[Federal Register Volume 80, Number 25 (Friday, February 6, 2015)]
[Proposed Rules]
[Pages 6802-6896]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-01666]
[[Page 6801]]
Vol. 80
Friday,
No. 25
February 6, 2015
Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 314 and 320
Abbreviated New Drug Applications and 505(b)(2) Applications; Proposed
Rule
Federal Register / Vol. 80 , No. 25 / Friday, February 6, 2015 /
Proposed Rules
[[Page 6802]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 314 and 320
[Docket No. FDA-2011-N-0830]
RIN 0910-AF97
Abbreviated New Drug Applications and 505(b)(2) Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing
regulations to implement Title XI of the Medicare Prescription Drug,
Improvement, and Modernization Act of 2003 (MMA), which amended
provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act)
that govern the approval of 505(b)(2) applications and abbreviated new
drug applications (ANDAs). This proposed rule would implement portions
of Title XI of the MMA that pertain to provision of notice to each
patent owner and the new drug application (NDA) holder of certain
patent certifications made by applicants submitting 505(b)(2)
applications or ANDAs; the availability of 30-month stays of approval
on 505(b)(2) applications and ANDAs that are otherwise ready to be
approved; submission of amendments and supplements to 505(b)(2)
applications and ANDAs; and the types of bioavailability and
bioequivalence data that can be used to support these applications.
This proposed rule also would amend certain regulations regarding
505(b)(2) applications and ANDAs to facilitate compliance with and
efficient enforcement of the FD&C Act.
DATES: Submit either electronic or written comments on the proposed
rule by May 7, 2015. Submit comments on information collection issues
under the Paperwork Reduction Act of 1995 by March 9, 2015 (see the
``Paperwork Reduction Act of 1995'' section of this document). See
section VII of this document for the proposed effective date of a final
rule based on this document.
ADDRESSES: You may submit comments by any of the following methods,
except that comments on information collection issues under the
Paperwork Reduction Act of 1995 must be submitted to the Office of
Regulatory Affairs, Office of Management and Budget (OMB) (see the
``Paperwork Reduction Act of 1995'' section of this document).
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following way:
Mail/Hand delivery/Courier (For paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include Docket No. FDA-
2011-N-0830 for this rulemaking. All comments received may be posted
without change to http://www.regulations.gov, including any personal
information provided. For additional information on submitting
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION
section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Janice L. Weiner, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6268, Silver Spring, MD 20993-0002, 301-
796-3601.
SUPPLEMENTARY INFORMATION:
Table of Contents
Executive Summary
I. Background
A. Hatch-Waxman Amendments
B. Requirements for Patent Certification or Statement
C. Patent Listing Requirements
D. MMA
II. Description of the Proposed Rule
A. Definitions
1. Overview of New, Revised, and Relocated Definitions
2. Proposed Amendments to Definitions in Sec. 314.3
3. Proposed Amendments to Definitions in Current Sec. 314.108
4. Definitions in Current Sec. 320.1
B. Submission of Patent Information (Proposed Sec. 314.53)
1. General Requirements for Submission of Patent Information
(Proposed Sec. 314.53(b) and (c))
2. When and Where To Submit Patent Information (Proposed Sec.
314.53(d))
3. Public Disclosure of Patent Information (Proposed Sec.
314.53(e))
4. Correction or Change of Patent Information (Proposed Sec.
314.53(f))
C. Patent Certification (Proposed Sec. Sec. 314.50(i) and
314.94(a)(12))
1. Method-of-Use Patents (Proposed Sec. Sec. 314.50(i)(1)(iii)
and 314.94(a)(12)(iii))
2. Method-of-Manufacturing Patents (Proposed Deletion of
Sec. Sec. 314.50(i)(2) and 314.94(a)(12)(iv))
3. Licensing Agreement (Proposed Sec. 314.50(i)(3))
D. Notice of Paragraph IV Certification (Proposed Sec. Sec.
314.52 and 314.95)
1. Timing of Notice
2. Notice Required for All Paragraph IV Certifications
3. Contents of Notice
4. Documentation of Timely Sending and Receipt of Notice
5. Administrative Consequence for Late Notice
E. Amended Patent Certifications (Proposed Sec. Sec.
314.50(i)(6) and 314.94(a)(12)(viii))
1. Amended Patent Certifications After a Finding of Infringement
2. Amended Certifications After Request by the NDA Holder to
Remove a Patent or Patent Information from the List
3. Amended Certifications Upon Patent Reissuance
4. Other Amended Certifications
F. Patent Certification Requirements for Amendments and
Supplements to 505(b)(2) Applications and ANDAs (Proposed Sec. Sec.
314.60, 314.70, 314.96, and 314.97)
1. Types of Amendments or Supplements for Which Patent
Certification is Required
2. Requirements for Notice of Paragraph IV Certifications and
Implications for 180-day Exclusivity
G. Amendments or Supplements to a 505(b)(2) Application for a
Different Drug and Amendments or Supplements to an ANDA That
Reference a Different Listed Drug (Proposed Sec. Sec. 314.60,
314.70, 314.96, and 314.97)
1. Amendments to an Unapproved ANDA (Proposed Sec. 314.96(c))
2. Supplements to an ANDA (Proposed Sec. 314.97(b))
3. Amendments to an Unapproved 505(b)(2) Application (Proposed
Sec. 314.60(e))
4. Supplements to a 505(b)(2) Application (Proposed Sec.
314.70(h))
H. Procedure for Submission of an Application Requiring
Investigations for Approval of a New Indication for, or Other Change
From, a Listed Drug (Proposed Sec. 314.54)
I. Petition to Request a Change From a Listed Drug (Proposed
Sec. 314.93)
J. Filing an NDA and Receiving an ANDA (Proposed Sec. 314.101)
1. Notification of Filing of a 505(b)(2) Application or Receipt
of an ANDA
2. Other Proposed Revisions
K. Approval of an NDA and ANDA (Proposed Sec. 314.105)
[[Page 6803]]
L. Refusal to Approve an NDA or ANDA (Proposed Sec. Sec.
314.125 and 314.127 and Related Provisions in Proposed Sec. Sec.
314.90 and 314.99)
M. Date of Approval of a 505(b)(2) Application or ANDA (Proposed
Sec. 314.107)
1. General (Proposed Sec. 314.107(a))
2. Effect of Patent(s) on the Listed Drug (Proposed Sec.
314.107(b))
3. Subsequent ANDA Submission (Proposed Sec. 314.107(c))
4. Delay of Approval Due to Exclusivity (Proposed Sec.
314.107(d))
5. Notification of Court Actions or Documented Agreement
(Proposed Sec. 314.107(e))
6. Computation of the 45-Day Time Clock (Proposed Sec.
314.107(f))
7. Conversion of Approval to Tentative Approval (Proposed Sec.
314.107(g))
N. Assessing Bioavailability and Bioequivalence for Drugs Not
Intended To Be Absorbed Into the Bloodstream (Proposed Sec. 320.23)
O. Miscellaneous
1. Clarifying Revisions and Editorial Changes
2. Effect of Other Rulemaking
III. Legal Authority
IV. Analysis of Impacts
A. Summary of the Benefits and Costs of the Proposed Rule
B. Summary of the Regulatory Flexibility Analysis
V. Paperwork Reduction Act of 1995
VI. Environmental Impact
VII. Effective Date
VIII. Federalism
IX. Request for Comments
X. References
Executive Summary
Purpose of the Regulatory Action
This proposed rule would implement portions of Title XI of the MMA
and revise and clarify FDA regulations relating to 505(b)(2)
applications and ANDAs in a manner intended to reduce unnecessary
litigation, reduce delays in the approval of 505(b)(2) applications and
ANDAs that are otherwise ready to be approved, and provide business
certainty to both brand name and generic drug manufacturers. The MMA
and sections 505, 505A, and 527 of the FD&C Act (21 U.S.C. 355, 355a,
and 360cc), in conjunction with our general rulemaking authority in
section 701(a) of the FD&C Act (21 U.S.C. 371(a)), serve as our
principal legal authority for this proposal.
Title XI of the MMA addressed two key concerns identified in a
Federal Trade Commission (FTC) report on anticompetitive strategies
that may delay access to generic drugs by: (1) Limiting the
availability of 30-month stays of approval on 505(b)(2) applications
and ANDAs that are otherwise ready to be approved and (2) establishing
conditions under which a first applicant would forfeit the 180-day
exclusivity period such that approval of subsequent ANDAs would no
longer be blocked. FDA has been implementing the MMA directly from the
statute for several years. Based on this experience, FDA is proposing
to amend its regulations to implement portions of the MMA that pertain
to 30-month stays and other matters not related to 180-day exclusivity.
FDA is proposing to amend its regulations regarding 505(b)(2)
applications and ANDAs to facilitate compliance with and efficient
enforcement of the FD&C Act, and to clarify and update these
regulations based on recent court decisions and our practical
experience implementing provisions related to the approval of 505(b)(2)
applications and ANDAs. For example, we are proposing to clarify
requirements for the NDA holder's description of the patented method of
use (the ``use code'') required for publication in FDA's ``Approved
Drug Products With Therapeutic Equivalence Evaluations'' (commonly
known as the Orange Book) to avoid overbroad use codes that may delay
approval of generic drugs. This is intended to facilitate FDA's
implementation of the statutory provisions that permit 505(b)(2) and
ANDA applicants to omit (``carve out'') protected conditions of use
from labeling and obtain approval for conditions of use that are not
covered by unexpired patents or exclusivity. As the U.S. Supreme Court
recently noted in Caraco Pharm. Labs. v. Novo Nordisk A/S: ``An
overbroad use code . . . throws a wrench into the FDA's ability to
approve generic drugs as the statute contemplates'' (132 S. Ct. 1670,
at 1684 (2012)).
Finally, we are proposing to update the regulations to codify FDA's
current practice and policy and thereby promote transparency.
Summary of the Major Provisions of the Regulatory Action
Submission of Patent Information. The proposed rule would revise
and streamline requirements related to submission of patent information
on: (1) Patents that claim the drug substance and/or drug product and
meet the requirements for patent listing on that basis; (2) drug
substance patents that claim only a polymorph of the active ingredient;
and (3) certain NDA supplements. The proposed rule would clarify
requirements for the submission of information related to patents that
have been reissued by the Patent and Trademark Office (PTO). The
proposed rule describes our approach to treating the original and
reissued patents as a ``single bundle'' of patent rights, which first
became relevant to approval of 505(b)(2) applications and ANDAs with
the submission of the original patent information.
We are proposing to codify our long-standing requirement that the
NDA holder's description of the patented method of use required for
publication in the Orange Book must contain adequate information to
assist FDA and 505(b)(2) and ANDA applicants in determining whether a
listed method-of-use patent claims a use for which the 505(b)(2) or
ANDA applicant is not seeking approval. To restrain overbroad use
codes, the proposed rule would expressly require that if the scope of
the method-of-use claim(s) of the patent does not cover every approved
use of the drug, the NDA holder's use code must describe only the
specific portion(s) of the indication or other method of use claimed by
the patent.
Timing of Submission of Patent Information. We are proposing to
expressly describe our current practice with respect to listing patent
information that has not been submitted to FDA within 30 days after
patent issuance. Although we list untimely filed patents pursuant to
section 505(c)(2) of the FD&C Act, we generally do not require an
applicant with a pending 505(b)(2) application or ANDA to provide a
patent certification to the untimely filed patent. Thus, the untimely
filed patent will neither delay approval of a pending 505(b)(2)
application or ANDA until patent expiration nor necessitate a carve-out
of information related to a patented method of use.
We are proposing to expand the category of untimely filed patent
information to include certain amendments to the NDA holder's
description of the approved method(s) of use claimed by the patent, if
such changes do not relate to a corresponding change in approved
labeling or are submitted more than 30 days after such labeling change.
This proposed regulatory revision is intended to reduce delays in
approval related to manipulation of patent use codes in a manner not
contemplated by the FD&C Act.
In addition, we are proposing to establish that the submission date
of patent information provided by an NDA holder after approval would be
the earlier of the date on which Form FDA 3542 is date-stamped by the
Office of Generic Drugs (OGD) Document Room or officially received
electronically by FDA. These proposed revisions are intended to
facilitate prompt listing in the Orange Book and to remove any
[[Page 6804]]
ambiguity about the date of submission in light of the implications for
the patent certification obligations of 505(b)(2) and ANDA applicants
that rely upon the listed drug.
Correction or Change of Patent Information. We are proposing to
enhance FDA's response to challenges to the accuracy or relevance of
submissions of patent use code information to the Agency, in certain
circumstances. If, in response to such a challenge, the NDA holder
confirms the accuracy of the information, fails to timely respond, or
submits a revision to the use code that does not provide adequate
clarity for FDA to determine whether the scope of a proposed labeling
carve-out would be appropriate based on the NDA holder's use code and
approved labeling, we are proposing to review proposed labeling carve-
out(s) for the 505(b)(2) application or ANDA with deference to the
505(b)(2) or ANDA applicant's interpretation of the scope of the
patent. In addition, we are proposing to expressly require the
correction or change of patent information by the NDA holder if: (1)
The patent or patent claim no longer meets the statutory requirements
for listing; (2) the NDA holder is required by court order to amend
patent information or withdraw a patent from the list; or (3) the term
of a listed patent is extended under patent term restoration
provisions. These proposed revisions would facilitate implementation of
the MMA provision related to patent withdrawal and efficient
enforcement of the FD&C Act.
Notice of Paragraph IV Certification--Timing. We are proposing to
revise our regulations to clearly delineate the two limitations on the
time frame within which notice of a paragraph IV certification can be
provided to the NDA holder and each patent owner: (1) The date before
which notice may not be given (reflecting FDA's long-standing practice)
and (2) the date, established by MMA, by which notice must be given.
For an original application, a 505(b)(2) or ANDA applicant must
send notice of a paragraph IV certification on or after the date on
which it receives an ``acknowledgment letter'' or a ``paragraph IV
acknowledgment letter'' from FDA stating that the application is
sufficiently complete to permit a substantive review, but not later
than 20 days after the date of the ``postmark'' (as defined in the
proposed rule) on such letter.
For an amendment or supplement, a 505(b)(2) or ANDA applicant must
send notice of a paragraph IV certification contained in an amendment
to an application (that has been received for substantive review) or in
a supplement to an approved application at the same time that the
amendment or supplement is submitted to FDA. We are proposing to
establish a date (the first working day after the day the patent is
published in the Orange Book) before which an ANDA applicant cannot
send valid notice of a paragraph IV certification to a newly listed
patent. This approach is intended to promote equity among ANDA
applicants seeking eligibility for 180-day exclusivity and to reduce
the burden on industry and FDA associated with serial submissions and
multiple notices of paragraph IV certifications related to a newly
issued patent.
Notice of a paragraph IV certification that has been sent
prematurely is invalid, and will not be considered to comply with the
FD&C Act's notice requirement. We are proposing administrative
consequences for ANDA applicants who fail to send notice of paragraph
IV certification within the statutory time frame established by the
MMA. The date the ANDA was submitted would be deemed to be delayed by
the number of days by which the time frame was exceeded, which may
result in the applicant losing eligibility for 180-day exclusivity.
Notice of Paragraph IV Certification--Content and Methods. We are
proposing revisions to the content of notice of a paragraph IV
certification to incorporate requirements added by the MMA and to
support the efficient enforcement of our regulations. We also are
proposing to expand the acceptable methods of sending notice of a
paragraph IV certification beyond registered or certified mail to
include ``designated delivery services.'' This would reduce the burden
on 505(b)(2) and ANDA applicants who currently must submit requests to
send notice by common alternate delivery methods.
Amended Patent Certifications. We are proposing to clarify the
requirements for a 505(b)(2) or ANDA applicant to amend a paragraph IV
certification after a judicial finding of patent infringement to
reflect statutory changes made by the MMA. We also are proposing to
clarify the circumstances and time frame in which a 505(b)(2) or ANDA
applicant must submit an amended patent certification after an NDA
holder has withdrawn a patent and requested removal of the patent from
the Orange Book. The proposed rule would codify our current practice of
not removing a withdrawn patent from the list until FDA has determined
that no first applicant is eligible for 180-day exclusivity or such
exclusivity is extinguished, and exempting 505(b)(2) applicants from
providing or maintaining a certification to withdrawn patents. The
proposed rule also clarifies an applicant's current patent
certification obligations with respect to a reissued patent, and
proposes implications for 180-day exclusivity and a 30-month stay. In
addition, the proposed rule would expressly codify the current
requirement for a 505(b)(2) or ANDA applicant to submit a patent
certification to a newly issued patent that claims the listed drug or
an approved method of use.
Amendments or Supplements: Patent Certification Requirements. We
are proposing to clarify and augment the patent certification
requirements for amendments and supplements to 505(b)(2) applications
and ANDAs to ensure that changes to the drug product that could be
protected by patent are accompanied by a new patent certification. A
new patent certification currently is required to accompany an
amendment or supplement to add a new indication or other condition of
use, or to add a new strength or change an existing strength. The
regulations also currently require a patent certification to be amended
if, at any time before approval, the applicant learns that the
previously submitted patent certification is no longer accurate. We are
proposing to augment this regulation by requiring a new patent
certification with an amendment to make other-than-minor changes in
product formulation or to change the physical form or crystalline
structure of the active ingredient.
Limitation on Submission of Certain Amendments and Supplements to a
505(b)(2) Application or ANDA. We are proposing to codify our current
interpretation of the MMA's prohibition on submitting an amendment or a
supplement to seek approval of: (1) ``[A] drug that is a different
drug'' than the drug identified in the original 505(b)(2) application;
or (2) ``a drug referring to a different listed drug'' than the drug
cited as the basis for ANDA submission. We are implementing these
parallel restrictions on submission of certain types of changes in an
amendment or a supplement to a 505(b)(2) application or ANDA in a
manner that is consistent with the statutory text and preserves a
meaningful opportunity for a single 30-month stay.
505(b)(2) Applications. We are proposing to require a 505(b)(2)
applicant to identify a pharmaceutically equivalent product, if already
approved, as a listed drug relied upon, and comply with applicable
regulatory requirements. This is intended to help ensure that the
505(b)(2) pathway is not used to circumvent the statutory patent
[[Page 6805]]
certification obligations that would have applied if the proposed
product was not ineligible for approval in an ANDA.
Date of Approval of a 505(b)(2) Application or ANDA. The proposed
rule would describe, in a more comprehensive manner, the timing of
approval of a 505(b)(2) application or ANDA based on the patent
certification(s) or statement(s) submitted by the 505(b)(2) or ANDA
applicant. We are proposing to revise the regulations to reflect the
MMA's limitation on multiple 30-month stays of approval of a 505(b)(2)
application or an ANDA containing a paragraph IV certification to
certain patents submitted to FDA on or after August 18, 2003.
We are proposing to clarify that the statutory 30-month stay begins
on the later of the date of receipt of notice of paragraph IV
certification by any owner of the listed patent or by the NDA holder
who is an exclusive licensee (or their representatives). This proposed
revision codifies our current practice and provides an efficient means
of ensuring that each patent owner or NDA holder receives the full
statutory 30-month stay.
We are proposing to codify the MMA's amendments that clarify the
type of Federal district and appellate court decisions in patent
litigation that will terminate a 30-month stay and lead to approval of
a 505(b)(2) application or ANDA that is otherwise eligible for
approval. We also are proposing to address other scenarios in which a
stay may be terminated, including written consent to approval by the
patent owner or exclusive patent licensee, a court order terminating
the stay, or a court order of dismissal without a finding of
infringement. This is intended to avoid unnecessary delays in approval
of generic drugs while upholding the statutory purpose of the stay
(i.e., to allow time for patent infringement claims to be litigated
prior to approval of the potentially infringing product).
Notification of Commercial Marketing. We are proposing to update
the regulations to reflect the MMA provisions that modify the types of
events that can trigger the start of the 180-day exclusivity period. A
first applicant would be required to submit correspondence to its ANDA
notifying FDA within 30 days of the date of first commercial marketing
of the drug product. If the first applicant does not notify FDA within
this time frame, we are proposing to deem the date of first commercial
marketing to be the date of the drug product's approval. This may have
the effect of shortening the 180-day exclusivity period in a similar
manner to the current regulatory consequence for failure to provide
``prompt'' notice of first commercial marketing.
Notification of Court Actions or Documented Agreements. We are
proposing to expand the scope of documentation that an applicant must
submit to FDA regarding patent-related court actions and documented
agreements to ensure that FDA is promptly advised of information that
may affect the timing of approval of a 505(b)(2) application or ANDA.
Costs and Benefits
FDA is proposing to amend the regulations for further
implementation of and consistency with the MMA and to make other
changes related to 505(b)(2) applications and ANDAs. These changes
would improve transparency, facilitate compliance and enforcement, and
preserve the balance struck in the Drug Price Competition and Patent
Term Restoration Act of 1984 (Pub. L. 98-417).
Although many provisions of this proposed rule would codify current
practice, elements of this proposal would lead to changes that generate
additional benefits and costs. The estimated annual monetized benefits
of this proposed rule are $194,314, and estimated annual monetized
costs are $91,371. We have identified, but are unable to quantify,
impacts from proposed changes to submitted patent information and the
implementation of an administrative consequence for ANDA applicants who
fail to provide notice of a paragraph IV certification within the time
frame required by the MMA.
I. Background
On December 8, 2003, the MMA (Pub. L. 108-173) was signed into law.
