-----------------------+-------------------+--------------------------+
| MMA Section           | Amended or Added  | Effective Date           |
|                       | Sections of the   |                          |
|                       | Act               | or Scope of              |
|                       |                   | Applicability            |
+=======================+===================+==========================+
| 1101(a)(1) and (b)(1) | 505(j)(2)(D) and  | A change in listed drug  |
|                       | 505(b)(4)         | or proposed drug made on |
| (Amending or          |                   | or after December 8,     |
| supplementing an      |                   | 2003                     |
| application)          |                   |                          |
+-----------------------+-------------------+--------------------------+
| 1101(a)(1) and (b)(1) | 505(j)(2)(B) and  | Any paragraph IV         |
|                       | 505(b)(3)         | certification submitted  |
| (Notice provisions)   |                   | on or after August 18,   |
|                       |                   | 2003 in an application,  |
|                       |                   | amendment, or supplement |
+-----------------------+-------------------+--------------------------+
| 1101(a)(2)(A)(ii)(I)  | 505(j)(5)(B)(iii) | Retroactive to patent    |
| and (b)(2)(B)(i)      | and 505(c)(3)(C)  | information submitted to |
|                       |                   | FDA on or after August   |
| (30-month stay        |                   | 18, 2003                 |
| provisions)           |                   |                          |
+-----------------------+-------------------+--------------------------+
| 1101(a)(2)(A)(ii)(II) | 505(j)(5)(B)(iii) | Any proceeding pending   |
| and (b)(2)(B)(ii)     | and 505(c)(3)(C)  | on or after December 8,  |
|                       |                   | 2003, regardless of the  |
| (Court decision       |                   | date on which the        |
| provisions for        |                   | proceeding was or is     |
| approval)             |                   | commenced                |
+-----------------------+-------------------+--------------------------+
| 1101(a)(2)(C) and     | 505(j)(5)(C) and  | Any proceeding pending   |
| (b)(2)(D)             | 505(c)(3)(D)      | on or after December 8,  |
|                       |                   | 2003, regardless of the  |
| (Civil action to      |                   | date on which the        |
| obtain patent         |                   | proceeding was or is     |
| certainty)            |                   | commenced                |
+-----------------------+-------------------+--------------------------+
| 1102(a)               | 505(j)(5)(B)(iv)  | ANDAs filed after        |
|                       | and 505(j)(5)(D)  | December 8, 2003 for a   |
| (180-day exclusivity  |                   | listed drug for which no |
| period)               |                   | paragraph IV             |
|                       |                   | certification had been   |
|                       |                   | made in any ANDA before  |
|                       |                   | December 8, 2003, except |
|                       |                   | as provided in the box   |
|                       |                   | immediately following    |
+-----------------------+-------------------+--------------------------+
| 1102(a)(2)            | New               | ANDAs filed after        |
|                       | 5                 | December 8, 2003,        |
| (Collusive agreement  | 05(j)(5)(D)(i)(V) | regardless of when the   |
| forfeiture provision) |                   | first paragraph IV       |
|                       |                   | certification was made   |
|                       |                   | for the listed drug      |
|                       |                   | referenced in any ANDA   |
+-----------------------+-------------------+--------------------------+
| 1102(b)(3)            | 505(j)(5)(B)(iv)  | ANDAs for a listed drug  |
|                       |                   | for which a paragraph IV |
| (Meaning of *decision |                   | certification was made   |
| of a court* that will |                   | in any ANDA before       |
| trigger the beginning |                   | December 8, 2003, and    |
| of 180-day            |                   | for which there was no   |
| exclusivity for       |                   | court decision or        |
| certain ANDAs)        |                   | commercial marketing     |
|                       |                   | that triggered 180-day   |
|                       |                   | exclusivity (under the   |
|                       |                   | Act pre-MMA) on or       |
|                       |                   | before December 8, 2003  |
+-----------------------+-------------------+--------------------------+
| 1103(a)               | 505(j)(8)         | December 8, 2003         |
|                       |                   |                          |
| (Bioavailability/     |                   |                          |
|                       |                   |                          |
| bioequivalence)       |                   |                          |
+-----------------------+-------------------+--------------------------+

[^1]: This guidance has been prepared by the Office of Generic Drugs
    (OGD) in the Center for Drug Evaluation and Research (CDER) in
    cooperation with the Office of Regulatory Policy (ORP) and the
    Office of the Chief Counsel (OCC) at the Food and Drug
    Administration.