Title XI of the MMA significantly amended provisions of the FD&C Act
that govern the approval of NDAs described by section 505(b)(2) of the
FD&C Act (21 U.S.C. 355(b)(2)) (505(b)(2) applications) and ANDAs
described by section 505(j) of the FD&C Act.
I.A. Hatch-Waxman Amendments
The 505(b)(2) application and ANDA approval pathways were enacted
as part of the Drug Price Competition and Patent Term Restoration Act
of 1984 (Pub. L. 98-417) (Hatch-Waxman Amendments). The Hatch-Waxman
Amendments reflect Congress's efforts to balance the need to ``make
available more low cost generic drugs by establishing a generic drug
approval procedure for pioneer drugs first approved after 1962'' with
new incentives for drug development in the form of marketing
exclusivity and patent term extensions (see H. Rept. 98-857, part 1, at
14-15 (1984), reprinted in 1984 U.S. Code Congressional and
Administrative News 2647 at 2647-2648). With passage of the Hatch-
Waxman Amendments, the FD&C Act describes different routes for
obtaining approval of two broad categories of drug applications: An
NDA, for which the requirements are set out in section 505(b) and (c)
of the FD&C Act, and an ANDA, for which the requirements are set out in
section 505(j). These categories can be further subdivided into a
``stand-alone'' NDA, a 505(b)(2) application, an ANDA, and a petitioned
ANDA.
A ``stand-alone NDA'' is an application submitted under section
505(b)(1) of the FD&C Act that contains full reports of investigations
of safety and effectiveness that were conducted by or for the applicant
or for which the applicant has a right of reference or use.
A 505(b)(2) application is an NDA that contains full reports of
investigations of safety and effectiveness, where at least some of the
information required for approval comes from studies not conducted by
or for the applicant and for which the applicant has not obtained a
right of reference or use (e.g., published literature or the Agency's
finding of safety and/or effectiveness for one or more listed drugs).
An ANDA is an application for a duplicate of a previously approved
drug that is submitted under the abbreviated approval pathway described
in section 505(j) of the FD&C Act. An ANDA must contain information to
show that the proposed product is the same as a previously approved
drug (the reference listed drug or RLD) with respect to active
ingredient, dosage form, route of administration, strength, labeling,
and conditions of use, among other characteristics. An ANDA applicant
also must demonstrate that its proposed product is bioequivalent to the
drug product selected by the Agency as the reference standard for
assessing bioequivalence with the RLD (see section II.A.2.z). (We note
that the drug product designated as the RLD may not necessarily be the
drug product identified in the Orange Book as the reference standard
for bioequivalence studies, for example, for drug product lines with
multiple strengths.) An applicant that can meet the requirements for
approval under section 505(j) of the FD&C Act may rely upon the
Agency's finding of safety and effectiveness for the RLD and need not
repeat the extensive nonclinical and clinical investigations required
for approval of a ``stand-alone'' NDA
[[Page 6806]]
submitted under section 505(b)(1) of the FD&C Act.
A ``petitioned ANDA'' is a type of ANDA for a drug that differs
from a previously approved drug product in dosage form, route of
administration, strength, or active ingredient (in a product with more
than one active ingredient), for which FDA has determined, in response
to a suitability petition submitted under section 505(j)(2)(C) of the
FD&C Act, that clinical studies are not necessary to demonstrate safety
and effectiveness.
The timing of approval for a 505(b)(2) application and an ANDA
(including a petitioned ANDA) is subject to the patent and marketing
exclusivity protections accorded the listed drug(s) relied upon and the
RLD, respectively. An NDA applicant (including a 505(b)(2) applicant)
is required to ``file with the application the patent number and the
expiration date of any patent which claims the drug for which the
applicant submitted the application or which claims a method of using
such drug and with respect to which a claim of patent infringement
could reasonably be asserted if a person not licensed by the owner
engaged in the manufacture[,] use, or sale of the drug'' (section
505(b)(1) of the FD&C Act). Upon approval of an application under
section 505(c) of the FD&C Act, we publish the patent information
provided by the applicant in the Orange Book, available electronically
on FDA's Web site at http://www.fda.gov/cder.
I.B. Requirements for Patent Certification or Statement
A 505(b)(2) application and ANDA must include a patent
certification described in section 505(b)(2) or 505(j)(2)(A)(vii) of
the FD&C Act, respectively, for each timely filed patent that claims
the listed drug(s) relied upon or RLD, respectively, or a method of
using the drug for which the applicant is seeking approval and for
which information is required to be filed under section 505(b) or
505(c) of the FD&C Act. For each unexpired patent listed in the Orange
Book, the 505(b)(2) or ANDA applicant must submit either a paragraph
III certification (section 505(b)(2)(A)(iii) or 505(j)(2)(A)(vii)(III)
of the FD&C Act) (delaying approval until the date on which such patent
will expire), a paragraph IV certification (section 505(b)(2)(A)(iv) or
505(j)(2)(A)(vii)(IV) of the FD&C Act) (certifying that such patent is
invalid or will not be infringed by the manufacture, use, or sale of
the drug product for which the 505(b)(2) application or ANDA is
submitted), or, with respect to a method-of-use patent, a statement
that the patent does not claim a use for which the applicant is seeking
approval (section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act).
If the patent information has not been filed with FDA (i.e., is not
listed in the Orange Book because the patent information has not been
submitted or is not eligible for listing) or the patent has expired, a
505(b)(2) or ANDA applicant may submit a paragraph I certification or
paragraph II certification, respectively (see section 505(b)(2)(A)(i)
and (ii) and 505(j)(2)(A)(vii)(I) and (II) of the FD&C Act). If, in the
opinion of the 505(b)(2) or ANDA applicant and to the best of their
knowledge, there are no patents that claim the listed drug(s) relied
upon or the RLD, respectively, or that claim a use of such drug, the
505(b)(2) or ANDA applicant may submit a ``no relevant patents''
certification (see Sec. 314.50(i)(1)(ii) or Sec. 314.94(a)(12)(ii)
(21 CFR 314.50(i)(1)(ii) or 314.94(a)(12)(ii)).
An applicant submitting a paragraph IV certification is required to
give notice of its paragraph IV certification to the holder of the NDA
for the listed drug(s) relied upon or RLD and each owner of the patent
that is the subject of the certification. Notice of a paragraph IV
certification subjects the 505(b)(2) or ANDA applicant to the risk that
it will be sued for patent infringement. If the NDA holder or patent
owner initiates a patent infringement action within 45 days after
receiving notice of the paragraph IV certification, there generally
will be a statutory 30-month stay of approval of the 505(b)(2)
application or ANDA while the patent infringement litigation is pending
(see section 505(c)(3)(C) and (j)(5)(B)(ii) of the FD&C Act). ANDA
applicants have a statutory incentive to challenge listed patents that
may be invalid, unenforceable, or not infringed by the drug product
described in the ANDA. The first applicant to submit a substantially
complete ANDA that contains, and for which the applicant lawfully
maintains, a paragraph IV certification may be eligible for a 180-day
period of marketing exclusivity (180-day exclusivity) during which
approval of subsequent ANDAs containing a paragraph IV certification to
a listed patent for the same drug product will not be granted (see
section 505(j)(5)(B)(iv) of the FD&C Act).
I.C. Patent Listing Requirements
In July 2002, the FTC published a report on ``Generic Drug Entry
Prior to Patent Expiration: An FTC Study'' (FTC Report) that, among
other things, identified circumstances in which ANDA applicants were
delayed in entering the market (see http://www.ftc.gov/sites/default/files/documents/reports/generic-drug-entry-prior-patent-expiration-ftc-study/genericdrugstudy_0.pdf). These circumstances included multiple
30-month stays of approval (related to paragraph IV certifications for
additional patents listed after ANDA submission) and a delay in
``triggering'' the start of a first applicant's 180-day period of
marketing exclusivity thereby blocking subsequent ANDA applicants. In
response to the FTC Report, FDA published a proposed rule in October
2002 to amend its patent listing requirements and to permit only a
single 30-month stay of approval for a 505(b)(2) application or ANDA
(see 67 FR 65448, October 24, 2002) (October 2002 proposed rule). The
final rule on ``Applications for FDA Approval to Market a New Drug:
Patent Submission and Listing Requirements and Application of 30-Month
Stays on Approval of [ANDAs] Certifying That a Patent Claiming a Drug
Is Invalid or Will Not Be Infringed'' was published in June 2003 (68 FR
36676, June 18, 2003) (June 2003 final rule).
I.D. MMA
The MMA was enacted on December 8, 2003, and superseded certain
sections of the June 2003 final rule regarding the application of 30-
month stays of approval of certain 505(b)(2) applications and ANDAs;
the superseded regulations were subsequently revoked by technical
amendment (see ``Application of 30-Month Stays on Approval of [ANDAs]
and Certain [NDAs] Containing a Certification That a Patent Claiming
the Drug Is Invalid or Will Not Be Infringed; Technical Amendment'' (69
FR 11309, March 10, 2004).
Title XI of the MMA addressed two key concerns identified in the
FTC Report by limiting the availability of 30-month stays of approval
on 505(b)(2) applications and ANDAs that are otherwise ready to be
approved (30-month stays) and by establishing conditions under which a
first applicant would forfeit the 180-day exclusivity period such that
approval of subsequent ANDAs would no longer be blocked. Section 1101
of the MMA provides that a 30-month stay of approval of a 505(b)(2)
application or ANDA is available only if patent infringement litigation
was initiated within the 45-day period after receipt of notice of a
paragraph IV certification for a patent that had been submitted to FDA
before the date of submission of the 505(b)(2) application or ANDA
(excluding an amendment or supplement to the
[[Page 6807]]
application). The resulting incentive for an applicant to change the
listed drug relied upon through an amendment of or a supplement to a
505(b)(2) application or ANDA is addressed by the MMA's prohibition of
the submission of certain types of changes (including those requiring
reference to a different listed drug) in an amendment of or supplement
to a 505(b)(2) application or ANDA. In addition, section 1101 of the
MMA amended the FD&C Act to specify the types of court actions that
will terminate a 30-month stay of approval.
Section 1101 of the MMA also created new requirements for 505(b)(2)
and ANDA applicants sending notice of a paragraph IV certification,
including changes to the timing and contents of such notice. In
addition, the MMA established conditions under which a 505(b)(2) or
ANDA applicant may bring a declaratory judgment action to obtain
``patent certainty'' (i.e., obtain a judicial determination of non-
infringement, invalidity, or unenforceability) with respect to a listed
patent for which it has given notice of a paragraph IV certification
but has not been sued by the NDA holder or patent owner(s) within the
statutory timeframe. If a patent infringement action is initiated
against the 505(b)(2) or ANDA applicant, the MMA provides that the
applicant may assert a counterclaim seeking an order requiring a
correction or deletion of the patent information submitted to FDA for
listing by the NDA holder or patent owner.
Section 1102 of the MMA altered the conditions under which a 180-
day period of marketing exclusivity is granted by requiring, among
other things, that a first applicant lawfully maintain the paragraph IV
certification contained in its submission of a substantially complete
ANDA. In addition, section 1102 of the MMA established conditions under
which a first applicant would forfeit the 180-day exclusivity period.
Section 1103 of the MMA clarified the types of bioavailability and
bioequivalence data that can be used to support a 505(b)(2) application
or ANDA for a drug that is not intended to be absorbed into the
bloodstream.
On March 3, 2004, we published a notice in the Federal Register
entitled ``Generic Drug Issues; Request for Comments'' (69 FR 9982)
(Request for MMA Comments) which invited public comment to further
identify issues related to the MMA provisions regarding 30-month stays,
180-day exclusivity, and bioavailability and bioequivalence, along with
any suggestions for how to resolve those issues. Comments received in
response to the Agency's Request for MMA Comments are addressed in this
document, as appropriate.
We are currently implementing the 180-day exclusivity provisions of
the MMA directly from the statute and will determine if additional
rulemaking is necessary in the future. Where a novel issue of
interpretation is raised by a particular factual scenario regarding
forfeiture of 180-day exclusivity, we may open a public docket or
otherwise seek comment from affected parties in advance of taking
action (see, e.g., Docket Nos. FDA-2007-N-0445 (acarbose tablets), FDA-
2007-N-0269 (granisetron hydrochloride injection), FDA-2007-N-0035
(ramipril capsules), and FDA-2008-N-0483 (dorzolamide hydrochloride--
timolol maleate ophthalmic solution), available at http://www.regulations.gov).
We invite interested parties to comment on any aspect of this
proposed rule. In addition to requesting general comments on this
proposal, we have identified issues throughout this document on which
we are specifically seeking comments.
II. Description of the Proposed Rule
This proposed rule implements portions of the MMA that pertain to
30-month stays and other matters not related to 180-day exclusivity,
and makes our regulations governing 505(b)(2) applications and ANDAs
consistent with amendments made to the FD&C Act by the MMA. In
addition, FDA is proposing to amend its regulations regarding 505(b)(2)
applications and ANDAs to facilitate compliance with and efficient
enforcement of the FD&C Act, and to clarify and update these
regulations based on our practical experience implementing the
provisions related to approval of 505(b)(2) applications and ANDAs.
Table 1 summarizes the proposed changes related to FDA's patent
listing, patent certification, and 30-month stay regulations in part
314 (21 CFR part 314) and bioavailability and bioequivalence
regulations in part 320 (21 CFR part 320):
Table 1--Highlights of Proposed Changes to FDA's Patent Listing, Patent
Certification, and 30-Month Stay Regulations \1\
------------------------------------------------------------------------
Proposed Changes See section of this
21 CFR Section to which changes document (identified in parentheses)
apply for more detailed information
regarding the proposed change
------------------------------------------------------------------------
314.3............................. Overview of New, Revised, and
Relocated Definitions (II.A.1).
Proposed Amendments to Definitions
in Sec. 314.3 (II.A.2).
Definitions in Current Sec.
314.108 (II.A.3).
Definitions in Current Sec. 320.1
(II.A.4).
314.50(i)(1)...................... Patent Certification Requirements
for Method-of-Use Patents (II.C.1).
Procedure for Submission of an
Application Requiring
Investigations for Approval of a
New Indication for, or Other Change
From, a Listed Drug (II.H).
314.50(i)(2)...................... Patent Certification Requirements
for Method-of-Manufacturing
Patents.
(II.C.2).
314.50(i)(3)...................... Licensing Agreements (II.C.3).
314.50(i)(4)...................... Untimely Filing of Patent
Information (II.B.2).
314.50(i)(6)...................... Amended Patent Certifications,
including:
a. Amended patent certifications
after a finding of infringement;
b. Amended certifications after a
request by the NDA holder to remove
a patent from the list;
c. Amended certifications upon
patent reissuance; and
d. Other amended certifications.
(II.E.1 through II.E.4).
314.52(b) and (d)................. Timing of Notice of Paragraph IV
Certification, including:
a. Date before which notice may not
be given;
b. Date by which notice must be
given; and
c. Certification of provision of
notice.
(II.D.1).
[[Page 6808]]
314.52(c)......................... Contents of Notice of Paragraph IV
Certification, including:
a. Statement that any required
bioavailability or bioequivalence
studies for a 505(b)(2) application
have been submitted;
b. Statement confirming receipt of
an acknowledgment letter or a
paragraph IV acknowledgment letter;
c. Documentation that paragraph IV
certification was submitted and
notice was sent only for patents
listed in the Orange Book; and
d. Offer of confidential access
accompanying notice.
(II.D.3).
314.52(d)......................... Notice Required for All Paragraph IV
Certifications.
(II.D.2).
314.52(e)......................... Documentation of Timely Sending and
Receipt of Notice of Paragraph IV
Certification, including:
a. Acceptable methods of sending
notice of paragraph IV
certification; and
b. Amendment documenting timely
sending and confirmation of receipt
of notice of paragraph IV
certification.
(II.D.4).
314.53(b) and (c)................. General Requirements for Submission
of Patent Information, including:
Revisions to scope of required
submission of patent information.
(II.B.1).
314.53(d)......................... When and Where To Submit Patent
Information, including:
a. Submission of patent information
for NDA supplements;
b. Untimely filing of patent
information;
c. Where to send submissions of Form
FDA 3542a and 3542; and
d. Submission date of patent
information.
(II.B.2).
314.53(e)......................... Public Disclosure of Patent
Information (II.B.3).
314.53(f)......................... Correction or Change of Patent
Information, including:
a. Patents that claim an approved
method of using the drug product
(method-of-use patents); and
b. Requests by NDA holder to remove
patent information from the list.
(II.B.4).
314.54............................ Procedure for Submission of an
Application Requiring
Investigations for Approval of a
New Indication for, or Other Change
From, a Listed Drug.
(II.H).
314.60(e)......................... Amendments to an Unapproved
505(b)(2) Application for A
Different Drug, including:
a. Applications within the scope of
section 505(b)(4)(A) of the FD&C
Act;
b. Proposed amendments subject to
section 505(b)(4)(A) of the FD&C
Act;
c. Exception for amendments to seek
approval of a different strength;
and
(II.G.3).
314.60(f)......................... Patent Certification Requirements
for Amendments to 505(b)(2)
Applications (II.F).
314.70(h)......................... Supplements to a 505(b)(2)
Application for A Different Drug
(II.G.4).
314.70(i)......................... Patent Certification Requirements
for Supplements to 505(b)(2)
Applications (II.F).
314.90............................ Refusal to Approve an NDA (II.L).
314.93............................ Petition to Request a Change From a
Listed Drug (II.I).
314.94(a)(12)(iii)................ Patent Certification Requirements
for Method-of-Use Patents (II.C.2).
314.94(a)(12)(iv)................. Patent Certification Requirements
for Method-of-Manufacturing Patents
(II.C.3).
314.94(a)(12)(viii)............... Amended Patent Certifications,
including:
a. Amended patent certifications
after a finding of infringement;
b. Amended certifications after a
request by the NDA holder to remove
a patent from the list;
c. Amended certifications upon
patent reissuance; and
d. Other amended certifications.
(II.E.1 through II.E.4).
314.95(b) and (d)................. Timing of Notice of Paragraph IV
Certification, including:
a. Date before which notice may not
be given;
b. Date by which notice must be
given; and
c. Certification of provision of
notice.
(II.D.1).
314.95(c)......................... Contents of Notice of Paragraph IV
Certification, including:
a. Statement confirming receipt of
an acknowledgment letter or a
paragraph IV acknowledgment letter;
b. Clarification that paragraph IV
certifications may be submitted
only for patents listed in the
Orange Book; and
c. Offer of confidential access
accompanying notice.
(II.D.3).
314.95(d)......................... Notice Required for All Paragraph IV
Certifications (II.D.2).
314.95(e)......................... Documentation of Timely Sending and
Receipt of Notice of Paragraph IV.
Certification, including:
a. Acceptable methods of sending
notice of paragraph IV
certification; and
b. Amendment documenting timely
sending and confirmation of receipt
of notice of paragraph IV
certification.
(II.D.4).
[[Page 6809]]
314.96(c)......................... Amendments to an Unapproved ANDA
That Reference a Different Listed
Drug, including:
a. Approval of a pharmaceutically
equivalent RLD in an NDA;
b. Changes to the proposed drug
product would result in
pharmaceutical equivalence to a
different RLD;
c. Exception for amendments to seek
approval of a different strength;
and
d. Procedure for submission of a new
ANDA that identifies a different
RLD.
(II.G.1).
314.96(d)......................... Patent Certification Requirements
for Amendments to ANDAs (II.F).
314.97(b)......................... Supplements to an ANDA That
Reference a Different Listed Drug.
a. Changes to the proposed drug
product would result in
pharmaceutical equivalence to a
different RLD;
b. Exception for supplements to seek
approval of a different strength;
and
c. Procedure for submission of a new
ANDA that identifies a different
RLD.
(II.G.2).
314.97(c)......................... Patent Certification Requirements
for Supplements to ANDAs (II.F).
314.99............................ Refusal to Approve an ANDA (II.L).
314.101........................... Notification of Filing of a
505(b)(2) Application or Receipt of
an ANDA and
Other Proposed Revisions (II.J.1
through II.J.2).
Administrative Consequence for Late
Notice of Paragraph IV
Certification (II.D.5).
314.105........................... Approval of an NDA and ANDA (II.K).
314.107(a)........................ Date of Approval of a 505(b)(2)
Application or ANDA (II.M.1).
314.107(b)........................ Effect of Patent(s) on the Listed
Drug, including:
a. Timing of approval based on
patent certification or statement;
b. Patent information filed after
submission of 505(b)(2) application
or ANDA;
c. Disposition of patent litigation;
and
d. Tentative approval.
(II.M.2).
314.107(c)........................ Subsequent ANDA Submission (II.M.3).
314.107(d)........................ Delay of Approval Due to Exclusivity
(II.M.4).
314.107(e)........................ Notification of Court Actions or
Documented Agreement (II.M.5).
314.107(f)........................ Computation of the 45-day time clock
(II.M.6).
314.107(g)........................ Conversion of Approval to Tentative
Approval (II.M.7).
314.108........................... Definitions in Current Sec.
314.108 (II.A.3).
314.125........................... Refusal to Approve an NDA (II.L).
314.127........................... Refusal to Approve an ANDA (II.L).
320.1............................. Definitions in Current Sec. 320.1
(II.A.4).
320.23............................ Assessing Bioavailability and
Bioequivalence for Drugs Not
Intended To Be Absorbed Into the
Bloodstream (II.N).
------------------------------------------------------------------------
\1\ These highlights reference important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.A. Definitions
II.A.1. Overview of New, Revised, and Relocated Definitions
We are proposing to amend Sec. 314.3(b) to define terms relevant
to amendments to the FD&C Act made by the MMA and to add definitions of
terms that have been used by the Agency for several years in the
context of implementing section 505(b) and (j) of the FD&C Act. We also
are proposing amendments to Sec. 314.3(b) and elsewhere to conform
with other changes that we are proposing in this regulation and to
incorporate new definitions. Although some of these revisions are not
required for implementation of the MMA, these proposed changes are
intended to enhance the clarity of our regulations in part 314 and
promote consistency throughout our regulations.
Several definitions that we are proposing to add to Sec. 314.3(b)
involve terms that are defined specifically by the MMA (see definitions
of ``180-day exclusivity,'' ``first applicant,'' ``substantially
complete application,'' and ``tentative approval'' in section II.A.2.
Our proposed definitions of these terms closely track the statutory
language with only minor editorial changes (see section
505(j)(5)(B)(iv)(I) and (j)(5)(B)(iv)(II) of the FD&C Act). We also are
proposing to add definitions of a ``paragraph IV acknowledgment
letter'' and an ``acknowledgment letter'' to Sec. 314.3(b), as the
term ``paragraph IV acknowledgment letter'' is relevant to amendments
made to section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act
regarding timing requirements for notices of paragraph IV
certifications (see section II.A.2).
We are proposing to add definitions of terms that have been
commonly used by the Agency over the years in the context of
implementing section 505(b) and (j) of the FD&C Act and part 314, but
that have not been expressly defined in Sec. 314.3(b) (see definitions
of ``abbreviated new drug application,'' ``ANDA,'' ``dosage form,''
``new drug application,'' ``NDA,'' ``ANDA holder,'' ``NDA holder,''
``patent owner,'' ``reference standard,'' ``strength,'' and
``therapeutic equivalents'' in section II.A.2). These proposed
definitions are intended to codify our longstanding use of these terms,
rather than substantively change the meaning.
We are proposing to revise the definitions of certain existing
terms in Sec. 314.3(b) (see definitions of ``listed drug'' and ``the
list'' in section II.A.2) to conform with other changes we are
proposing in this regulation and to clarify the distinction between
approvals and tentative approvals (see section II.K). We also are
proposing to revise the definitions of ``abbreviated application'' and
``applicant'' in Sec. 314.3(b) to reflect statutory changes made by
the Food and Drug Administration Modernization Act of
[[Page 6810]]
1997 (Public Law 105-115) (FDAMA) that eliminated the previous need to
distinguish between ANDAs and abbreviated antibiotic applications. We
are proposing amendments to Sec. 314.3(b) and elsewhere to incorporate
terms used by the Agency into existing definitions (see proposed
amendments to definition of ``applicant'' to use terms ``NDA'' and
``ANDA'' in lieu of ``application'' and ``abbreviated application,''
respectively, in section II.A.2).
For clarity and ease of reference, we are proposing to add
definitions of ``paragraph IV certification'' and ``commercial
marketing'' to Sec. 314.3(b) based on the current use of these terms
in other sections of part 314. As discussed in section II.A.2.v, a
paragraph IV certification is defined by section 505(b)(2)(A)(iv) and
(j)(2)(A)(vii)(IV) of the FD&C Act and currently described in
implementing regulations in part 314. Commercial marketing of certain
drug products is a statutory trigger for beginning the period of 180-
day exclusivity and is described in current and proposed regulations
(see sections II.A.2.l and II.M.3). We also are proposing to move the
definitions of the terms ``active moiety'' and ``date of approval'' in
current Sec. 314.108(a) to Sec. 314.3(b). These definitions are
relevant to matters covered in other sections of part 314 and thus
appropriate for inclusion in the general definition section for this
part.
We also are proposing to add definitions of ``active ingredient,''
``inactive ingredient,'' and the related term ``component'' to Sec.
314.3(b) based on the current definitions in Sec. 210.3(b) (21 CFR
210.3(b)). These definitions reflect the current use of these terms in
other sections of part 314.
Finally, we are proposing to move the definitions that currently
are in Sec. 320.1(a) through (g) to Sec. 314.3(b) for ease of
reference and organizational convenience. The terms currently defined
in Sec. 320.1 (``bioavailability,'' ``drug product,'' ``pharmaceutical
equivalents,'' ``pharmaceutical alternatives,'' ``bioequivalence,''
``bioequivalence requirement,'' and ``same drug product formulation'')
are relevant to matters covered in part 314 in addition to matters in
part 320, and certain of these terms are already used in part 314. (As
noted elsewhere in this document, our proposed amendments to part 320
(discussed in section II.N) would make clear that proposed terms
defined in Sec. 314.3 will be applicable to part 320 when those terms
are used in part 320.) With three exceptions (the definitions of
``bioavailability,'' ``bioequivalence,'' and ``drug product,''
discussed in section II.A.2), we are proposing to move the definitions
in existing Sec. 320.1(a) through (g) to Sec. 314.3(b) without
changes. We are proposing to modify the definition of bioavailability
in current Sec. 320.1(a) to reflect a statutory change made by the
MMA. We are proposing conforming revisions to the definition of
bioequivalence. It is not necessary to move the definition of drug
product in Sec. 320.1(b) to Sec. 314.3 because this section already
includes a definition of drug product that we believe is functionally
identical.
II.A.2. Proposed Amendments to Definitions in Sec. 314.3
II.A.2.a. 180-day exclusivity period. The MMA defines the term
``180-day exclusivity period'' for purposes of section 505(j)(5) of the
FD&C Act to mean ``the 180-day period ending on the day before the date
on which an application submitted by an applicant other than a first
applicant could become effective under this clause'' (see section
505(j)(5)(B)(iv)(II)(aa) of the FD&C Act). We are proposing to
supplement this definition for ANDAs subject to the MMA to incorporate
the statutory trigger for 180-day exclusivity, as described in section
505(j)(5)(B)(iv)(I) of the FD&C Act, and make minor editorial changes.
In proposed Sec. 314.3(b), the term ``180-day exclusivity period'' is
defined as the 180-day period beginning on the date of the first
commercial marketing of the drug (including the commercial marketing of
the RLD) by any first applicant of an ANDA (see discussion of
``commercial marketing'' and ``first applicant'' in sections II.A.2.l
and II.A.2.q). The 180-day period ends on the day before the date on
which an ANDA submitted by an applicant other than a first applicant
could be approved (see section 505(j)(5)(B)(iv)(I) through
(j)(5)(B)(iv)(II)(aa) of the FD&C Act). As reflected in the
parenthetical reference to commercial marketing of the RLD, the 180-day
exclusivity period may be triggered by the commercial marketing of an
``authorized generic drug,'' as that term is currently defined in Sec.
314.3(b).
FDA interprets the 180-day exclusivity provisions added by the MMA
to apply only to ANDAs referring to an RLD for which the first ANDA was
submitted after December 8, 2003, whether or not that ANDA contained a
paragraph IV certification at the time of submission (see section
1102(b)(1) of the MMA (Effective Date provision)). If one or more ANDAs
were submitted before December 8, 2003, but the first paragraph IV
certification was submitted in an ANDA after that date, all ANDAs would
be governed by the pre-MMA 180-day exclusivity provisions in order to
impose the same statutory exclusivity scheme on all ANDAs referencing a
specific RLD and avoid a possible disparate effect on ANDA applicants
simultaneously undertaking the same patent challenge (see FDA's letter
to ANDA applicants for topiramate sprinkle capsules dated April 15,
2009, available on FDA's Web site at http://www.fda.gov).
II.A.2.b. Abbreviated application, abbreviated new drug
application, or ANDA. We are proposing to revise the definition of
``abbreviated application'' to include the alternate terms
``abbreviated new drug application'' and ``ANDA'' for clarity and
administrative efficiency. Conforming revisions have been proposed
throughout the sections of parts 314 and 320 in this rulemaking to
incorporate the commonly used acronym ``ANDA'' in place of references
to ``abbreviated application'' and ``abbreviated new drug
application.''
In addition, we are proposing to delete the text in Sec. 314.3(b)
that explains that the term '' `[a]bbreviated application' applies to
both an abbreviated new drug application and an abbreviated antibiotic
application'' to reflect statutory changes made by FDAMA. Section 125
of FDAMA repealed section 507 of the FD&C Act under which marketing
applications, including ANDAs, for antibiotics had been approved. FDAMA
provided that ANDAs for antibiotics previously approved under section
507 of the FD&C Act would be deemed approved under section 505(j) of
the FD&C Act. We note that there have been subsequent amendments to the
FD&C Act involving applications for antibiotic drugs (see QI Program
Supplemental Funding Act of 2008, Public Law 110-379 (2008)); however,
these amendments are not specifically addressed in this proposed
rulemaking.
II.A.2.c. Acknowledgment letter. We are proposing to define the
term ``acknowledgment letter'' as a counterpart to the term ``paragraph
IV acknowledgment letter,'' which is proposed for inclusion in Sec.
314.3(b) to facilitate implementation of the MMA's requirements for the
timing of notice of a paragraph IV certification (see sections II.A.2.u
and II.D.1). We propose to define ``acknowledgment letter'' as a
written, postmarked communication from FDA to an applicant stating that
the Agency has determined that a 505(b)(2) application or ANDA is
sufficiently complete to permit a substantive review. The proposed
definition states that an acknowledgment letter indicates that the
505(b)(2) application is regarded as
[[Page 6811]]
filed or the ANDA is regarded as received. An acknowledgment letter is
used for 505(b)(2) applications and ANDAs that contain a patent
certification or statement other than a paragraph IV certification for
the listed drug(s) relied upon or RLD, respectively (compare definition
of ``paragraph IV acknowledgment letter'' discussed in section
II.A.2.u).
Although the term ``acknowledgment letter'' applies to both
505(b)(2) applications and ANDAs that contain a patent certification or
statement other than a paragraph IV certification, there are important
practical differences between the letters for each type of application.
In FDA's Center for Drug Evaluation and Research (CDER), the Office of
Generic Drugs (OGD) reviews ANDAs after submission to determine whether
the ANDA may be received for substantive review under Sec.
314.101(b)(1). OGD will send an acknowledgment letter (or a paragraph
IV acknowledgment letter, if appropriate) to the applicant after a
determination has been made that the ANDA is sufficiently complete to
permit a substantive review.
For NDAs, including 505(b)(2) applications, a determination
regarding whether the application may be filed is made within 60 days
after FDA is in receipt of the application as provided in Sec.
314.101(a)(1). In the absence of a refusal to file letter sent to the
NDA applicant on or before day 60, the NDA is deemed filed. In the
context of a 505(b)(2) application, our proposed definition of
``acknowledgment letter'' reflects the current practice by CDER's
Office of New Drugs (OND) with respect to its notification of issues
identified during the filing review (filing communication) to the
applicant generally not later than 14 calendar days after the 60-day
filing date. This filing communication is informally known as a ``74-
day letter'' (see Manual of Policies and Procedures (MAPP) 6010.5,
``NDAs: Filing Review Issues'' (effective May 8, 2003) (available on
FDA's Web site at http://www.fda.gov). Under our proposed definition,
the filing communication sent by the OND review division to the
505(b)(2) applicant is the ``acknowledgment letter'' from FDA stating
that the 505(b)(2) application is sufficiently complete to permit a
substantive review.
It should be noted that if an original ANDA contains a patent
certification or statement other than a paragraph IV certification, and
the applicant submits an amendment containing a paragraph IV
certification before the ANDA has been received for substantive review,
the applicant may receive, for administrative reasons, an
acknowledgment letter, rather than a paragraph IV acknowledgment
letter. This contingency is addressed in proposed Sec. 314.95 by the
use of both terms.
II.A.2.d. Act. We are proposing to modify the definition of ``act''
in Sec. 314.3(b) so that the citation to the U.S. Code reflects
sections added to the FD&C Act by FDAMA, the Food and Drug
Administration Amendments Act of 2007 (FDAAA), the Food and Drug
Administration Safety and Innovation Act (FDASIA), and other
legislation.
II.A.2.e. Active ingredient. We are proposing to add the definition
of ``active ingredient'' currently in Sec. 210.3(b)(7) to Sec.
314.3(b) without changes. The term ``active ingredient'' is relevant to
matters covered in part 314 in addition to matters in part 210 and thus
appropriate for inclusion in the general definition section for this
part.
II.A.2.f. Active moiety. We are proposing to move the definition of
the term ``active moiety'' in current Sec. 314.108(a) to Sec.
314.3(b) without changes. This definition is relevant to matters
covered in other sections of part 314 and thus appropriate for
inclusion in the general definition section for this part.
II.A.2.g. ANDA holder and NDA holder. We are proposing to define
the terms ``ANDA holder'' and ``NDA holder'' to mean the applicant that
owns an approved ANDA or NDA, respectively. These terms have been
commonly used by the Agency over the years in the context of
implementing section 505(b) and (j) of the FD&C Act and part 314, but
have not been expressly defined in Sec. 314.3(b).
II.A.2.h. Applicant. We are proposing to revise the definition of
``applicant'' to conform with other changes that we are proposing in
this regulation and incorporate the commonly used acronyms ``NDA'' and
``ANDA.'' In addition, we are proposing to delete the reference to ``an
antibiotic drug'' in the current definition of ``applicant'' to reflect
statutory changes made by FDAMA that eliminated the previous need to
distinguish between a new drug and an antibiotic drug.
II.A.2.i. Application, new drug application, or NDA. We are
proposing to revise the definition of ``application'' to include the
alternate terms ``new drug application'' and ``NDA'' for clarity and
administrative efficiency. Conforming revisions have been proposed
throughout the sections of parts 314 and 320 in this rulemaking to
incorporate the commonly used acronym ``NDA'' in place of references to
``application'' and ``new drug application.'' In addition, we are
proposing to expressly state that the terms ``application, new drug
application, or NDA'' refer to ``stand-alone'' applications submitted
under section 505(b)(1) of the FD&C Act and to 505(b)(2) applications.
Although certain regulations in part 314 refer specifically to
505(b)(2) applications, 505(b)(2) applications also are subject to any
applicable regulations governing new drug applications.
We considered replacing the term ``application'' with ``new drug
application or NDA,'' rather than including ``new drug application'' or
``NDA'' as alternate terms, because the term ``application'' is
sometimes used to generally refer to any application (e.g., a ``stand-
alone'' NDA, 505(b)(2) application, or ANDA) in a concise manner.
However, such a proposal would have necessitated additional conforming
revisions throughout part 314 that are beyond the scope of this
rulemaking. We are proposing to replace the term ``application'' with
``NDA or ANDA'' in certain sections of part 314 to clarify the text and
reflect FDA's longstanding interpretation of the provision (see, e.g.,
the definition of ``specification'' in proposed Sec. 314.3(b)).
II.A.2.j. Bioavailability, bioequivalence. The MMA amended the
definitions of ``bioavailability'' and ``bioequivalence'' in section
505(j)(8)(A) and (j)(8)(C) of the FD&C Act to confirm that, for drugs
not intended to be absorbed into the bloodstream, FDA may ``assess
bioavailability by scientifically valid measurements intended to
reflect the rate and extent to which the active ingredient or
therapeutic ingredient becomes available at the site of drug action''
(emphasis added). For such drugs, the MMA provides that FDA may
establish ``alternative scientifically valid methods to show
bioequivalence . . .'' (see section 505(j)(8)(C) of the FD&C Act
(emphasis added)). Section 1103(b) of the MMA expressly states that the
amendments to section 505(j)(8)(A) and (j)(8)(C) of the FD&C Act ``do[]
not alter the standards for approval of drugs under section 505(j)'' of
the FD&C Act.
The amendments to section 505(j)(8)(A) and (C) of the FD&C Act
codify FDA's current practice, based on its existing regulations in
Sec. Sec. 320.1(a) and (e), 320.23(a)(1), and 320.24 and
implementation of those regulations, regarding assessment of
bioavailability and demonstration of bioequivalence for drugs not
intended to be absorbed into the bloodstream (see Schering Corp. v.
FDA, 51 F.3d 390 (3d Cir. 1995), cert. denied, 516 U.S. 907 (1995)
(holding that FDA's regulatory standard in Sec. 320.1(e) for
bioequivalence of non-
[[Page 6812]]
systemically effective drugs is a permissible construction of the
statute); see also section II.N).
We are proposing to revise the definitions of bioavailability and
bioequivalence in Sec. 320.1(a) and (e) to incorporate the textual
revisions made in section 505(j)(8)(A) of the FD&C Act and move the
revised definitions to Sec. 314.3(b) in light of their relevance to
matters covered in part 314 in addition to matters in part 320. The
proposed definitions include a statement that for drug products that
are not intended to be absorbed into the bloodstream, bioavailability
and bioequivalence may be assessed by scientifically valid measurements
intended to reflect the rate and extent to which the active ingredient
or active moiety becomes available at the site of action (emphasis
added). FDA will evaluate the scientific appropriateness of
methodologies to assess the bioavailability or demonstrate the
bioequivalence of non-systemically absorbed drugs based on the best
available scientific evidence. We do not interpret section 505(j)(8)(A)
and (j)(8)(C) of the FD&C Act to require full analytical method
validation (which may have the effect of altering the standards for
approval of ANDAs, contrary to section 1103(b) of the MMA), but rather
methods that FDA considers to be scientifically valid or appropriate
(see Docket No. FDA-2004-N-0062-0013 (comment submitted by the
Biotechnology Industry Organization (BIO)) at 2 to 3, available at
http://www.regulations.gov (BIO MMA Comment).
To clarify our interpretation of ``bioavailability'' and conform
the definition with terminology used to define bioequivalence, we are
proposing to revise the reference to ``site of action'' in current
Sec. 320.1(a) to ``site of drug action'' (see Sec. 320.1(e)). For
locally-acting drug products that are not systemically absorbed or have
low systemic bioavailability, a pharmacokinetic comparison of drug and/
or metabolite concentrations in plasma would not always reflect the
rate and extent to which the active ingredient or active moiety becomes
available at the site of drug action (e.g., gastrointestinal tract or
lungs). This is consistent with our historical interpretation and
application of this term and the express language of section
505(j)(8)(A) of the FD&C Act.
In addition, we are proposing to substitute the term ``active
moiety'' for the statutory term ``therapeutic ingredient'' in the
definitions of ``bioavailability'' and ``bioequivalence.'' This
approach reflects our longstanding judgment that the term ``active
moiety'' is more appropriate than the term ``therapeutic ingredient''
in the context of section 505(j)(8)(A) of the FD&C Act (see, e.g.,
``Abbreviated New Drug Application Regulations''; final rule, 57 FR
17950 at 17972, April 28, 1992) (1992 final rule) (``Congress clearly
intended a meaning different from `active ingredient' by the term
`therapeutic ingredient' or it would not have used both terms [in what
is now section 505(j)(8) of the FD&C Act]. The term `active moiety'
refers to the molecule or ion in an active ingredient, excluding those
appended portions of the molecule that cause the ingredient to be an
ester, or a salt or other noncovalent derivative that is responsible
for the physiological or pharmacological action of the ingredient.'')
We also are proposing clarifying revisions in Sec.
314.94(a)(7)(iii) relevant to bioequivalence studies. Proposed Sec.
314.94(a)(7)(iii) would state that the requirements for submission of a
description of the analytical and statistical methods used in each
bioequivalence study applies to in vitro bioequivalence studies as well
as in vivo bioequivalence studies. An in vitro study used to establish
or support bioequivalence may include, for example, an in vitro kinetic
binding study, an in vitro equilibrium binding study, a permeability
study, and a study of plume geometry, spray pattern, or droplet or
particle size distribution for nasal spray products.
II.A.2.k. Bioequivalence requirement. We are proposing to move the
definition of ``bioequivalence requirement'' currently in Sec.
320.1(f) to Sec. 314.3(b), with a minor grammatical correction, for
ease of reference and organizational convenience. The term
``bioequivalence requirement'' is relevant to matters covered in part
314 in addition to matters in part 320 and thus appropriate for
inclusion in the general definition section for this part.
II.A.2.l. Commercial marketing. We are proposing to define
``commercial marketing'' to mean the introduction or delivery for
introduction into interstate commerce of a drug product described in an
approved ANDA, outside the control of the ANDA holder, except for
investigational use under part 312 of this chapter, but does not
include transfer of the drug product for reasons other than sale to
parties identified in the approved ANDA.
This proposed definition is based on the use of this term in
current Sec. 314.107(c)(4); however, we are proposing to alter the
scope of the exclusion for transfer of the drug product for reasons
other than sale. Section 314.107(c)(4) currently provides that
commercial marketing ``does not include transfer of the drug product
for reasons other than sale within the control of the manufacturer or
application holder'' (emphasis added). Our proposed definition is
intended to clarify that the ANDA holder's shipment of a drug product
described in an approved ANDA to any party named in the ANDA for
purposes described in the ANDA (e.g., contract packaging) is not
``commercial marketing'' of the drug product even though such transfer
arguably places the drug products outside of the control of the
manufacturer for some period of time. However, shipment of the drug
product to any other party or for any other purpose would not fall
within this exception and would be considered ``commercial marketing''
(i.e., an introduction or delivery for introduction into interstate
commerce of a drug product described in an approved ANDA outside the
ANDA holder's control). For example, if the ANDA holder ships the drug
product to a wholesaler, a repackager not identified in the ANDA, or
directly to a pharmacy, hospital, health maintenance organization, or
other like entity, the ANDA holder will have commercially marketed the
product as of the date of its shipment (if the ANDA holder complies
with the notification requirement described in proposed Sec.