[^2]: See *Generic Drug Issues; Request for Comments* (69 FR 9982).

[^3]: The MMA added a related provision to the Act with respect to
    505(b)(2) applications: "An applicant may not amend or supplement
    \[a 505(b)(2) application\] to seek approval of a drug that is a
    different drug than the drug identified in the application as
    submitted to the Secretary" (section 505(b)(4)(A) of the Act). This
    guidance does not pertain to the foregoing provision on 505(b)(2)
    applications because that provision does not use the term *listed
    drug*, and the MMA only directs FDA to issue guidance with respect
    to the provision applicable to 505(j) applications.

[^4]: This definition reads:

    > *Listed drug* means a new drug product that has an effective
    > approval under section 505(c) of the \[A\]ct for safety and
    > effectiveness or under section 505(j) of the \[A\]ct, which has
    > not been withdrawn or suspended under section 505(e)(1) through
    > (e)(5) or (j)(5) of the \[A\]ct, and which has not been withdrawn
    > from sale for what FDA has determined are reasons of safety or
    > effectiveness. Listed drug status is evidenced by the drug
    > product's identification as a drug with an effective approval in
    > the current edition of FDA's "Approved Drug Products with
    > Therapeutic Equivalence Evaluations" \[commonly referred to as the
    > Orange Book\] or any current supplement thereto.... A drug product
    > is deemed to be a listed drug on the date of effective approval of
    > the application or abbreviated application for that drug product
    > (21 CFR 314.3(b)).

[^5]: Separate approved drug products, other than products with
    different strengths, will ordinarily have different NDA numbers.

[^6]: Section 505(c)(3)(C) and 505(j)(5)(B)(iii) of the Act.

[^7]: See MMA Title XI section 1101(c)(1).

[^8]: See MMA Title XI section 1101(a)(2)(A)(ii)(II)(aa) and
    1101(b)(2)(B)(ii)(II) (creating new section 505(j)(5)(B)(iii)(I)(aa)
    and 505(c)(3)(C)(i)(I) of the Act, respectively); see also MMA Title
    XI section 1101(a)(2)(A)(ii)(II)(cc) and 1101(b)(2)(B)(ii)(IV)
    (amending section 505(j)(5)(B)(iii)(III) and 505(c)(3)(C)(iii) of
    the Act, respectively).

[^9]: See MMA Title XI section 1101(a)(2)(A)(ii)(II)(aa) and
    1101(b)(2)(B)(ii)(II) (creating new section 505(j)(5)(B)(iii)(I)(bb)
    and 505(c)(3)(C)(i)(II) of the Act, respectively); see also MMA
    Title XI section 1101(a)(2)(A)(ii)(II)(cc) and 1101(b)(2)(B)(ii)(IV)
    (amending section 505(j)(5)(B)(iii)(III) and 505(c)(3)(C)(iii) of
    the Act, respectively).

[^10]: See MMA Title XI section 1101(a)(2)(A)(ii)(II)(bb) and
    1101(b)(2)(B)(ii)(III) (creating new section
    505(j)(5)(B)(iii)(II)(aa)(AA) and 505(c)(3)(C)(ii)(I)(aa) of the
    Act, respectively); see also MMA Title XI section
    1101(a)(2)(A)(ii)(II)(dd) and 1101(b)(2)(B)(ii)(V) (creating new
    section 505(j)(5)(B)(iii)(IV) and 505(c)(3)(C)(iv) of the Act,
    respectively).

[^11]: See MMA Title XI section 1101(a)(2)(A)(ii)(II)(bb) and
    1101(b)(2)(B)(ii)(III) (creating new section
    505(j)(5)(B)(iii)(II)(aa)(BB) and 505(c)(3)(C)(ii)(I)(bb) of the
    Act, respectively); see also MMA Title XI section
    1101(a)(2)(A)(ii)(II)(dd) and 1101(b)(2)(B)(ii)(V) (creating new
    section 505(j)(5)(B)(iii)(IV) and 505(c)(3)(C)(iv) of the Act,
    respectively).

[^12]: See MMA Title XI section 1101(a)(2)(A)(ii)(II)(bb) and
    1102(b)(2)(B)(ii)(III) (creating new section
    505(j)(5)(B)(iii)(II)(bb) and 505(c)(3)(C)(ii)(II) of the Act,
    respectively); see also MMA Title XI section
    1101(a)(2)(A)(ii)(II)(dd) and 1101(b)(2)(B)(ii)(V) (creating new
    section 505(j)(5)(B)(iii)(IV) and 505(c)(3)(C)(iv) of the Act,
    respectively).