314.107(c)(2)).
The first commercial marketing of a drug is discussed in section
II.A.2.a (definition of the 180-day exclusivity period).
II.A.2.m. Component. We are proposing to add the definition of
``component'' currently in Sec. 210.3(b)(3) to Sec. 314.3(b) without
changes. The term ``component'' is used within the defined term
``active ingredient'' and thus is appropriate for inclusion in the
general definition section for this part (see section II.A.2.e).
II.A.2.n. Date of approval. We are proposing to move the definition
of ``date of approval'' currently in Sec. 314.108(a) to Sec. 314.3(b)
with several revisions. These proposed revisions to the definition of
``date of approval'' are not intended to alter our interpretation of
Sec. 314.108.
Our proposed revisions to the definition of ``date of approval''
incorporate use of the term ``approval letter,'' which also is defined
in Sec. 314.3(b), and broaden the definition to include the date of
approval for an ANDA. In addition, we are proposing to remove from the
definition of ``date of approval'' the caveat that the date of approval
is the date on the approval
[[Page 6813]]
letter ``whether or not final printed labeling or other materials must
still be submitted as long as approval of such labeling or materials is
not expressly required'' (Sec. 314.108(a)). This qualification is
inapplicable to the date of approval of an ANDA because final printed
labeling is required as a condition of approval (see Sec. Sec.
314.94(a)(8) and 314.127(a)(7)). With respect to NDAs (including
505(b)(2) applications), Sec. 314.105(b) specifically addresses the
circumstances under which FDA will approve an NDA and issue the
applicant an approval letter on the basis of draft labeling, and it is
unnecessary to summarize this approach in the definition of ``date of
approval.''
As proposed for revision, the ``date of approval'' is the date on
the approval letter from FDA stating that the NDA or ANDA is approved.
The date of approval refers only to a final approval and not to a
tentative approval. We note that the date on the approval letter
generally appears on the last page containing the electronic signature
(endorsement).
II.A.2.o. Dosage form. We are proposing to define ``dosage form''
to mean the physical manifestation containing the active and inactive
ingredients that delivers a dose of the drug product. This includes
such factors as (i) the physical appearance of the drug product, (ii)
the physical form of the drug product prior to dispensing to the
patient, (iii) the way the product is administered, and (iv) design
features that affect frequency of dosing. This term has been commonly
used by the Agency over the years in the context of implementing
section 505(j) of the FD&C Act and part 314. However, except for the
examples of dosage forms used in the definition of ``drug product,''
the term ``dosage form'' not been expressly defined in Sec. 314.3(b).
The dosage form is generally determined based on the form of the
product before dispensing to the patient (see Abbott Laboratories v.
Young, 691 F. Supp. 462, 464 n. 1 (D.D.C. 1988) (``The final dosage
form of a drug is the form in which it appears prior to administration
to the patient''), remanded on other grounds, 920 F.2d 984 (D.C. Cir.
1990), cert. denied, 502 U.S. 819 (1991)). This is consistent with
other factors such as physical recognition, dosing, and manner of
administration that contribute to the determination of dosage form.
Appendix C to the Orange Book lists the dosage form categories for
currently marketed products.
II.A.2.p. Drug product. A ``drug product'' is a finished dosage
form (for example, a tablet, capsule, or solution) that contains a drug
substance, generally, but not necessarily, in association with one or
more other ingredients. We are proposing to delete a similar definition
of ``drug product'' in current Sec. 320.1(b) when we move the
definitions in Sec. 320.1 to Sec. 314.3(b), to reflect the fact that
Sec. 314.3(b) already includes a definition of drug product. Although
the two definitions of ``drug product'' differ slightly in wording, we
believe that they are functionally identical, so that this proposed
revision is intended to eliminate redundancy but not result in any
substantive change in our interpretation of part 320.
II.A.2.q. First applicant. The MMA defines the term ``first
applicant'' for purposes of section 505(j)(5) of the FD&C Act (see
section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act). We are proposing to
add the statutory definition, with minor editorial changes and
additional clarifying text, to Sec. 314.3(b) to facilitate our
continuing implementation of the 180-day exclusivity provisions of the
FD&C Act. We are proposing to define ``first applicant'' in Sec.
314.3(b) to mean an applicant that, on the first day on which a
substantially complete ANDA containing a paragraph IV certification is
submitted for approval of a drug, submits a substantially complete ANDA
that contains, and for which the applicant lawfully maintains, a
paragraph IV certification for the drug. We are proposing to delete the
definition of ``applicant submitting the first application'' in current
Sec. 314.107(c)(2) because it is superseded by the statutory
definition (see section II.M.3). We note that an applicant may be a
``first applicant'' based on the submission of a paragraph IV
certification in an amendment to an ANDA if other criteria are met.
We interpret the term ``drug'' in the statutory definition of
``first applicant'' to mean ``drug product'' as currently defined in
Sec. 314.3(b) (see section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act).
Consistent with our longstanding practice, we note that different
strengths of a drug product constitute different drug products. For
example, different ANDA applicants seeking approval for different
strengths of a drug product approved in a single NDA may each be first
applicants with respect to a different strength of the drug product, if
other applicable statutory and regulatory requirements are met (see
Apotex, Inc. v. Shalala, 53 F. Supp. 2d 454 (D.D.C.), aff'd, 1999 U.S.
App. LEXIS 29571 (D.C. Cir. 1999)). In addition, there may be multiple
first applicants for a single drug product if more than one ANDA
applicant first submitted a substantially complete ANDA that contains,
and for which the applicant lawfully maintains, a paragraph IV
certification on the same day.
We have interpreted the statutory requirement for a first applicant
to ``lawfully maintain'' a paragraph IV certification to mean that the
ANDA applicant must, as a condition of retaining first applicant
status, continue to lawfully assert that a relevant listed patent
(i.e., at least one of the patents for which a paragraph IV
certification qualified the ANDA applicant for first applicant status)
is invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of the drug for which the ANDA is submitted (see Letter
from G. Buehler, Director, Office of Generic Drugs, to ANDA Applicant
regarding 180-day exclusivity for dorzolamide/timolol ophthalmic
solution, Docket No. FDA-2008-N-0483-0017 at 5-6, available at http://www.regulations.gov) (Dorzolamide/Timolol Letter). This approach
comports with comments that we received on the interpretation of the
phrase ``lawfully maintained'' in response to the Request for MMA
Comments (see Docket No. FDA-2004-N-0062-0006 (comment submitted by the
Pharmaceutical Research and Manufacturers of America (PhRMA)) at 3-5,
available at http://www.regulations.gov (PhRMA MMA Comment); see also
Docket No. FDA-2004-N-0062-0009 (comment submitted by Eli Lilly and
Company) at 1-2, available at http://www.regulations.gov (Lilly MMA
Comment)).
For example, if an ANDA applicant is sued for infringement of a
patent that qualified the applicant for first applicant status and a
court enters a final decision from which no appeal has been or can be
taken that the patent is infringed (or signs a settlement order or
consent decree in the action that includes a finding of infringement
and does not permit market entry before patent expiration), the ANDA
applicant can no longer lawfully maintain a paragraph IV certification
with respect to the infringed patent (see Dorzolamide/Timolol Letter at
6). As discussed in section II.E.1, the ANDA applicant is required to
submit an amended patent certification under Sec.
314.94(a)(12)(i)(A)(3) (paragraph III certification) in these
circumstances. In addition, an ANDA applicant can no longer lawfully
maintain a paragraph IV certification when the patent expires or if an
ANDA applicant changes its certification from a paragraph IV
certification to a 505(j)(2)(A)(viii)
[[Page 6814]]
statement (see proposed Sec. 314.94(a)(12)(viii)(C) and (D); see also
Dorzolamide/Timolol Letter at 6, note 5).
It should be noted that an amendment to a substantially complete
ANDA does not mean that the ANDA is no longer substantially complete or
that a first applicant has not lawfully maintained its paragraph IV
certification (unless the amendment requires a new patent certification
and the amended patent certification is not a paragraph IV
certification). However, if a first applicant submits several major
amendments to its ANDA, there is a risk that the applicant may not be
able to obtain tentative approval within 30 months after the date on
which the ANDA is filed, thereby forfeiting its eligibility for any
180-day exclusivity period (see section 505(j)(5)(D)(i)(IV) of the FD&C
Act).
We note that certain definitions, such as the definition of ``first
applicant,'' may be revised or supplemented in the future as we
continue to implement the 180-day exclusivity provisions of the MMA.
II.A.2.r. Inactive ingredient. We are proposing to add the
definition of ``inactive ingredient'' currently in Sec. 210.3(b)(8) to
Sec. 314.3(b) without changes. The term ``inactive ingredient'' is
relevant to matters covered in part 314 in addition to matters in part
210 and thus appropriate for inclusion in the general definition
section for this part.
II.A.2.s. Listed drug. We are proposing to revise the definition of
``listed drug'' to clarify that a listed drug includes a drug product
that is listed in the discontinued section of the Orange Book and that
has not been withdrawn or suspended under section 505(e)(1) through
(e)(5) or 505(j)(6) of the FD&C Act or withdrawn from sale
(irrespective of whether the NDA has been withdrawn) for what FDA has
determined are reasons of safety or effectiveness. Accordingly, the
proposed definition in Sec. 314.3(b) would state that a listed drug is
a new drug product that ``has been approved'' instead of one that ``has
an effective approval.'' With respect to the exceptions to listed drug
status, we are correcting the paragraph number in the reference to the
statutory provision under which an ANDA may be withdrawn or suspended
for reasons of safety or effectiveness (see section 505(j)(6) of the
FD&C Act).
In addition, we are proposing conforming revisions to incorporate
other changes we are proposing in this rulemaking regarding the
distinction between approvals and tentative approvals (see section
II.K) and reliance upon the electronic version of the Orange Book (see
section II.A.2.ee).
Listed drug status is evidenced by the drug product's
identification in the current FDA's ``Approved Drug Products With
Therapeutic Equivalence Evaluations'' (the list) as an approved drug.
However, we note that a drug product is deemed to be a listed drug on
the date of the approval letter for the NDA or ANDA for that drug
product, rather than the date on which the product is listed in the
Orange Book.
II.A.2.t. Original application, original NDA. We are proposing to
revise the definition of ``original application'' to include the
alternate term ``original NDA'' for clarity and administrative
efficiency. In addition, we are proposing to replace references to
``application'' with ``NDA'' for consistency with other changes in this
proposed rulemaking. These minor revisions are not intended to
substantively change the meaning of the term ``original application.''
II.A.2.u. Paragraph IV acknowledgment letter. We are proposing to
define ``paragraph IV acknowledgment letter'' to mean a written,
postmarked communication from the FDA to an applicant stating that the
Agency has determined that a 505(b)(2) application or ANDA containing a
paragraph IV certification is sufficiently complete to permit a
substantive review (compare definition of ``acknowledgment letter''
discussed in section II.A.2.c). An acknowledgment letter or paragraph
IV acknowledgment letter indicates that the 505(b)(2) application is
regarded as filed or the ANDA is regarded as received.
The proposed definition of ``paragraph IV acknowledgment letter''
is intended to facilitate implementation of the MMA's timing
requirements for notice to the NDA holder and each patent owner of a
paragraph IV certification. A 505(b)(2) or ANDA applicant is required
to send notice of its paragraph IV certification within 20 days after
the date of the postmark on the paragraph IV acknowledgment letter (see
section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act and
section II.D.1).
In response to the Request for MMA Comments, the Generic
Pharmaceutical Association (GPhA) requested that FDA amend Sec.
314.101(b)(2) to state that FDA will notify the applicant ``in writing
via a postmarked notice'' that the ANDA has been received in light of
the MMA's timing requirements for notice of paragraph IV certification
(see Docket No. FDA-2004-N-0062-0012 (comment submitted by GPhA) at 4-
5, available at http://www.regulations.gov) (GPhA MMA Comment).
Incorporation of the term ``paragraph IV acknowledgment letter'' in
proposed Sec. 314.101(b)(2) would address this concern with respect to
ANDAs (see section II.J). In addition, although OGD currently sends a
paragraph IV acknowledgment letter in an envelope bearing a postmark
made by the U.S. Postal Service, we are proposing to broaden the
definition the ``postmark'' to accommodate electronic transmissions in
the future (see section II.A.2.y).
For ANDAs, OGD currently sends a ``paragraph IV acknowledgment
letter'' to confirm the date on which the ANDA was received and to
establish the timeframe within which an ANDA applicant must send notice
of a paragraph IV certification contained in the original ANDA (see
section II.D.1). The letter also provides ANDA applicants with an
overview of the notice requirements associated with submission of a
paragraph IV certification to a listed patent for the RLD.
For 505(b)(2) applications that rely on the Agency's finding of
safety and/or effectiveness for a listed drug and include a paragraph
IV certification for a listed patent, the Notification of Issues
Identified during the Filing Review (filing communication), sometimes
referred to as the ``74-day letter,'' would constitute the ``paragraph
IV acknowledgment letter'' defined in Sec. 314.3. Unlike the paragraph
IV acknowledgment letter for ANDAs, the OND filing communication is
typically sent in a franked envelope that may not bear a postmark made
by the U.S. Postal Service. For purposes of Sec. 314.52(b) and (c) (21
CFR 314.52(b) and (c)) only, the ``date of the postmark'' on the
``paragraph IV acknowledgment letter'' will be considered to be 4
calendar days after the date on which the filing communication is
signed by the signatory authority (generally the Division Director or
designee in the OND review division), which generally reflects the date
on which the document is received by the U.S. Postal Service (see
definition of ``postmark'' in proposed Sec. 314.3). For example, if
the filing communication is electronically signed by the Division
Director or designee on Thursday, April 7th, the date of the postmark
on the paragraph IV acknowledgment letter for the 505(b)(2)
application, for purposes of Sec. 314.52(b), would be Monday, April
11th. If OND sends the filing communication via electronic transmission
in the future, then our proposed definition of ``postmark'' in Sec.
314.3(b) would apply.
As noted previously, the paragraph IV acknowledgment letter
triggers the
[[Page 6815]]
requirements in proposed Sec. Sec. 314.52(b) and 314.95(b) for sending
notice of the paragraph IV certification. The proposed difference in
interpreting the term ``postmark'' as applied to paragraph IV
acknowledgment letters for 505(b)(2) applications reflects current OND
practice regarding the mailing of filing communications, which should
occur no later than 74 days after the date of submission of the
505(b)(2) application. In addition, although an indisputable date of
mailing is needed for competing ANDAs that may be eligible for a period
of 180-day exclusivity, a 505(b)(2) application does not raise these
concerns. We invite comment on this proposed approach or whether an
alternative approach should be considered.
II.A.2.v. Paragraph IV certification. We are proposing to define
``paragraph IV certification'' in Sec. 314.3(b) to mean a patent
certification of invalidity, unenforceability, or noninfringement
described in Sec. 314.50(i)(1)(i)(A)(4) or Sec.
314.94(a)(12)(i)(A)(4) for 505(b)(2) applications and ANDAs,
respectively. This term is routinely used by the Agency and applicants
to refer to this type of patent certification. The addition of the term
``paragraph IV certification'' to Sec. 314.3(b) would provide a
convenient means of clearly referencing the patent certification
described in the section 505(b)(2)(A)(iv) and (j)(2)(A)(vii)(IV) of the
FD&C Act and implementing regulations.
II.A.2.w. Patent owner. We are proposing to define ``patent owner''
as the owner of the patent for which information is submitted for an
NDA. A patent may be owned by more than one person. If a patent owner
seeks to have its designated representative receive notice of a
paragraph IV certification by a 505(b)(2) or ANDA applicant that relies
upon a listed drug claimed by the patent, the patent owner should
ensure that current information regarding the correspondence address,
in accordance with 37 CFR 1.33(d), is submitted to the PTO.
II.A.2.x. Pharmaceutical alternatives and pharmaceutical
equivalents. We are proposing to revise the definition of
``pharmaceutical equivalents'' to clarify that this term is intended to
refer to drug products in identical dosage forms and route(s) of
administration that contain identical amounts of the identical active
ingredient. The requirement for pharmaceutically equivalent products to
have the same route(s) of administration is consistent with FDA's
current practice, as described in section 1.2 of the preface to the
Orange Book (33rd Edition, 2013, at vii). We are not proposing any
changes to the definition of ``pharmaceutical alternatives.''
We are proposing to move the definitions of ``pharmaceutical
alternatives'' and ``pharmaceutical equivalents'' currently in Sec.
320.1(c) and (d) to Sec. 314.3(b), for ease of reference and
organizational convenience. The concepts of ``pharmaceutical
alternatives'' and ``pharmaceutical equivalents'' are relevant to
matters covered in part 314 (including but not limited to Sec. 314.94
and proposed Sec. Sec. 314.50(i)(1)(i)(C), 314.93(f), 314.96(c), and
314.97(b), discussed in section II.G.1-2, II.H, and II.I) in addition
to matters in part 320 (21 CFR part 320).
II.A.2.y. Postmark. We are proposing to define the term
``postmark'' in Sec. 314.3(b) to address the MMA's requirement that a
505(b)(2) or ANDA applicant send notice of its paragraph IV
certification within ``20 days after the date of the postmark on the
notice [i.e., the paragraph IV acknowledgment letter] with which [FDA]
informs the applicant that the application has been filed'' (see
section 505(b)(3)(B)(i) and 505(j)(2)(B)(ii)(I) of the FD&C Act). The
term ``postmark'' is not used elsewhere in section 505 of the FD&C Act
or in our current regulations in part 314. In light of the transition
by FDA and regulated industry to electronic communications, an
interpretation of the term ``postmark'' to mean a postmark made by the
U.S. Postal Service (``U.S. postmark'') could quickly become outdated.
The purpose of the postmark in section 505(b)(3)(B)(i) and
(j)(2)(B)(ii)(I) of the FD&C Act is to establish a verifiable date from
which the 20-day notice period runs. Accordingly, we are proposing a
broader definition of a ``postmark'' to mean ``an independently
verifiable evidentiary record of the date on which a document is
transmitted, in an unmodifiable format, to another party. For postmarks
made by the U.S. Postal Service or a designated delivery service, the
date of transmission is the date on which the document is received by
the domestic mail service of the U.S. Postal Service or by a designated
delivery service. For postmarks documenting an electronic event, the
date of transmission is the date (in a particular time zone) that FDA
sends the electronic transmission on its host system as evidenced by a
verifiable record. If the sender and the intended recipient are located
in different time zones, it is the sender's time zone that provides the
controlling date of electronic transmission.'' This proposed definition
of ``postmark'' is adapted from the definition of ``electronic
postmark'' in regulations issued by the Internal Revenue Service (IRS)
with respect to electronic filing of documents required under 26 U.S.
C. 7502 (see 26 CFR 301.7502-1(d)(3)(ii)).
We invite comment on our proposed interpretation of the term
``postmark'' in the context of a paragraph IV acknowledgment letter
from FDA to an applicant for a 505(b)(2) application or ANDA, and
whether our regulations should be amended to define differently the
specific date from which the 20-day notice period runs.
II.A.2.z. Reference standard. We are proposing to define
``reference standard'' as the drug product selected by FDA that an
applicant seeking approval of an ANDA must use in conducting an in vivo
bioequivalence study required for approval. This proposed definition
reflects the Agency's longstanding use of this term, as described in
the preamble to our 1992 final rule implementing the Hatch-Waxman
Amendments (``FDA intends the reference listed drug to be the same drug
product selected by the agency as the reference standard for
bioequivalence determinations'' (57 FR 17950 at 17954). By generally
designating a single drug product as the standard to which generic
versions must be shown to be bioequivalent, FDA seeks to avoid possible
significant variations among generic drugs, which could result if such
drugs were compared to different drug products.
The reference standard is identified in the Orange Book by the word
``yes'' in the ``RLD'' column. In certain circumstances, a drug product
approved in an ANDA (including a petitioned ANDA) may be designated as
the reference standard for bioequivalence studies intended to support
approval of an ANDA. For example, if the RLD is a drug product approved
in an NDA that has been withdrawn from marketing (for reasons other
than safety or effectiveness), a therapeutically equivalent drug
product approved in an ANDA may be designated as the reference
standard.
We recognize that the term ``reference standard'' has other
meanings, including in the context of part 314 (see Sec.
314.50(e)(1)(C)) regarding submission of representative samples of
reference standards used in analytical studies, excluding
pharmacopoeial reference standards). The proposed definition of
``reference standard'' applies solely to the product used in conducting
an in vivo bioequivalence study required for approval.
II.A.2.aa. Same drug product formulation. We are proposing to move
the definition of ``same drug product formulation'' currently in Sec.
320.1(g) to Sec. 314.3(b), without changes, for ease of reference and
organizational
[[Page 6816]]
convenience. The term ``same drug product formulation'' is relevant to
matters covered in part 314 (including but not limited to Sec. Sec.
314.94 and 314.96) in addition to matters in part 320.