[^13]: See section 505(j)(5)(B)(iv) of the Act.

[^14]: 505(b)(2) applications do not qualify for 180-day exclusivity.

[^15]: See section 505(j)(5)(B)(iv) of the Act; *Mylan Pharmaceuticals,
    Inc. v. Shalala*, 81 F. Supp. 2d 30 (D.D.C. 2000).

[^16]: See MMA Title XI section 1102(b)(3) (defining, for this purpose,
    *decision of a court* as used in section 505(j)(5)(B)(iv) of the
    Act).

[^17]: See MMA Title XI section 1101(a)(1)(A) and 1101(b)(1)(A)
    (amending section 505(j)(2)(B)(i) and 505(b)(3)(A) of the Act,
    respectively); see also MMA Title XI section 1101(c)(2).

[^18]: See MMA Title XI section 1101(a)(1)(A) and 1101(b)(1)(A)
    (amending section 505(j)(2)(B)(ii) and 505(b)(3)(B) of the Act,
    respectively).

[^19]: See *Applications for FDA Approval to Market a New Drug: Patent
    Submission and Listing Requirements and Application of 30-Month
    Stays on Approval of Abbreviated New Drug Applications Certifying
    That a Patent Claiming a Drug Is Invalid or Will Not Be Infringed*;
    Final Rule (68 FR 36676; June 18, 2003).

[^20]: See *Application of 30-Month Stays on Approval of Abbreviated New
    Drug Applications and Certain New Drug Applications Containing a
    Certification That a Patent Claiming the Drug Is Invalid or Will Not
    Be Infringed*; Technical Amendment (69 FR 11309; March 10, 2004).

[^21]: See MMA Title XI section 1101(c)(2).

[^22]: See MMA Title XI section 1101(a)(1)(A) and 1101(b)(1)(A)
    (amending section 505(j)(2)(B) and 505(b)(3) of the Act,
    respectively).

[^23]: 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).

[^24]: See MMA Title XI section 1101(a)(2)(A)(ii)(I) and
    1101(b)(2)(B)(i) (amending section 505(j)(5)(B)(iii) and
    505(c)(3)(C) of the Act, respectively).

[^25]: Under the regulations in effect before FDA adopted its August 18,
    2003, Final Rule, multiple 30-month stays could arise in the case of
    later-listed patents if (1) an ANDA or 505(b)(2) application had
    already been subject to one such stay based on a paragraph IV
    certification to a patent listed before the application's
    submission, and (2) the ANDA or 505(b)(2) applicant made a
    subsequent paragraph IV certification to a patent listed after the
    application's submission that triggered another timely patent
    infringement lawsuit.

[^26]: See MMA Title XI section 1101(a)(2)(A) and 1101(b)(2)(B)
    (amending section 505(j)(5)(B)(iii) and 505(c)(3)(C) of the Act,
    respectively); see also MMA Title XI section 1101(c)(3).

[^27]: See MMA Title XI section 1101(a)(1)(A) and 1101(b)(1)(A)
    (amending section 505(j)(2)(B)(i) and 505(b)(3)(A) of the Act,
    respectively); see also MMA Title XI section 1101(c)(2).

[^28]: See MMA Title XI section 1101(a)(1) (creating new section
    505(j)(2)(B)(ii)(II) of the Act).

[^29]: See MMA Title XI section 1101(a)(2)(A)(ii)(I) (amending section
    505(j)(5)(B)(iii) of the Act).

[^30]: MMA Title XI section 1101(a)(2)(A)(ii)(I) (amending section
    505(j)(5)(B)(iii) of the Act).

[^31]: See MMA Title XI section 1102(b)(1).

[^32]: The exception relating to forfeiture based on a first ANDA
    applicant's entry into an anti-competitive agreement applies if
    conditions specified in the MMA are met, regardless of when the
    first ANDA paragraph IV certification for the listed drug was made
    (see MMA Title XI section 1102(b)(2)). The second exception relates
    to the MMA's definition of the term *decision of a court* for
    purposes of section 505(j)(5)(B)(iv) of the Act. As discussed in
    response to question 2 in subsection II.B of this document, the
    MMA's definition of this term applies to alter the court decision
    trigger for 180-day exclusivity for all ANDAs other than those filed
    after December 8, 2003, for a listed drug for which no paragraph IV
    certification was made in any ANDA before that date (see MMA Title
    XI section 1102(b)(3)).