II.A.2.bb. Strength. We are proposing to define the term
``strength'' in Sec. 314.3(b) to mean the amount of drug substance
contained in, delivered, or deliverable from a drug product. The amount
of drug substance contained in, delivered, or deliverable from a drug
product includes: (i)(A) The total quantity of drug substance in mass
or units of activity in a dosage unit or container closure (e.g.,
weight/unit dose, weight/volume or weight/weight in a container
closure, or units/volume or units/weight in a container closure) and/
or, as applicable (i)(B) the concentration of the drug substance in
mass or units of activity per unit volume or mass (e.g., weight/weight,
weight/volume, or units/volume). If these weights and measures are not
applicable to a type of drug product or dosage form, then the strength
of the drug product may be described by such other criteria the Agency
establishes for determining the amount of drug substance contained in,
delivered, or deliverable from the drug product. For example, the
strength of certain drug-device combination products (such as a
transdermal delivery system) may be expressed as the amount of drug
substance delivered per unit time.
This proposed definition is intended to codify FDA's interpretation
of the term ``strength'' in the context of section 505(j)(2)(A)(iii) of
the FD&C Act. This proposed definition also will facilitate
implementation of certain statutory provisions added by the MMA
regarding amendments and supplements that seek approval of a
``different strength'' (see section 505(b)(4)(B) and (j)(2)(D)(ii) of
the FD&C Act). Different strengths of a drug product constitute
different drug products.
The amount of the drug substance ``delivered'' from a drug product
is intended to describe the mass of drug substance delivered to the
patient either per unit time (e.g., as in transdermal delivery system)
or per actuation (e.g., as in metered dose inhalers) and excludes
excess drug substance that although not available for labeled use, is
necessary to allow for the specified total delivery (e.g., a specified
number of hours for a transdermal delivery system or a specified number
of actuations for a metered dose inhaler).
The amount of drug substance ``deliverable from'' a drug product is
intended to exclude the excess volume allowed by the U.S. Pharmacopeia
(USP) (to permit withdrawal and administration of the labeled volume of
an injectable product) from the description of the ``strength'' of the
drug product (see 21 CFR 201.51(g)).
FDA has a longstanding history of considering a difference in the
total quantity of drug substance of a parenteral product (e.g., a
single or multiple dose vial) or a difference in the concentration of a
parenteral product to be a difference in the ``strength'' of the
product for purposes of section 505(j)(2)(A)(iii) of the FD&C Act. FDA
considers it important to review proposed differences in the total drug
content or the concentration of a parenteral product because such
changes can result in medication errors and incorrect dosing of
patients. Accordingly, the strength of a parenteral drug product is
determined by both criteria in paragraph (i) of the proposed
definition--i.e., the total quantity of drug substance in a container
closure and the concentration of the drug substance.
For other dosage forms, the strength of the drug product is
determined based only on the criteria in paragraph (i)(A) or (i)(B) of
the proposed definition. For example, the strength of a solid oral
dosage form is determined only by the total quantity of drug substance
in a dosage unit (e.g., a 25-milligram (mg) tablet). In contrast, the
strength of a semisolid dosage form is typically determined by the
concentration of the drug substance. For example, the strength of a
cream is generally expressed by the concentration as a weight/weight
percentage reflecting the mass of the drug substance per unit mass of
the drug product.
We recognize that the weights and measures described in paragraph
(i) of the proposed definition may not be applicable to all types of
drug product or dosage forms. Accordingly, paragraph (ii) of the
proposed definition provides that the strength of the drug product may
be described by such other criteria as the Agency establishes for
determining the amount of drug substance contained in, delivered, or
deliverable from the drug product.
It should be emphasized that the proposed definition of strength
refers to the amount of the drug substance (active ingredient), and not
the amount of the active moiety, in the drug product. However, we
recognize that approved drug products formulated with a salt of an acid
or a base (commonly referred to as ``salt drug products'') may use the
active moiety in the name rather than the drug substance to conform
with a drug product naming policy established by the USP. Although the
USP naming policy describes the ``strength'' of a drug product as the
amount of active moiety present in the product, the strength of the
drug product for purposes of section 505(j)(2)(A)(iii) of the FD&C Act
is the amount of the drug substance. These approaches to describing the
strength of the drug product do not conflict because if two drug
products containing the same drug substance are demonstrated to have
the same ``strength'' in terms of active moiety, they will always have
the same strength in terms of drug substance. For example, a tablet
drug product that contains 125 mg of the drug substance ``novelpril
maleate'' equivalent to 100 mg of the active moiety ``novelpril'' would
be expressed as ``novelpril tablet 100 mg.'' Based on the proposed
definition in Sec. 314.3(b), the strength of the drug product is 125
mg of the drug substance ``novelpril maleate.'' The label for this
product would describe both the ``strength'' expressed in terms of
active moiety and the strength expressed in terms of drug substance.
The Agency recognizes that this naming policy will result in situations
in which the ``strength'' that directly follows the drug product name
for such products will be expressed in terms of active moiety and not
in terms of drug substance, and that this might be confusing. FDA seeks
comment on this approach to the proposed definition of strength in
light of these considerations.
We also generally invite comment on whether this proposed
definition adequately encompasses the broad range of dosage forms and
drug products to which a proposed definition of ``strength'' in Sec.
314.3(b) would apply.
II.A.2.cc. Substantially complete application. The MMA defines the
term ``substantially complete application'' for purposes of section
505(j)(5) of the FD&C Act (see section 505(j)(5)(B)(iv)(II)(cc) of the
FD&C Act). We are proposing to define ``substantially complete
application'' in Sec. 314.3(b) to incorporate this statutory
definition with minor editorial revisions. As proposed, a
``substantially complete application'' would mean an ANDA that on its
face is sufficiently complete to permit a substantive review and
contains all the information required under section 505(j)(2)(A) of the
FD&C Act and Sec. 314.94. For an application to be substantially
complete, any information referenced in the application must have been
provided to the Agency. For example, FDA will refuse to receive an ANDA
for which a referenced Drug Master File has not been submitted or that
omitted relevant stability or bioequivalence data as of the date of
submission of the ANDA. There may be other bases for finding that an
application is not substantially
[[Page 6817]]
complete--for example, electronic submissions that are not readable or
do not follow FDA's recommendations for electronic application format
may be determined to be not substantially complete and refused for
receipt.
In addition, we are proposing conforming revisions to Sec.
314.101(b) to clarify that receipt of an ANDA means that FDA has made a
threshold determination that the ANDA is substantially complete (see
section II.J). Our proposed replacement of the current criterion
``sufficiently complete to permit a substantive review'' with the
synonymous term ``substantially complete application'' is not intended
to alter the meaning. Rather, we are seeking to use defined terms
consistently throughout our regulations.
II.A.2.dd. Tentative approval. The MMA defines the term ``tentative
approval'' for purposes of section 505(j)(5) of the FD&C Act to mean
``notification to an applicant by the Secretary that an [ANDA] meets
the requirements of [section 505(j)(2)(A)], but cannot receive
effective approval because the application does not meet the
requirements of [section 505(j)(5)(B)], there is a period of
exclusivity for the listed drug under [section 505(j)(5)(F)] or section
505A, or there is a 7-year period of exclusivity for the listed drug
under section 527'' (section 505(j)(5)(B)(iv)(II)(dd)(AA) of the FD&C
Act). We are proposing to define ``tentative approval'' in Sec.
314.3(b) to incorporate the statutory text and extend this general
definition, with appropriate conforming revisions, to include tentative
approval of an NDA (including a 505(b)(2) application).
Proposed Sec. 314.3(b) defines ``tentative approval'' to mean the
notification that an NDA (including a 505(b)(2) application) or ANDA
otherwise meets the requirements for approval under the FD&C Act, but
cannot be approved because there is unexpired orphan drug exclusivity
for a listed drug, or that a 505(b)(2) application or ANDA otherwise
meets the requirements for approval under the FD&C Act, but cannot be
approved until the conditions in Sec. 314.107(b)(1)(iii), (b)(3), or
(c) are met, because there is a period of exclusivity for the listed
drug under Sec. 314.108 or section 505A of the FD&C Act (21 U.S. C.
355a), or because a court order pursuant to 35 U.S. C. 271(e)(4)(A)
orders that the application may be approved no earlier than the date
specified. Proposed Sec. 314.107(b)(4) describes the circumstances in
which FDA will issue a tentative approval letter (see section
II.M.2.d).
The proposed definition of ``tentative approval'' clarifies that a
drug product that is granted tentative approval is not an approved drug
and will not be approved until FDA issues an approval letter after any
necessary additional review of the NDA or ANDA (compare section
505(j)(5)(B)(iv)(II)(dd)(BB) of the FD&C Act). We have proposed minor
editorial revisions to the limitation described in the statute to
replace references to ``effective approval'' of an NDA or ANDA with
language reflecting our current practice. As discussed in section II.K,
the Agency does not issue approval letters with delayed effective
dates.
II.A.2.ee. The list. We are proposing to revise the definition of
``the list'' to mean the list of approved drug products published in
FDA's current ``Approved Drug Products With Therapeutic Equivalence
Evaluations,'' available electronically on FDA's Web site (http://www.fda.gov/cder). These clarifying revisions reflect our longstanding
practice of relying upon the electronic version of the Orange Book
(currently available at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm), which is updated on a regular basis and can be accessed
from FDA's Web site. We are proposing to delete the words ``current
edition,'' ``any current supplement,'' and ``publication'' from the
definition as these phrases imply reference to a printed version. As
discussed in section II.B.3, the Agency no longer arranges for
publication of an annual printed edition or monthly printed supplements
to the Orange Book.
Although the format of the electronic version of the Orange Book
may change with advances in technology, FDA intends to maintain a
publicly available version of the list that includes, among other
things: Approved NDAs and ANDAs; therapeutic equivalence evaluations
(as applicable); exclusivity granted to a listed drug; patents
submitted for listing by the NDA holder; use codes for method-of-use
patents; requests to remove a patent from the list; and, upon request
on a prospective basis, the date on which patents are received by FDA
for listing.
II.A.2.ff. Therapeutic equivalents. We are proposing to define
``therapeutic equivalents'' as approved drug products that are
pharmaceutical equivalents and for which bioequivalence has been
demonstrated. Therapeutic equivalents can be expected to have the same
clinical effect and safety profile when administered to patients under
the conditions of use specified in the labeling. This proposed
definition reflects the Agency's longstanding interpretation of this
term as set forth in section 1.2 of the preface to the Orange Book
(33rd Edition, 2013, at vii).
II.A.3. Proposed Amendments to Definitions in Current Sec. 314.108
As discussed in sections II.A.1, II.A.2.f, and II.A.2.n, we are
proposing to move the definitions of the terms ``active moiety'' and
``date of approval'' from Sec. 314.108(a) to Sec. 314.3(b). We are
proposing to amend Sec. 314.108 to state that the definitions in Sec.
314.3 (in addition to other definitions in Sec. 314.108) apply to
Sec. 314.108.
We also are proposing to add a definition of ``bioavailability
study'' to Sec. 314.108(a) to clarify the scope of this term as used
in section 505(c)(3)(E)(iii), (c)(3)(E)(iv), (j)(5)(F)(iii), and
(j)(5)(F)(iv) of the FD&C Act and Sec. 314.108(b)(4) and (b)(5)
regarding certain exclusivity determinations. The FD&C Act provides
that a ``bioavailability study'' is not a type of ``new clinical
investigations . . . essential to the approval of the application [or
supplement] and conducted or sponsored by the applicant'' eligible for
a 3-year period of exclusivity during which a 505(b)(2) application or
ANDA may not be approved for the same conditions of approval (see
section 505(c)(3)(E)(iii), (c)(3)(E)(iv), (j)(5)(F)(iii), and
(j)(5)(f)(iv) of the FD&C Act; see also Sec. 314.108(b)(4) and
(b)(5)).
The proposed definition of ``bioavailability study'' means a study
to determine the bioavailability or the pharmacokinetics of a drug.
This definition incorporates by reference the revised definition of
``bioavailability'' proposed in Sec. 314.3. This proposed revision is
intended to clarify that a pharmacokinetic study, which generally is
conducted in the same manner as a bioavailability study, also is not
eligible for 3-year exclusivity. Although not specifically defined in
part 314, the term ``pharmacokinetics'' is generally understood to
refer to the way a drug is handled by the body, which is described by
pharmacokinetic measures (such as area under the curve and
concentration at the maximum) and other derived measures (such as
clearance, half-life, and volume of distribution). The values of these
measures reflect the absorption (A), distribution (D), and elimination
(E) of a drug from the body. A drug can be eliminated by both
metabolism (M) to one or more active and inactive metabolites and
excretion of the unchanged drug. The overall set of processes is often
referred to as ADME, which ultimately controls systemic exposure to a
drug and its metabolites after drug administration.
[[Page 6818]]
II.A.4. Definitions in Current Sec. 320.1
We are proposing to move the definitions in current Sec. 320.1(a)
through (g) to Sec. 314.3(b). We are proposing this change for ease of
reference because certain terms defined in current Sec. 320.1 already
are set forth in other parts of our regulations (e.g.,
``bioequivalence''). Proposed Sec. 320.1 would simply state that the
definitions in Sec. 314.3(b) apply to part 320.
II.B. Submission of Patent Information (Proposed Sec. 314.53)
II.B.1. General Requirements for Submission of Patent Information
(Proposed Sec. 314.53(b) and (c))
Section 314.53(b) of our regulations requires that an applicant
submitting an NDA (including a 505(b)(2) application), an amendment to
an NDA, or, except as provided in Sec. 314.53(d)(2), a supplement to
an approved application, submit the patent information described in
Sec. 314.53(c) on Forms FDA 3542a and 3542 with the filing or upon and
after approval, respectively. The information provided in Form FDA 3542
for any patent which claims the drug or a method of using the drug and
with respect to which a claim of patent infringement could reasonably
be asserted if a person not licensed by the owner engaged in the
manufacture, use, or sale of the drug is published in the Orange Book
after approval of the NDA or the supplement.
In the Federal Register of April 30, 2007 (72 FR 21266), we
responded to comments submitted to FDA regarding FDA's request for an
extension of approval of the collection of information related to
patent submission and listing requirements involving Forms FDA 3542a
and 3542 (April 2007 notice). At that time, we made certain revisions
to Forms FDA 3542a and 3542 and the instructions for completing those
forms to clarify acceptable practices in accordance with our existing
regulations. Other proposed changes to Forms FDA 3542a and 3542 would
have required revisions to the regulations upon which the requirements
in Forms FDA 3542a and 3542 are based. In sections II.B.1.a and
II.B.2.a, we propose certain revisions to the content of patent
information submitted to FDA and the circumstances under which
submission of patent information is required. These changes to the
required submission of patent information are intended to clarify the
basis for requiring certain information, revise and streamline our
requirements, and describe acceptable approaches to compliance with
applicable regulations.
Table 2 summarizes the proposed changes related to reporting
requirements for submission of patent information:
Table 2--Highlights of Proposed Changes Regarding Patent Reporting
Requirements \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
General Requirements (Sec. 314.53(c)(1)) General Requirements (Sec.
314.53(c)(1))
Patent information will not be accepted Patent information
unless it is complete and submitted on will not be accepted unless
the appropriate forms (Form FDA 3542a or it is submitted on the
3542). appropriate forms (Form FDA
3542a or 3542) and contains
the information required in
Sec. 314.53(c)(2).
Reporting Requirements (Sec. Reporting Requirements (Sec.
314.53(c)(2)) 314.53(c)(2))
The required information and verification The required information and
in Sec. 314.53(c)(2)(i) and (c)(2)(ii) verification in Sec.
includes: 314.53(c)(2)(i) and
(c)(2)(ii) includes:
Information on whether the Information on
patent has been submitted previously whether the drug
for the NDA. substance patent claims
Information on whether the a polymorph that is the
patent is a re-issued patent of a same active ingredient
patent submitted previously for that is described in the
listing for the NDA or supplement. pending NDA or
supplement, and, if so,
has test data described
in Sec. 314.53(b)(2).
Information on
whether the drug
substance patent claims
only a polymorph that is
the same active
ingredient that is
described in the pending
NDA or supplement, and,
if so, has test data
described in Sec.
314.53(b)(2).
Method-of-Use Patents (Sec. Method-of-Use Patents (Sec.
314.53(c)(2)(i)(O) and (c)(2)(ii)(P)) 314.53(c)(2)(i)(O) and
(c)(2)(ii)(P))
The required information and verification The required information and
in Sec. 314.53(c)(2)(i) and (c)(2)(ii) verification in Sec.
includes: 314.53(c)(2)(i) and
(c)(2)(ii) includes:
Information on each method-of- Information on
use patent including the following: each method-of-use
patent including the
following:
(2) Identification of the specific (2) Identification of
section of the proposed labeling the specific
for the drug product that section(s) of the
corresponds to the method of use proposed labeling for
claimed by the patent submitted the drug product that
(3) The description of the corresponds to the
patented method of use as method of use claimed
required for publication. by the patent
submitted (if the
scope of the method-of-
use claim(s) of the
patent does not cover
every use of the drug,
the applicant must
identify only the
specific portion(s) of
the indication or
other condition of use
claimed by the
patent);
(3) The description of
the patented method of
use as required for
publication (which
must contain adequate
information to assist
505(b)(2) and ANDA
applicants in
determining whether a
listed method-of-use
patent claims a use
for which the
505(b)(2) or ANDA
applicant is not
seeking approval).
[No corresponding regulation] Exceptions to Required
Submission of Patent
Information (Sec.
314.53(c)(2)(i)(S) and
314.53(c)(2)(ii)(T))
If the applicant
submits information for a
patent that claims the drug
substance (active
ingredient) and meets the
requirements for listing on
that basis, then the
applicant is not required
to provide information on
whether that patent also
claims the drug product
(composition/formulation).
If the applicant
submits information for a
patent that claims the drug
product (composition/
formulation) and meets the
requirements for listing on
that basis, then the
applicant is not required
to provide information on
whether that patent also
claims the drug substance
(active ingredient).
[[Page 6819]]
However, an
applicant that submits
information for a method-of-
use patent must also submit
information regarding
whether that patent also
claims either the drug
substance or the drug
product.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.B.1.a. Drug substance (active ingredient) and drug product
(formulation or composition) patents. We are proposing to revise Sec.
314.53(c)(1) to clarify that FDA accepts patent information submitted
on Form FDA 3542a or 3542, as appropriate, as long as the form contains
the information required in Sec. 314.53(c). The statement in our
current regulations that FDA ``will not accept the patent information
unless it is complete . . .'' has generated confusion in some cases,
particularly where a portion of the specific information requested in a
section on FDA Form FDA 3542a or 3542 was not applicable to the patent
for which the form was submitted. By proposing to revise Sec.
314.53(c)(1) to state that we will not accept the patent information
unless it ``contains the information required in paragraph (c)(2) of
this section,'' we are clarifying that FDA will accept a submission of
patent information on Form FDA 3542a or 3542, as appropriate, that
omits patent information requested on the form where that omission is
permitted under an exception in Sec. 314.53(c)(2).
We are proposing to add Sec. 314.53(c)(2)(i)(S) and (c)(2)(ii)(T)
to describe exceptions to the required submission of patent
information. Proposed Sec. 314.53(c)(2)(i)(S)(1) and (c)(2)(ii)(T)(1)
state that if a patent claims the drug substance that is the active
ingredient in the drug product for which approval is sought or has been
granted, respectively, and is eligible for listing in the Orange Book,
it is not necessary for an applicant to provide information on whether
the patent also claims the drug product. Similarly, we are proposing to
add Sec. 314.53(c)(2)(i)(S)(2) and (c)(2)(ii)(T)(2) to provide that if
a patent claims the drug product for which approval is sought or has
been granted, respectively, and is eligible for listing in the Orange
Book, it is not necessary for an applicant to provide information on
whether the patent also claims the drug substance that is the active
ingredient in the drug product. These proposed revisions to our
regulations provide that an applicant need only satisfy the
requirements for patent listing set forth in section 505(b)(1) and
(c)(2) of the FD&C Act and, subject to Sec. 314.53(c)(2)(i)(O)(3) and
(c)(2)(ii)(P)(4), discussed in this section of the document, need not
identify each basis on which the patent claims the drug. The
designation of a patent as claiming the drug substance and/or drug
product for purposes of listing in the Orange Book is not intended to
define the scope of the patent claims that an NDA holder or patent
owner may assert against a 505(b)(2) or ANDA applicant based on a
listed patent.
Whether or not the applicant provides information stating that the
patent claims the drug substance or the drug product, an applicant must
submit information regarding whether the patent claims one or more
methods of using the drug product for which approval is sought or has
been granted (method-of-use patent). We are proposing to add Sec.
314.53(c)(2)(i)(O)(3) and (c)(2)(ii)(P)(4) to confirm that the proposed
exceptions to required submission of patent information do not alter
the requirements for submission of method-of-use patent information.
The information regarding method-of-use patents is required for
implementation of the patent certification and statement provisions of
the FD&C Act. Section 505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act
provide that a 505(b)(2) and ANDA applicant, respectively, may submit a
statement for a method-of-use patent which does not claim a use for
which the applicant is seeking approval, instead of a patent
certification under section 505(b)(2)(A)(iii) or 505(j)(2)(A)(vii)(III)
of the FD&C Act (paragraph III certification) or a paragraph IV
certification to the listed patent. Information on whether a patent
claims the drug substance or drug product in addition to whether the
patent claims one or more methods of use is required because a
505(b)(2) or ANDA applicant that avails itself of the statutory
provision that permits it to not seek approval of a method of use
claimed by the patent (and carve out from product labeling the method-
of-use information claimed by the patent) would still be required to
submit a patent certification with respect to any drug substance or
drug product claims covered by the same listed patent (see Letter from
Janet Woodcock, M.D., Director, CDER, to Rosemarie R. Wilk-Orescan,
Novo Nordisk Inc., and James F. Hurst, Winston & Strawn LLP, dated
December 4, 2008, regarding Docket Nos. FDA-2008-P-0343-0009 and FDA-
2008-P-0411-0006, available at http://www.regulations.gov) (Repaglinide
Citizen Petition Response). For example, a 505(b)(2) or ANDA applicant
may submit a statement under section 505(b)(2)(B) or
505(j)(2)(A)(viii), respectively, of the FD&C Act for a method-of-use
patent that does not claim a use for which the applicant is seeking
approval and a paragraph IV certification for any remaining drug
substance, drug product, or other method-of-use claims covered by the
same patent. This approach is sometimes described as a ``split
certification'' to the patent.
We note that a 505(b)(2) or ANDA applicant that submitted a
paragraph IV certification in addition to a statement under section
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act must comply with the
notice requirements for a paragraph IV certification and may be subject
to a 30-month stay of approval if patent infringement litigation is
initiated within the statutory timeframe. An ANDA applicant that
submitted a paragraph IV certification and a statement pursuant to
section 505(j)(2)(A)(viii) of the FD&C Act to a listed patent also may
be eligible for 180-day exclusivity based on its paragraph IV
certification if the applicant is a ``first applicant'' and meets other
statutory and regulatory requirements.
II.B.1.b. Drug substance patents that claim only a polymorph of the
active ingredient. Section 314.53(c)(2)(i)(M)(2) and (c)(2)(ii)(N)(2)
currently require submission of information on whether the patent
claims a polymorph (generally, a drug substance with a different
crystalline (including solvates and hydrates) or amorphous form of the
same drug substance) that is the same active ingredient as that
described in the pending NDA, amendment, or supplement. We explained in
the preamble to the June 2003 final rule that ``it would be consistent
to interpret `drug substance' for patent submission and listing
purposes as including certain drug substances having different physical
forms if they would be
[[Page 6820]]
considered the same active ingredient for ANDA approval purposes'' (68
FR 36676 at 36678).
We are proposing to revise these regulations to state that an
applicant is only required to provide information on whether the patent
claims a polymorph that is the same active ingredient described in the
pending NDA, amendment, or supplement if the only basis on which the
patent is eligible for listing is that it claims the polymorph. Based
on comments received from industry on this issue (see April 2007
notice) and inquiries from applicants regarding completion of Forms FDA
3542a and 3542, we have tentatively concluded that our regulations need
to be modified. With respect to a patent that claims the drug substance
or drug product described in the pending NDA, amendment, or supplement
and one or more polymorphic forms of the drug substance, an applicant
is not required to provide information on whether the patent claims a
polymorph if the patent otherwise meets the statutory requirements for
submission of patent information regarding the drug substance or drug
product.
Similarly, we are proposing to make conforming revisions to Sec.
314.53(b)(1), (b)(2), (c)(2)(i)(M)(3), and (c)(2)(ii)(N)(3) to provide
that the applicant certification regarding test data required by Sec.
314.53(b) applies only to patents that claim only a polymorph. This
provision also had generated confusion, and we are proposing revisions
for clarification.
II.B.1.c. Method-of-use patents. Section 314.53(b)(1) currently
states that an applicant ``shall separately identify each pending or
approved method of use and related patent claim.'' This text has been
subject to differing interpretations by applicants as to whether our
regulations require submission of patent information (and completion of
Forms FDA 3542a and 3542) on a claim-by-claim basis. In the June 2003
final rule, we explained that we require identification of individual
patent claims for method-of-use patents to assist 505(b)(2) and ANDA
applicants in determining whether a listed method-of-use patent claims
a use for which the 505(b)(2) or ANDA applicant is not seeking approval
(see 68 FR 36676 at 36682 and 36685). In the April 2007 notice, we
clarified that ``consistent with our regulations at Sec. 314.53(b)(1),
. . . an applicant may list together multiple patent claims for each
pending or approved method of use. However, each pending or approved
method of use must be separately identified and therefore will require
separate listing(s) of method-of-use information in section 4 of Forms
FDA 3542a and 3542. Therefore, if a patent claims one or more methods
of use that apply to a pending application or approved product, each
pending or approved method of use would need to be listed separately
along with the patent claim number(s) for the patent claim(s) for the
pending or approved method of use. A single Form FDA 3542a or Form FDA
3542, as appropriate, may be used to list a patent claiming more than
one method of use, provided that each method of use is listed
separately along with the patent claim number(s) for the patent
claim(s) for the pending or approved method of use. This regulatory
approach accomplishes the statutory objective of providing adequate
information to permit ANDA and 505(b)(2) applicants to file statements
which assert that the method-of-use patent does not claim a use for
which the applicant is seeking approval'' (72 FR 21266 at 21268).
We are proposing to revise Sec. 314.53(b)(1) by replacing the word
``claim'' with ``claim(s)'' in the phrase ``shall separately identify
each pending or approved method of use and related patent claim.'' This
proposed revision is intended to further clarify that an applicant may
list together multiple patent claims for a pending or approved method
of use on Forms FDA 3542a and 3542, respectively. However, each pending
or approved method of use must be separately identified and therefore
will require separate listing(s) of method-of-use information in
section 4 of Forms FDA 3542a and 3542.
We also are proposing to revise Sec. 314.53(b)(1),
(c)(2)(i)(O)(2), (c)(2)(ii)(P)(2) and (c)(2)(ii)(P)(3) to enhance
compliance by NDA applicants with the requirements for identifying the
specific section(s) of product labeling that correspond to the method
of use claimed by the patent and, upon approval, describing the
approved method of use claimed by the patent, as required for
publication in the Orange Book. Proposed Sec. 314.53(b)(1) would
expressly require that if the scope of the method-of-use claim(s) of a
patent does not cover every use of the drug, the applicant must
identify only the specific sections of product labeling that correspond
to the specific portion(s) of the indication or other condition of use
claimed by the patent. The specific product labeling that corresponds
to the protected use may appear in sections of the labeling other than
``Indications and Usage.'' This proposed revision and conforming
revisions to proposed Sec. 314.53(c)(2)(i)(O)(2) and (c)(2)(ii)(P)(2)
would address situations in which the scope of the method of use
claimed by the patent is narrower than the indication or other
condition of use described in product labeling. In such cases, the NDA
applicant must identify only the specific sections of product labeling
that correspond to the portion(s) of the indication or other condition
of use claimed by the patent and not the broader indication or other
condition of use in the product labeling which may include, but not be
limited to, the use claimed by the patent. Accurate identification of
the specific sections of product labeling that correspond to the use
claimed by the patent is necessary to enable FDA to implement section
505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, which permit
505(b)(2) and ANDA applicants to omit protected conditions of use from
labeling. This information regarding product labeling also is necessary
for FDA to evaluate whether the omission of aspects of the listed
drug's labeling protected by patent would render the proposed drug
product less safe or effective than the listed drug for all remaining
non-protected conditions of use and preclude approval (see Sec.
314.127(a)(7); see also Sec. 314.94(a)(8)(iv)).
Proposed Sec. 314.53(c)(2)(ii)(P)(3) would codify our longstanding
requirement that the NDA applicant's description of the patented method
of use (the ``use code'') required for publication in the Orange Book
must contain adequate information to assist FDA and 505(b)(2) and ANDA
applicants in determining whether a listed method-of-use patent claims
a use for which the 505(b)(2) or ANDA applicant is not seeking
approval. If the scope of the method-of-use claim(s) of the patent does
not cover every approved use of the drug, the NDA holder's ``use code''
must contain only the specific portion(s) of the indication or other
method of use claimed by the patent. This requirement is necessary to
effectively implement the statutory provisions that permit 505(b)(2)
and ANDA applicants to submit a statement that the applicant is not
seeking approval for the use claimed in the listed patent instead of a
patent certification to the listed patent with respect to the method of
use claim(s) (see section 505(b)(2)(B) and (j)(2)(C)(viii) of the FD&C
Act, respectively). We require the NDA holder to submit an accurate
description, subject to the verification requirements in Sec.
314.53(c)(2)(ii)(R), of the method of use within the scope of the
patent that claims an approved use of the drug to implement these
statutory provisions. As the U.S. Supreme Court noted in Caraco Pharm.
Labs. v. Novo
[[Page 6821]]
Nordisk A/S: ``An overbroad use code . . . throws a wrench into the
FDA's ability to approve generic drugs as the statute contemplates''
(132 S. Ct. 1670, at 1684 (2012)).
II.B.1.d. Patents previously submitted for listing. We are
proposing to revise Sec. Sec. 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to
remove the requirement that an applicant provide information regarding
whether the patent has been submitted previously for the NDA or
supplement. This requirement was intended to assist the Orange Book
staff with their administrative listing responsibilities (see 68 FR
36676 at 36686). In response to a request for clarification of the
purpose of this inquiry (see 72 FR 21266 at 21269) and to streamline
the patent information submission requirements, we are proposing to
revise Sec. Sec. 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to request
information on whether the patent is a reissuance of a patent submitted
previously for listing in the Orange Book for the NDA or supplement,
including the original patent number of the listed patent (see section
II.B.1.e).
If a patent has been submitted previously for listing in the Orange
Book, we currently request information on whether the expiration date
is a new expiration date (Sec. 314.53(c)(2)(i)(K) and (c)(2)(ii)(L)).
For example, a patent expiration date may be extended after NDA
approval in response to a request for patent term restoration pursuant
to 35 U.S.C. 156 (see proposed Sec. 314.53(f)(2)(ii), discussed in
section II.B.4.b). We are continuing to request this information.
We note that our proposed revisions to the patent information
submission requirements for supplements to an approved NDA (see section
II.B.2.a) are designed to identify, among other things, whether patents
previously submitted for listing for the underlying NDA continue to
claim the changed product as approved in the supplement.
II.B.1.e. Reissued patents. We are proposing certain revisions to
our regulations to describe our requirements regarding submission of
information related to patents that have been reissued by the PTO.
Generally, a patent may be reissued to correct certain errors in the
scope of claims or defects in a specification or drawing that otherwise
would have invalidated, in whole or in part, the patent (see 35 U.S.C.
251). Accordingly, a reissued patent may affect both the patent
certification or statement submitted by a 505(b)(2) or ANDA applicant
and the infringement claims that could be asserted by the patent owner
or NDA holder.
Although we recognize that the original patent is surrendered upon
patent reissuance (see 37 CFR 1.178(a)), we are proposing to treat the
original patent and the reissued patent as a ``single bundle'' of
patent rights, albeit patent rights that may have changed with
reissuance, for purposes of administering the patent certification
requirements of the FD&C Act and any 30-month stay of approval or 180-
day exclusivity that relates to a paragraph IV certification to the
original patent (see discussion in section II.E.4). FDA's role in
listing patents remains ministerial (see 59 FR 50338 at 50349, October
3, 1994 (1994 final rule); 68 FR 36676 at 36687 (June 2003 final
rule)); however, we are mindful of the implications of reissued patents
in fulfilling our statutory obligations regarding implementation of the
patent certification and statement, 30-month stay, 180-day exclusivity,
and tentative approval provisions of the FD&C Act. We are proposing
these revisions to describe the responsibilities of an NDA applicant
associated with listing a reissued patent. The requirements for a
505(b)(2) or ANDA applicant to provide an appropriate patent
certification or statement to a reissued patent are discussed in
section II.E.4).
We currently receive submissions of patent information for reissued
patents and list those patents that are eligible for listing in the
Orange Book. Reissued patents are identified by the PTO with the
letters ``RE'' preceding the patent number and, because a patent is
reissued for the unexpired part of the term of the original patent,
have the same expiration date as the original patent. If the scope of
claims was narrowed or broadened upon reissuance, the NDA applicant or
holder may submit a reissued patent for listing in the Orange Book with
a revised designation of whether the patent claims the drug substance,
drug product, and/or a method or use, or with a revised use code.
Proposed Sec. 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) would provide
that an NDA applicant or holder is required to include information on
whether a patent submitted for listing is a reissuance of a patent
previously submitted for listing for the NDA or supplement. Submission
of patent information for reissued patents is subject to the 30-day
timeframe for timely filed patent information set forth in section
505(c)(2) of the FD&C Act. As discussed further in section II.B.2.b,
the timely filing of patent information for a reissued patent
(including a reissued patent with a broadened scope of claims) does not
alter the patent certification obligations of a 505(b)(2) or ANDA
applicant whose application was pending when the original patent was
filed by the holder of an approved application for listing more than 30
days after patent issuance (``late listed''). In other words, if a
505(b)(2) or ANDA applicant is not required to provide a patent
certification or statement to the original patent pursuant to Sec.
314.50(i)(4) or Sec. 314.94(a)(12)(vi) because the patent was late
listed, the 505(b)(2) or ANDA applicant would not be required to
provide a patent certification or statement to the reissued patent even
if timely filed following reissuance. This approach recognizes that the
original and reissued patents comprise a ``single bundle'' of patent
rights, which first became relevant to approval of 505(b)(2)
applications and ANDAs with the submission of the patent information
prior to reissuance. As described in section II.E.3, the date of
submission of the original patent information also determines the
availability of a 30-month stay arising from patent infringement
litigation resulting from notice of a paragraph IV certification to the
original or reissued patent (see section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act).
An original patent that has been reissued would remain listed in
the Orange Book until FDA determined that any first ANDA applicant is
no longer eligible for 180-day exclusivity or the 180-day exclusivity
period has expired (see section II.E.4). We intend to designate
original patents that have been reissued and remain listed in the
Orange Book for this reason with the suffix ``*RE'' based on
information submitted by the NDA applicant or holder in accordance with
Sec. 314.53(c)(2)(ii)(K). In the absence of this designation, an
applicant that submits an ANDA after a reissued patent is listed in the
Orange Book may not provide a patent certification or statement with
respect to the original patent. Instead, the ANDA applicant must
provide a patent certification or statement to the reissued patent.
[[Page 6822]]
Should the scope of a reissued patent be narrowed such that it is
no longer eligible for listing under section 505(b)(1) or 505(c)(2) of
the FD&C Act, the NDA holder is required to request that the patent or
patent information be removed from listing in the Orange Book (``patent
delisting''), subject to the exceptions set forth in proposed Sec.
314.53(f)(2) (see discussion in section II.B.4.b).
II.B.2. When and Where To Submit Patent Information (Proposed Sec.
314.53(d))
Table 3 summarizes the proposed changes regarding when and where to
submit patent information:
Table 3--Highlights of Proposed Changes Regarding Submission of Patent
Information \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Supplements (Sec. 314.53(d)(2)(i))... Supplements (Sec.
314.53(d)(2)(i)).
Applicant must submit patent Applicant must submit
information required under Sec. patent information required
314.53(c) for a patent that claims the under Sec. 314.53(c) for a
drug, drug product, or method of use patent that claims the drug
for which approval is sought in a substance, drug product, or
supplement: method of use for which
(A) to change the formulation;......... approval is sought in a
(B) to add a new indication or other supplement:
condition of use;. (A) to change the dosage form
(C) to change the strength;............ or route of administration;
(D) to make any other patented change (B) to change the strength; or
regarding the drug, drug product, or (C) to change the drug product
method of use.. from prescription to OTC use.
Supplements (Sec. 314.53(d)(2)(ii)).. Supplements (Sec.
If an applicant submits a supplement 314.53(d)(2)(ii)).
for a change described in Sec. If an applicant submits a
314.53(d)(2)(i), the following patent supplement for a change other
information submission requirements than one described in Sec.
apply:. 314.53(d)(2)(i), the following
patent information submission
requirements apply:
If previously submitted If previously
patent information claims the submitted patent information
changed product, the applicant claims the changed product,
must submit a certification with the applicant is not required
the supplement identifying the to resubmit this patent
patents that claim the changed information unless the
product. description of the patented
method of use would change
upon approval of the
supplement, and FDA will
continue to list this patent
information for the product;
If no patents, including If previously
previously submitted patents, submitted patent information
claim the changed product, it must no longer claims the changed
so certify. product, the applicant must
submit a request to remove
that patent information from
the list at the time of
approval of the supplement;
If one or more
existing drug substance, drug
product, or method-of-use
patents claim the changed drug
product for which approval is
sought in the supplement and
such patent information has
not been submitted to FDA, the
applicant must submit the
patent information required
under Sec. 314.53(c).
Patent information deadline (Sec. Newly issued patents (Sec.
314.53(d)(3)). 314.53(d)(3)).
If a patent is issued for If a patent is issued
a drug, drug product, or method of for a drug substance, drug
use after an application is product, or method of use
approved, the applicant must after an NDA is approved, the
submit to FDA the required patent applicant must submit to FDA
information within 30 days of the the required patent
date of patent issuance. information within 30 days of
the date of patent issuance.
If the required patent
information is not submitted
within 30 days of patent
issuance, FDA will list the
patent, but patent
certifications will be
governed by the provisions
regarding untimely filed
patents at Sec. Sec.
314.50(i)(4) and (i)(6) and
314.94(a)(12)(vi) and
(a)(12)(viii).
Late submission of patent information Untimely filing of patent
(Sec. Sec. 314.50(i)(4) and information (Sec. Sec.
314.94(a)(12)(vi)). 314.50(i)(4) and
314.94(a)(12)(vi)).
[Provision directed to Except as provided in
submission of required patent Sec. 314.53(f)(1), an NDA
information in general.]. holder's amendment to the
description of the approved
method(s) of use claimed by
the patent will be considered
untimely filing of patent
information if:
--the amendment is submitted
more than 30 days after patent
issuance and it is not related
to a corresponding change in
approved product labeling; or
--the amendment is submitted
more than 30 days after a
corresponding change in
approved product labeling.
Copies (Sec. 314.53(d)(4))........... Submission of Forms FDA 3542a
and 3542 (Sec.
314.53(d)(4)).
Applicant must submit an Applicant must submit
archival copy and a copy for the patent information required by
chemistry, manufacturing, and Sec. 314.53(c)(1) and
controls (CMC) section of the (c)(2)(i), Sec. 314.50(h),
review copy to the CDER Central or Sec. 314.70(f) on Form
Document Room. FDA 3542a to the CDER Central
Document Room at the address
identified on FDA's Web site.
[cir] Form FDA 3542a should not
be submitted to the Orange
Book Staff in the Office of
Generic Drugs.
Applicant must submit Applicant must submit
patent information by letter patent information required by
separate from, but at the same Sec. 314.53(c)(1) and
time as, submission of the (c)(2)(ii) on Form FDA 3542 to
supplement. the Office of Generic Drugs,
Document Room, Attention:
Orange Book Staff.
Submission date (Sec. 314.53(d)(5)).. Submission date (Sec.
314.53(d)(5)).
Patent information will be Patent information
considered submitted to FDA as of will be considered submitted
the date the information is to FDA for purposes of Sec.
received by the Central Document 314.53(d)(3) as of the earlier
Room. of the date the information
submitted on Form FDA 3542 is
date-stamped by the Office of
Generic Drugs, Document Room,
or officially received
electronically by FDA through
the Electronic Submissions
Gateway.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
[[Page 6823]]
II.B.2.a. Submission of patent information for NDA supplements
(proposed Sec. 314.53(d)(2)). We are proposing to revise the
requirements for submission of patent information for NDA supplements
to reduce duplicative submissions of patent information and enhance
efficiency.
Section 314.53(c) requires submission of patent information for
certain types of supplements that relate to the drug product or a
method of using the drug product, namely those supplements that seek
approval to change the formulation, add a new indication or other
condition of use, change the strength, or make any other patented
change regarding the drug, drug product, or any method of use (see
Sec. 314.53(d)(2)(i)(A) through (d)(2)(i)(D)). This approach avoided
unnecessary resubmission of patent information with supplements that
did not involve a change to the drug product or a method of using the
product or involved a change that could not be patented (see 54 FR
28872 at 28910, July 10, 1989; and 59 FR 50338 at 50344). We are
proposing to eliminate certain of these patent information submission
requirements for supplements that seek approval for a change to an
approved product and for which existing patents listed in the Orange
Book for the specific drug product that is the subject of the
supplement continue to claim the changed product (see proposed Sec.
314.53(d)(2)(ii)(A)). These proposed revisions to our regulations also
address a comment submitted by an association representing research-
based pharmaceutical and biotechnology companies that ``submission of
Forms FDA 3542a and 3542 with submission and upon approval,
respectively, of an NDA supplement is redundant where the information
has not changed since the form last was filed, imposes a burden on
sponsors, and serves no statutory purpose'' (72 FR 21266 at 21270).
Our proposed revisions to Sec. 314.53(d)(2) would create two broad
categories of supplements for purposes of patent information submission
based on whether the supplement is a type for which approval would
result in a new entry in the Orange Book. For supplements that seek
approval for a change that will result in a new entry in the Orange
Book (e.g., a change to the dosage form, route of administration,
strength (including changes to concentration or total drug content), or
prescription drug status (i.e., change the drug product from
prescription use to over-the-counter (OTC) use)), an applicant must
continue to submit patent information required under Sec. 314.53(c)
with submission of the supplement and following approval, respectively.
Although these types of changes may not necessarily result in a
submission of different patent information, by requiring an NDA holder
to submit complete patent information for a supplement that, if
approved, would result in a new entry in the Orange Book, we ensure
that patent information listed for the new entry clearly expresses the
NDA holder's view regarding which patent(s) claim the drug or a method
of using the drug as approved in the supplement. For example, different
strengths of a drug product may have different patent coverage with
respect to method-of-use patents that claim a dosing regimen or
indication. In such a case, patent information would be required to be
submitted with the filing of the NDA supplement and would be required
to be submitted upon approval of the NDA supplement. This submission of
patent information on Forms FDA 3542a and 3542 would, among other
things, identify with specificity the new method of use claimed by the
patent with reference to the proposed or approved labeling,
respectively, for the drug product. If the patents listed for the
approved NDA also claim the drug or method of using the drug for which
approval is sought in the NDA supplement, we will permit an applicant
to submit a statement declaring that the patents currently listed for a
specific NDA (identified by NDA number and product number as listed in
the Orange Book) also claim the drug or method of using the drug for
which approval is sought in the NDA supplement, if this statement is
accompanied by the signed patent declaration verification required by
Sec. 314.53(c)(2)(i)(Q) and (c)(2)(ii)(R) and if patent information
required by Sec. 314.53(c)(2)(ii) previously was submitted (see June
2003 final rule (68 FR 36676 at 36681)). This proposed approach
fulfills the statutory requirements for patent listing set forth in
section 505(b)(1) and (c)(2) of the FD&C Act and ensures that patents
listed for separate entries for drug products in the Orange Book are
supported by an unambiguous submission of applicable patent
information.
It should be noted that proposed Sec. 314.53(d)(2)(i)(A) is
intended to encompass only the types of changes in dosage form or route
of administration that may be submitted as an NDA supplement and does
not apply to proposed changes in dosage form or route of administration
that should be submitted as a separate application (see guidance for
industry entitled ``Submitting Separate Marketing Applications and
Clinical Data for Purposes of Assessing User Fees'' (December 2004),
available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079320.pdf)
(Separate Marketing Application Guidance). Similarly, we note that
proposed Sec. 314.53(d)(2)(i)(C) describes supplements to change the
drug product from prescription use to OTC status for all conditions of
use, because a separate marketing application would be required for a
change to OTC status for fewer than all conditions of use.
Our proposal would eliminate the automatic requirement for
submission of patent information with a supplement seeking approval for
a change in formulation or new indication or other condition of use
(except for those conditions of use described in Sec.
314.53(d)(2)(i)). However, new submission of patent information would
still be required if the patent(s) that claim the product as changed by
the supplement differ from the patent(s) currently listed for the drug
product. For supplements that seek approval for a change to a listed
product that would not result in a new entry in the Orange Book (i.e.,
a change other than one of the changes described in proposed Sec.
314.53(d)(2)(i)), an applicant needs to evaluate whether each patent
for which information is currently listed in the Orange Book for the
drug product continues to claim the changed product. If existing
patents listed for the product approved in the original application
claim the product as changed by the supplement, the applicant is not
required to resubmit this patent information unless the description of
the method of use claimed by a patent would change upon approval of the
supplement (see proposed Sec. 314.53(d)(2)(ii)(A)). (In this regard,
we note that an untimely filed patent that claims the product approved
in the original application cannot be transformed into a timely filed
patent with submission of a supplement.)
If, however, a listed patent no longer claims the product as
changed by the supplement (e.g., a new formulation is no longer claimed
by a patent listed for the original formulation of the drug product),
then the applicant must submit a request to correct or remove the
patent information from the list in accordance with proposed Sec.
314.53(f)(2) at the time of approval of the supplement.
Correspondingly, if one or more existing patents claim the product
[[Page 6824]]
as changed by the supplement (e.g., a supplement seeking approval for a
new indication) and this patent information has not been submitted to
FDA, the applicant must submit the patent information with the
supplement and following approval. The requirement in proposed Sec.
314.53(d)(2)(ii)(C) also would apply to submission of patent
information for a patent currently listed for the drug as approved in
the original application that claims the drug approved in the
supplement in a new way (e.g., a new or additional method of use) and
for which the patent information would be required to be submitted
under Sec. 314.53(c). In this case, the applicant would be required to
comply with Sec. 314.53(c) and submit patent information describing
the new or additional method of use claimed by the patent with the
supplement and following approval.
As noted previously in this section of the document, the Agency has
received comments criticizing as redundant the requirement for
submission of Forms FDA 3542a and 3542 with submission and upon
approval, respectively, of an NDA supplement where the information has
not changed since the form last was filed (see April 2007 notice).
Section 505(b)(1) of the FD&C Act requires the submission of patent
information with the filing of a supplement to an NDA. To the extent
that patents currently listed for the drug product continue to claim
the product as changed by the supplement, we interpret the statute to
not require resubmission of duplicative patent information. In
circumstances other than those described in proposed Sec.
314.53(d)(2)(ii)(A), an applicant or sponsor must submit required
patent information with submission and upon approval of a supplement.
This requirement facilitates the prompt listing of patent information
postapproval by requiring applicants to complete their initial
assessment of relevant patents with submission of their application and
during the pendency of its review.
We are proposing a conforming revision to Sec. 314.70(f) to
clarify that an applicant that submits a supplement to an NDA
(including a 505(b)(2) application) also must comply with the patent
information requirements under Sec. 314.53.
II.B.2.b. Untimely filing of patent information (proposed
Sec. Sec. 314.53(d)(3), 314.50(i)(4), and 314.94(a)(12)(vi)). We are
proposing to supplement Sec. 314.53(d)(3) to expressly describe our
longstanding practice with respect to listing untimely filed patents.
Proposed Sec. 314.53(d)(3) states that if the required patent
information is not submitted within 30 days of the issuance of the
patent, FDA will list the patent, but patent certifications will be
governed by the provisions regarding untimely filed patents in
Sec. Sec. 314.50(i)(4) and (i)(6) and 314.94(a)(12)(vi) and
(a)(12)(viii) of this part. We also are proposing to revise Sec. Sec.
314.50(i)(4) and 314.94(a)(12)(vi) to include certain amendments to the
description of the approved method(s) of use claimed by the patent
within the category of untimely filed patent information.
Section 505(c)(2) of the FD&C Act requires an NDA holder to file
patent information for a patent issued after the date of approval of
the application within 30 days of patent issuance. (As clarified in
proposed Sec. 314.53(c)(2)(ii), this statutory requirement for timely
filing does not apply to patent information submitted prior to approval
of an NDA or supplement, even if the patent information is submitted to
FDA more than 30 days after the patent is issued by the PTO.)
Section 505(c)(2) of the FD&C Act further directs the Agency to
publish information on the newly-issued patent upon its submission, and
we have interpreted this statutory provision to require listing in the
Orange Book irrespective of whether the patent information has been
timely filed. Although we list untimely filed patents pursuant to
section 505(c)(2) of the FD&C Act, we generally do not require an
applicant with a pending 505(b)(2) application or ANDA to provide a
patent certification to a patent for which the NDA holder failed to
comply with the statutory timeframe for submission of patent
information after approval. Accordingly, the untimely filed patent will
neither delay approval of a pending 505(b)(2) application or ANDA until
patent expiration nor necessitate a carve-out of information related to
a patented method of use.
Although an applicant with a pending 505(b)(2) application or ANDA
that references the drug product generally would not be required to
submit a patent certification to an untimely filed patent that was
late-listed as to the pending 505(b)(2) application or ANDA, we would
permit an applicant to submit and maintain a patent certification
(including a paragraph IV certification) or a statement pursuant to
section 505(b)(2)(B) or 505(j)(2)(B)(viii) of the FD&C Act, if desired.
For example, a 505(b)(2) or ANDA applicant may wish to submit a
paragraph IV certification to challenge the late-listed patent and
obtain patent certainty (i.e., determine whether the NDA holder or
patent owner will initiate a patent infringement action against the
applicant) instead of possibly marketing at risk.
We also are proposing to revise Sec. Sec. 314.50(i)(4) and
314.94(a)(12)(vi) to state that, except as provided in Sec.
314.53(f)(1), an NDA holder's amendment to the description of the
approved method(s) of use claimed by the patent will be considered
untimely filing of patent information if:
The amendment is submitted more than 30 days after patent
issuance and it is not related to a corresponding change in approved
product labeling or
the amendment is submitted more than 30 days after a
corresponding change in approved product labeling.
This proposed revision is consistent with the objective of ensuring
that prospective 505(b)(2) and ANDA applicants have timely notice of
changes to the asserted patent coverage for a listed drug. In addition,
proposed Sec. Sec. 314.50(i)(4) and 314.94(a)(12)(vi) would complement
proposed revisions to Sec. 314.53 that are intended to enhance NDA
holders' compliance with the requirement to accurately identify the
specific sections of product labeling that correspond to the use
claimed by the patent (see section II.B.1.c). If an amendment to change
the patent use code is not related to a corresponding change in
approved product labeling and is submitted more than 30 days after
patent issuance (or patent reissuance), then the patent information is
properly considered untimely filed. In accordance with Sec. Sec.
314.50(i)(4) and 314.94(a)(12)(vi), an untimely filed method-of-use
patent does not require a patent certification or statement and would
not delay approval of a pending 505(b)(2) application or ANDA.
Similarly, if an amendment to change the patent use code is submitted
more than 30 days after a corresponding change in approved product
labeling, then the amendment lacks a clear temporal or substantive link
to the specific section(s) of approved product labeling claimed by the
patent, and the patent information is untimely filed.
An applicant with a pending 505(b)(2) application or ANDA that
seeks to confirm that a newly listed patent was untimely filed (and may
not require a patent certification in accordance with Sec.
314.50(i)(4) or Sec. 314.94(a)(12)(vi)) should contact the Orange Book
staff. Irrespective of whether the patent was untimely filed (and thus
late-listed as to the pending 505(b)(2) application or ANDA) or timely
filed (and thus ``later listed'' as to the pending 505(b)(2)
application or ANDA), a paragraph IV certification submitted for a
patent filed with FDA after the date on which a
[[Page 6825]]
505(b)(2) application or ANDA (that is later determined to be
substantially complete) was submitted will not give rise to a 30-month
stay (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act and
section II.G).
We note, however, that a 505(b)(2) application or ANDA submitted
after the untimely filed patent is listed in the Orange Book is
required to submit an appropriate patent certification or statement to
the patent. As we explained in the 1994 final rule, ``[t]he approach
adopted by the Agency as best embodying the compromise adopted by
Congress requires that if an NDA applicant submits required patent
information on an approved drug product more than 30 days after
issuance of the patent, FDA will publish the untimely information, but
will not require ANDA and 505(b)(2) applicants with pending
applications that have previously submitted a certification, i.e. those
applicants that would be prejudiced by the late submission, to
recertify to the new patent. Only applicants that initially submit
ANDA's or 505(b)(2) applications after the submission of the patent
information or whose pending applications do not contain a valid
certification at the time of submission would be required to submit a
certification as to that patent. . . . While this could result in two
categories of ANDA's for a pioneer drug, those without certifications
for the late-filed patent and those with certifications for that
patent, this approach is the best means for discouraging manipulation
of the patent filing scheme and providing optimum notice of applicable
patents'' (59 FR 50338 at 50340, response to comment 7).
We remind NDA holders that patents issued after approval of a drug
under section 505(c) of the FD&C Act include reissued patents (see
section II.B.1.e) as well as patents that claim a drug product listed
in the discontinued section of the Orange Book. With reference to the
latter category, we note that a 505(b)(2) or ANDA applicant may rely
upon a drug product listed in the discontinued section of the Orange
Book to the extent that the product was not withdrawn for reasons of
safety or effectiveness (see Sec. 314.151 with respect to ANDAs).
Accordingly, we encourage NDA holders to ensure that they continue to
comply with the statutory requirements for patent listing for products
that have been discontinued from marketing.
We also are proposing to revise Sec. 314.50(i)(4) to remove an
incorrect reference to the possible submission of a certification under
Sec. 314.50(i)(1)(ii) after the NDA holder's untimely filing of patent
information. If a 505(b)(2) applicant is required to submit a patent
certification to untimely filed patent information as provided in
proposed Sec. 314.50(i)(4), a ``no relevant patents'' statement under
Sec. 314.50(i)(1)(ii) would not be an acceptable patent certification.
Finally, we are proposing to revise the heading for Sec.
314.53(d)(3) to ``newly issued patents'' to better characterize the
text and emphasize its applicability to patents issued after approval
of an NDA or supplement. We also are proposing to revise the heading
for proposed Sec. Sec. 314.50(i)(4) and 314.94(a)(12)(vi) to
``untimely filing of patent information'' and to make conforming
revisions to the text of these sections for consistent use of
terminology.
II.B.2.c. Where to send submissions of Forms FDA 3542a and 3542
(proposed Sec. 314.53(d)(4)). We are proposing to require that patent
information filed on Form FDA 3542 upon and after approval of an NDA or
supplement be submitted directly to the Orange Book staff through the
OGD Document Room. The Orange Book staff will send an archival copy of
this patent information to CDER's Central Document Room for filing with
the NDA.
Our proposal to require that NDA holders submit post-approval
patent information directly to the Orange Book staff is intended to
facilitate prompt listing of patent information in the Orange Book
after Form FDA 3542 has been officially received by the Agency.
Currently, many NDA holders submit a duplicate or courtesy copy of Form
FDA 3542 to the Orange Book staff electronically or via facsimile at
the time of their submission of Form FDA 3542 to CDER's Central
Document Room. This patent information is listed in the Orange Book
upon receipt by the Orange Book staff, and the Orange Book explains
that the date on which patent information is published ``may not
reflect the official receipt date as described in 21 CFR
314.53(d)(5).'' However, this practice may result in publication of
patent information prior to receipt by the official repository
identified in our regulations and cause confusion for prospective first
applicants and applicants with a pending 505(b)(2) application or ANDA
seeking to determine whether or not the patent is late-listed. Proposed
Sec. 314.53(d)(4) designates the OGD Document Room as an official
repository for submissions of Form FDA 3542, and proposed Sec.
314.53(d)(5) (see section II.B.2.d) clarifies that the submission date
of patent information provided by an NDA holder after approval of an
application is the earlier of the date on which Form FDA 3542 is date-
stamped by the OGD Document Room or officially received electronically
by FDA though the Electronic Submissions Gateway. These proposed
revisions to the regulations are intended to enhance efficiency and
ensure that patent information is promptly listed after its receipt.
We note, however, that patent information submitted on Form FDA
3542a with the filing of an NDA, amendment, or supplement, and prior to
approval of the application must continue to be submitted directly to
the NDA as required by Sec. 314.50(h) or Sec. 314.70(f), as
appropriate. An applicant should not submit a copy of Form FDA 3542a to
the Orange Book staff; the Orange Book staff should only receive patent
information submitted after approval of the NDA or supplement. An
applicant should not submit a copy of the patent to FDA with submission
of Form FDA 3542a or 3542.
II.B.2.d. Submission date of patent information (proposed Sec.
314.53(d)(5)). We are proposing to revise Sec. 314.53(d)(5) to
clarify, for purposes of Sec. 314.53(d)(3), that the submission date
of patent information provided by an NDA holder after approval of an
application is the earlier of the date on which Form FDA 3542 is date-
stamped by the OGD Document Room or officially received electronically
by FDA though the Electronic Submissions Gateway (i.e., at the
completion of electronic transmission). Our current regulations state
that the information shall be considered submitted to FDA on the date
it is received by the Central Document Room. We note that patent
information sent to another location at FDA is not considered received
by FDA for purposes of Sec. 314.53(d)(3) on timely filing and a
505(b)(2) or ANDA applicant's patent certification obligations pursuant
to Sec. 314.50(i)(4) and (i)(6) or Sec. 314.94(a)(12)(vi) and
(a)(12)(viii), respectively, unless it is sent to the official
repository identified in the regulation.
These proposed revisions are intended to remove any ambiguity about
the date of submission in light of the implications of untimely filing
of patent information on the patent certification obligations of
505(b)(2) applicants and ANDA applicants that rely upon the listed drug
(see Sec. Sec. 314.50(i)(4) and 314.94(a)(12)(vi)). In this regard, we
note that the patent certification obligations of a 505(b)(2) or ANDA
applicant arise upon the receipt by the official repository at FDA of
the NDA holder's submission of patent information for a listed drug
rather than the timing of publication of the patent
[[Page 6826]]
information in the Orange Book (see section 505(b)(2)(A) and
(j)(2)(A)(vii) of the FD&C Act; see also Teva Pharms., USA, Inc. v.
Leavitt, 548 F.3d 103, at 108 (D.C. Cir. 2008) (noting that FDA ``has
consistently required ANDA applicants to certify to patents recently
submitted to FDA, even if FDA had not yet published the patent in any
version of the Orange Book'')).
However, for purposes of eligibility for 180-day exclusivity, an
ANDA applicant is not permitted to submit a paragraph IV certification
to a patent (e.g., a recently issued patent that claims the RLD) before
the first working day after the day the patent is listed in the Orange
Book (see section II.D.1.b.ii and II.E.4).
In addition, proposed Sec. 314.53(d)(5) would change the addressee
to whom submission of Form FDA 3542 should be sent from the Central
Document Room to the OGD Document Room or the Electronic Submissions
Gateway, consistent with proposed Sec. 314.53(d)(4) discussed in
section II.B.2.c.
II.B.3. Public Disclosure of Patent Information (Proposed Sec.
314.53(e))
We are proposing to delete the reference in Sec. 314.53(e) to
monthly supplements to the Orange Book because the Agency no longer
arranges for publication of monthly printed supplements to the Orange
Book. Patent information listed in the Orange Book, which may be
accessed from the Agency's Web site, has been updated on a daily basis
for several years. This correction to Sec. 314.53(e) is consistent
with our proposed revision of the definition of ``the list'' in Sec.
314.3(b) to mean the list of approved drug products published in FDA's
current ``Approved Drug Products With Therapeutic Equivalence
Evaluations'' available electronically on FDA's Web site at http://www.fda.gov/cder.
Section 314.53(e) provides that copies of the patent information
submitted on Form FDA 3542 may be requested from FDA's Freedom of
Information Staff. We are proposing to revise Sec. 314.53(e) to
replace the reference to a request for copies of the ``file'' to copies
of the ``submitted patent information.'' This revision is proposed for
clarity and does not represent a substantive change. We note, for
example, that some prospective 505(b)(2) or ANDA applicants have
requested copies of the patent information submitted on Form FDA 3542
for patents listed for a listed drug in the Orange Book to determine
the scope of the labeling identified by the NDA holder as relating to
the use claimed by the patent. Copies of Form FDA 3542 also have been
requested to obtain address information for the agent or representative
authorized to receive notice of patent certification if the patent
owner or NDA holder does not reside or have a place of business in the
United States. We anticipate additional requests for the information
submitted on Form FDA 3542 and may elect to proactively post on FDA's
Web site a copy of Form FDA 3542 for patents listed in the Orange Book
in advance of a request under the Freedom of Information Act (see
Presidential Documents, Memorandum for the Heads of Executive
Departments and Agencies on Transparency and Open Government (January
21, 2009) (74 FR 4685, January 26, 2009); see also Office of the
Attorney General, Memorandum for the Heads of Executive Departments and
Agencies on The Freedom of Information Act (March 19, 2009), available
at http://www.usdoj.gov/ag/foia-memo-march2009.pdf).
II.B.4. Correction or Change of Patent Information (Proposed Sec.
314.53(f))
We are proposing to revise Sec. 314.53(f) to differentiate the
procedure for correction or change of patent information by the NDA
holder (proposed Sec. 314.53(f)(2)) from the procedure for requests by
persons other than the NDA holder. Proposed Sec. 314.53(f) also would
address certain issues that have arisen regarding method-of-use patents
and enhance FDA's response to challenges to the accuracy or relevance
of submissions of this patent information to the Agency. We are
proposing to redesignate the current text of Sec. 314.53(f) as Sec.
314.53(f)(1). We are proposing to add new Sec. 314.53(f)(2) to
implement section 505(j)(5)(D)(i)(I)(bb)(CC) of the FD&C Act, as added
by the MMA, and to make other changes for the efficient enforcement of
the FD&C Act.
Table 4 summarizes the proposed changes related to correction or
change of patent information:
Table 4--Highlights of Proposed Changes Regarding Correction or Change
of Patent Information \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Correction of patent information errors Correction or change of patent
(Sec. 314.53(f)). information--Requests by
persons other than the NDA
holder (Sec. 314.53(f)(1)).
If any person disputes the If any person disputes
accuracy or relevance of patent the accuracy or relevance of
information submitted to FDA under patent information submitted
Sec. 314.53 and published by FDA in to FDA under Sec. 314.53 and
the list, that person must first published by FDA in the list,
notify FDA (OGD Document Room, Attn: that person must first notify
Orange Book Staff) in writing stating FDA (OGD Document Room, Attn:
the grounds for disagreement. FDA then Orange Book Staff) in a
will request that the NDA holder written or electronic
confirm the correctness of the patent communication titled
information.. ``314.53(f) Patent Listing
Dispute'' that states the
grounds for disagreement. FDA
then will request that the NDA
holder confirm the correctness
of the patent information
within 30 days.
For listed patents
that claim an approved method
of using the drug product, FDA
will request that the NDA
holder confirm the correctness
of the ``Use Code'' in the
Orange Book, and provide
information on the specific
approved use claimed by the
patent that enables FDA to
make a determination in
accordance with section
505(b)(2)(B) or
(j)(2)(C)(viii) of the FD&C
Act.
Unless the NDA holder Unless the NDA holder
withdraws or amends its patent withdraws or amends its patent
information in response to FDA's information in response to
request to confirm the correctness of FDA's request to confirm the
the patent information, FDA will not correctness of the patent
change the patent information in the information, FDA will not
list. change the patent information
in the list.
--If there is insufficient
information to make a
determination in accordance
with section 505(b)(2)(B) or
(j)(2)(C)(viii) of the FD&C
Act and the NDA holder has
confirmed the correctness of
its description of the
specific approved use claimed
by the patent, the Agency will
review the proposed labeling
for the 505(b)(2) application
or ANDA with deference to the
505(b)(2) or ANDA applicant's
interpretation of the scope of
the patent.
[[Page 6827]]
Correction or change of patent
information--Requests by the
NDA holder (Sec.
314.53(f)(2)).
If the NDA holder
determines that a patent or
patent claim no longer meets
the statutory requirements for
listing, the NDA holder must
promptly notify FDA to
withdraw the patent
information and request that
the patent information be
removed from the list.
If the NDA holder is
required by court order to
amend patent information or
withdraw a patent from the
list, it must submit a copy of
the order to FDA (OGD Document
Room, Attn: Orange Book Staff)
within 14 days of order entry.
FDA will remove a patent from
the list if there is no first
applicant eligible for 180-day
exclusivity or upon the
expiration of the 180-day
period.
If the term of a
listed patent is extended
under 35 U.S.C. 156(e), the
NDA holder must submit on Form
FDA 3542 a correction to the
patent expiration date within
30 days of receipt of a
certificate of extension or
documentation of an extension
of the patent term.
Corrections or changes
to previously submitted patent
information, other than
withdrawal of a patent and
requests to remove a patent
from the list (delisting
requests), must be submitted
on Form FDA 3542 or 3542a, as
appropriate.
Withdrawal of a patent
and delisting requests must be
submitted as described in Sec.
314.53(d)(4), except it need
not be submitted on Form FDA
3542. The patent withdrawal
and delisting request must
contain the NDA number, each
product to which the request
applies, and the patent
number.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.B.4.a. Requests by persons other than the NDA holder--patents
that claim an approved method of using the drug product (proposed Sec.
314.53(f)(1)). To efficiently implement the statutory provisions in
section 505(b)(2)(B) and (j)(2)(C)(viii) of the FD&C Act, we are
proposing to enhance the mechanism for challenging the accuracy or
relevance of information with respect to method-of-use patents
submitted to the Agency under Sec. 314.53 and listed in the Orange
Book.
In the preamble to the June 2003 final rule on patent submission
and listing requirements, we discussed our longstanding position,
codified in Sec. 314.53(b) and (c)(2), that ``only method-of-use
patents that claim a use of the drug product in the pending or approved
application must be submitted'' (68 FR 36676 at 36681). The June 2003
final rule further explained: ``The declarant must describe each
individual method of use for which a patent is submitted for listing,
and identify the corresponding language found in the labeling of the
approved NDA that corresponds to that method of use. This information
will expedite our review of ANDA and 505(b)(2) applications that do not
seek approval for all the approved uses. In determining whether an ANDA
applicant can `carve out' the method of use, rather than certify to the
listed patent, we will rely on the description of the approved use
provided by the NDA holder or patent owner in the patent declaration
and listed in the Orange Book'' (68 FR 36676 at 36682).
An NDA holder or patent owner must provide adequate information in
its submission of patent information to enable potential 505(b)(2) and
ANDA applicants to avail themselves of the statutory provision that
permits a 505(b)(2) or ANDA applicant to not certify to a patent by
stating that it is not seeking approval for the method of use claimed
by the listed patent (see section 505(b)(2)(B) and (j)(2)(C)(viii) of
the FD&C Act, respectively) and carving out from product labeling the
corresponding use information. Our July 2007 revision of Forms FDA
3542a and 3542 clarifies, in its instructions, that ``[t]he use code
designates a method of use patent that claims the approved indication
or use of a drug product. Each approved use claimed by the patent
should be separately identified in this section and contain adequate
information to assist 505(b)(2) and ANDA applicants in determining
whether a listed method of use patent claims a use for which the
505(b)(2) or ANDA applicant is not seeking approval'' (Form FDA 3542,
section 4.2b).
Section 314.53(f) currently provides that, upon notification of the
grounds for a disagreement with the accuracy or relevance of the patent
submission, FDA will request that the NDA holder confirm the
correctness of the patent information or omission of patent
information. Proposed Sec. 314.53(f)(1) would establish a 30-day
timeframe in which the NDA holder is required to respond to FDA's
request in order to facilitate timely resolution of the patent listing
dispute.
Proposed Sec. 314.53(f)(1) also would further specify that, in
response to notification of a patent listing dispute for a listed
patent that claims an approved method of using the drug product, FDA
will request that the NDA holder confirm the correctness of its
description of the approved indication or method of use that has been
included as the ``use code'' in the Orange Book, and provide
information on the specific approved use claimed by the patent that
enables the Agency to make a determination in accordance with section
505(b)(2)(B) or (j)(2)(C)(viii) of the FD&C Act. If the patent has been
listed and the NDA holder confirms the accuracy of the patent
information, fails to timely respond to FDA's request under Sec.
314.53(f), or submits a revision to the use code that does not provide
adequate clarity for FDA to determine whether the scope of the proposed
labeling carve-out would be appropriate based on the NDA holder's use
code and approved labeling, FDA is proposing to review a proposed
labeling carve-out(s) for the 505(b)(2) application or ANDA with
deference to the 505(b)(2) or ANDA applicant's interpretation of the
scope of the patent. In determining whether a proposed omission of use
information
[[Page 6828]]
from labeling is appropriate, the Agency will consider the use code and
labeling information submitted by the NDA holder on Form FDA 3542, the
history of labeling changes related to approval of an indication(s) for
the drug product, the 505(b)(2) or ANDA applicant's interpretation of
the scope of the patent, the need for consistent labeling among
products approved under section 505(j) of the FD&C Act, and the
requirements of Sec. Sec. 314.94(a)(8)(iv) and 314.127(a)(7), as
appropriate.
The following hypothetical example illustrates our approach under
proposed Sec. 314.53(f)(1) to determining whether an ANDA applicant's
proposed labeling carve-out would be appropriate: The NDA holder
submits Form FDA 3542 to the Office of Generic Drugs, Document Room,
Attention: Orange Book Staff, within 30 days after issuance of the '321
patent claiming a method of using the drug product Gaindrolone. The NDA
holder provided the use code ``to promote weight gain after weight loss
in certain types of patients'' for each patent that it submitted for
listing in the Orange Book, but did not specifically identify the
approved use(s) (e.g., patient population(s)) claimed by the patent. In
section 4.2a of Form FDA 3542, the NDA holder further identified the
patented method of use claimed in patent claims 8, 9, and 10 of the
'321 patent with specific reference to the following sections of the
approved labeling for the drug product: Indications and Usage
(``indicated as adjunctive therapy to promote weight gain after weight
loss following extensive surgery, chronic infections, or severe
trauma'') and Dosage and Administration. Applicant A submits an ANDA
that cites Gaindrolone as the basis for ANDA submission and contains a
505(j)(2)(A)(viii) statement with respect to the '321 patent. Applicant
A also notifies the Agency in a written communication titled
``314.53(f) Patent Listing Dispute'' that the use code listed in the
Orange Book for the '321 patent is overbroad as Applicant A interprets
the scope of the '321 patent to be limited to ``adjunctive therapy to
promote weight gain after weight loss following chronic infections.''
Applicant A contends that other approved patient populations are not
within the scope of the '321 patent. FDA subsequently provides the NDA
holder with the Applicant A's basis for disagreement with the accuracy
of the listed patent information and requests that the NDA holder
confirm the correctness of the description of the specific approved use
claimed by the patent or revise the description within 30 days. The NDA
holder confirms the use code ``to promote weight gain after weight loss
in certain types of patients'' and thus does not provide adequate
clarity for the Agency to make a determination in accordance with
section 505(j)(2)(A)(viii) of the FD&C Act on whether Applicant A could
carve out the patented use in ``certain types of patients'' and seek
approval for the remaining uses. Accordingly, FDA reviews the proposed
ANDA labeling with deference to Applicant A's interpretation of the
scope of the patent and approves the ANDA for ``adjunctive therapy to
promote weight gain after weight loss following extensive surgery or
severe trauma.'' As noted in the June 2003 final rule, ``the claim-by-
claim listing of method-of-use patents will permit ANDA and 505(b)(2)
applicants to assess whether they are seeking approval for a use
claimed in the listed patent, and thus determine whether to submit a
patent certification or a section viii statement. Additionally, we
[FDA] can verify that the certification or statement is correct, and
that only the appropriate methods of use are included in the proposed
labeling for the ANDA or 505(b)(2) drug product'' (68 FR 36676 at
36685). Applicant A has a strong incentive to interpret the scope of
the patent correctly to avoid being subject to patent infringement
litigation following ANDA approval and potentially enjoined from
marketing its product. The use code submitted by the NDA holder remains
listed in the Orange Book (compare June 2003 final rule (68 FR 36676 at
36683) (``[u]se codes are intended to alert ANDA and 505(b)(2)
applicants to the existence of a patent that claims an approved use.
They are not meant to substitute for the applicant's review of the
patent and the approved labeling'').
In the same example above, we note that if the NDA holder had
responded to FDA's request by revising the description of the specific
approved use claimed by the patent in a manner that provided sufficient
information for the Agency to make a determination in accordance with
section 505(j)(2)(A)(viii) of the FD&C Act on whether Applicant A could
carve out the patented use, FDA would have no occasion to review the
proposed ANDA labeling with deference to Applicant A's interpretation
of the scope of the patent. For example, if the NDA holder submitted a
revised Form 3542 that provided a revised use code (hypothetically ``to
promote weight gain after weight loss following chronic infections or
severe trauma'') and specifically referred to the corresponding portion
of the approved labeling, there would be sufficient information for the
Agency to make a determination in accordance with section
505(j)(2)(A)(viii) of the FD&C Act. Accordingly, there would be no
ambiguity that would warrant review of the proposed ANDA labeling with
deference to Applicant A's interpretation of the scope of the patent,
even if Applicant A's interpretation differed from that of the NDA
holder.
As previously discussed in the June 2003 final rule, we reiterate
that the Agency's role in patent listing is ministerial and does not
involve substantive review of patents (see 68 FR 36676 at 36683).
Rather, our proposed revisions to the regulations in 314.53(f) are
intended to provide the Agency with the information necessary to
implement section 505(b)(2)(B) and (j)(2)(C)(viii) of the FD&C Act. FDA
believes that enhancing the mechanism for challenging overbroad use
codes listed in the Orange Book may cause NDA holders to be more
circumspect in their original submission of patent information to FDA.
Accordingly, we expect that there will rarely be a need for the Agency
to review the proposed labeling for the 505(b)(2) application or ANDA
with deference to the 505(b)(2) or ANDA applicant's interpretation of
the scope of the patent. However, we invite comment on this proposed
approach to enhancing FDA's response to challenges to the accuracy or
relevance of submissions of patent information to the Agency, while
maintaining the Agency's ministerial role in patent listing.
II.B.4.b. Requests by NDA Holder To Remove Patent Information From the
List (Proposed Sec. 314.53(f)(2))
II.B.4.b.i. Patents or patent claims that no longer meet the
statutory requirements for listing. Section 1102(a)(2) of the MMA
amends section 505(j)(5)(D)(i)(I) of the FD&C Act to define certain
events that constitute forfeiture of 180-day exclusivity. As noted in
section I, we are implementing the 180-day exclusivity provisions of
the MMA directly from the statute and will determine if additional
rulemaking is necessary in the future. Where a novel issue of
interpretation is raised by a particular factual scenario regarding
forfeiture of 180-day exclusivity, we may open a public docket or
otherwise seek comment from affected parties in advance of taking
action (see section I.D). However, we are proposing at this time to add
Sec. 314.53(f)(2) regarding requests by an NDA holder to remove patent
information from the list to implement section
505(j)(5)(D)(i)(I)(bb)(CC) of the FD&C
[[Page 6829]]
Act (forfeiture of 180-day exclusivity due to failure to market where
the patent or patent information that qualified the first applicant for
180-day exclusivity is withdrawn by the NDA holder), and to clarify our
current practice with respect to withdrawal of a patent or patent
information by an NDA holder.
Under proposed Sec. 314.53(f)(2), if the NDA holder determines
that a patent or patent claim (e.g., a method-of-use claim) no longer
meets the statutory requirements for listing, the NDA holder is
required to promptly notify FDA to withdraw the patent or patent
information and request that the patent or patent information be
removed from the list. Circumstances under which a patent or patent
claim no longer meets the statutory requirements for listing include,
but are not limited to, a judicial finding of invalidity or
unenforceability for a listed patent, from which no appeal has been or
can be taken, or a court order to amend patent information or withdraw
a patent from the list. We note that an NDA applicant that determined
that a patent or patent claim submitted on Form FDA 3542a no longer met
the statutory requirements for listing prior to NDA approval would
``withdraw'' the patent or patent claim by not including the patent or
patent claim in its submission of Form FDA 3542 upon approval of the
NDA or NDA supplement. There is no need to submit a request to remove
the patent or patent claim from the list because such patent
information is listed in the Orange Book only upon approval of the NDA
or NDA supplement.
The FD&C Act does not provide an independent cause of action for a
505(b)(2) or ANDA applicant seeking an order requiring an NDA holder to
correct or delete patent information listed in the Orange Book (see
section 505(c)(3)(D)(ii)(II) and (j)(5)(C)(ii)(II) of the FD&C Act; see
also Mylan Pharmaceuticals, Inc. v. Thompson, 268 F.3d 1323 (Fed. Cir.
2001) (holding that the pre-MMA statutory scheme did not recognize a
cause of action for delisting a patent from the Orange Book, and that
``such an action would be a private right of action barred by the
[act]'')). If a 505(b)(2) or ANDA applicant successfully asserts a
counterclaim to a patent infringement action to obtain an order
requiring the NDA holder to amend or withdraw patent information from
the list (see section 505(c)(3)(D)(ii)(I) and (j)(5)(C)(ii)(I) of the
FD&C Act), the NDA holder must withdraw the patent or patent
information and request that the patent or patent information be
removed from the list. The Agency will not remove the patent or patent
information in response to a request, accompanied by a copy of the
court order, from the 505(b)(2) or ANDA applicant or on its own. We are
proposing to require an NDA holder to submit a copy of a court order
requiring amendment or withdrawal of patent information to the Orange
Book Staff through the Office of Generic Drugs Document Room within 14
calendar days of the date on which the order was entered. By providing
a 14-day timeframe within which an NDA holder must notify FDA of this
type of court order, the proposed regulation would facilitate the NDA
holder's compliance with obligations under the FD&C Act and applicable
regulations and ensure that pending 505(b)(2) applications or ANDAs
that have provided a patent certification to the amended or withdrawn
patent are not inappropriately delayed if they are otherwise eligible
for approval. The Orange Book Staff subsequently will forward a copy of
the court order to the NDA through the CDER Central Document Room.
We recognize that for patents that meet the statutory criteria for
listing in the Orange Book, fewer than all of the patent claims may be
the subject of litigation against a particular 505(b)(2) or ANDA
applicant. In such a case, a judicial finding of invalidity for certain
patent claims and withdrawal of that patent information by submission
of an amended Form FDA 3542 may not necessarily be reflected in the
Orange Book (unless, for example, all drug product claims were
invalidated and only a method-of-use claim remained). Accordingly, it
would be prudent for current and prospective 505(b)(2) and ANDA
applicants to be aware of relevant court decisions in patent litigation
(see also the 1994 final rule (59 FR 50338 at 50346) (noting the
prudence of conducting patent searches to identify patents that may be
ineligible for listing in the Orange Book but that may be infringed by
a proposed product)).
Consistent with our current practice, proposed Sec. 314.53(f)(2)
states that we will remove a patent from the Orange Book when the NDA
holder has informed us that the patent no longer meets the statutory
requirements for listing if there is no first applicant eligible for
180-day exclusivity or upon the expiration of the 180-day exclusivity
period of a first applicant.
Proposed Sec. 314.53(f)(2) also applies to amendment of the patent
information to remove a claim (drug substance, drug product, or method
of use) from the list. For example, if a patent is listed in the Orange
Book as claiming the drug product and a method of use, and an NDA
holder withdrew only the drug product claim and requested that the drug
product claim be removed from the list, we would remove the drug
product claim from the Orange Book if there is no first applicant
eligible for 180-day exclusivity or upon the expiration of the 180-day
exclusivity period of a first applicant. This provision is intended to
address scenarios in which an ANDA applicant has submitted a paragraph
IV certification with respect to the drug substance or drug product
claim and a 505(j)(2)(C)(viii) statement with respect to a method-of-
use claim for a single patent.
When an NDA holder has withdrawn a patent and submitted to FDA a
request to remove the patent from the Orange Book, we currently
identify this request in a separate column in the Orange Book titled
``Delist Requested.'' If an NDA holder withdraws a patent claim (e.g.,
a method-of-use claim in a patent that also claims the drug product)
and submits to FDA a request to remove the patent claim from the Orange
Book, we intend to identify this request with a symbol (e.g., an
asterisk) in the column for that claim. These notations signal that the
patent or patent claim remains listed in the Orange Book only to
preserve a first applicant's eligibility for 180-day exclusivity for
their pending ANDA or during the period of 180-day exclusivity after
approval of the first applicant's ANDA. While the patent or patent
claims remain listed in the Orange Book, subsequent ANDA applicants
must submit or maintain an appropriate patent certification or
statement with respect to the patent or patent claims for which the
delisting request has been submitted. This requirement is consistent
with preservation of a first applicant's eligibility for 180-day
exclusivity because the 180-day exclusivity period bars approval of
subsequent ANDAs for the same drug product that also contain a
paragraph IV certification to the patent (see section
505(j)(5)(B)(iv)(I) of the FD&C Act). However, a 505(b)(2) applicant is
not required to certify or maintain a previous certification to the
patent for which a request to remove the patent from the list has been
submitted, because such a patent remains listed in the Orange Book only
for purposes of preserving a first ANDA applicant's eligibility for
180-day exclusivity.
An applicant can determine that a patent or patent claim has been
removed from the Orange Book if it no longer appears in the Orange Book
patent listings for the drug product at issue. In addition, FDA
maintains a separate Web page linked from the ``search by patent''
[[Page 6830]]
option on the Orange Book Web page that identifies patents that have
been recently delisted (currently located at http://www.accessdata.fda.gov/scripts/cder/ob/docs/delist.cfm).
II.B.4.b.ii. Patent term restoration. Proposed Sec.
314.53(f)(2)(ii) directs NDA holders to submit a correction to the
expiration date of their listed patent if the term of the patent is
extended under the patent term restoration provisions of 35 U.S.C. 156,
and sets a timeframe for compliance. With respect to patents eligible
for listing in the Orange Book, the Hatch-Waxman Amendments generally
provide that the terms of certain patents may be extended for a period
of up to 5 years if the patent claims a product or method of using a
product that has been subject to a defined regulatory review period
before commercial marketing or use (see 35 U.S.C. 156(a)). We are
proposing to require the NDA holder to submit the correction to the
patent expiration date on Form FDA 3542 within 30 calendar days of
receipt of a certificate of extension as described in 35 U.S.C.
156(e)(1) or documentation of an extension of the term of the patent as
described in 35 U.S.C. 156(e)(2). The 30-day timeframe within which an
NDA holder must notify FDA of the patent term extension is consistent
with the statutory timeframe set forth in section 505(c)(2) of the FD&C
Act for filing with FDA the patent number and patent expiration date of
any patent that claims the drug or method of using the drug and is
issued after NDA approval. Although extension of the patent term of a
previously issued patent is not explicitly within the scope of section
505(c)(2) of the FD&C Act, the proposed 30-day timeframe for submission
of a correction of the patent expiration date is consistent with the
objective of ensuring that prospective 505(b)(2) and ANDA applicants
have timely notice of changes to the asserted patent coverage for a
listed drug.
II.B.4.b.iii. Submissions to FDA. Proposed Sec. 314.53(f)(2)(iii)
would require that corrections or changes to previously submitted
patent information (other than withdrawal of a patent or requests to
remove a patent from the list) must be submitted on Form FDA 3542a or
3542, as appropriate. This proposed requirement is intended to
facilitate listing of patent information in the Orange Book and ensure
that patent information is accompanied by the patent declaration
verification required by Sec. 314.53(c)(2)(i)(Q) and (c)(2)(ii)(R) and
set forth in the certification requirements of Form FDA 3542a or 3542,
respectively. We note that we will not accept corrections or changes
that are not submitted on the appropriate forms. However, an NDA holder
may elect to submit a cover letter highlighting the corrections or
changes made in the accompanying Form FDA 3542. An NDA holder's
withdrawal of fewer than all of a previously submitted patent's claims
(e.g., withdrawal of the method of use claim(s) for a patent that also
claims the drug product) would be considered a correction or change to
patent information for purposes of proposed Sec. 314.53(f)(2)(iii)
because the patent would remain listed in the Orange Book.
However, proposed Sec. 314.53(f)(2)(iv) clarifies that an NDA
holder's withdrawal of a patent and request to remove a patent from the
Orange Book is not required to be submitted on Form FDA 3542a (with
respect to pre-approval withdrawal of a patent) or FDA Form FDA 3542.
The withdrawal of a patent must be submitted as an amendment to the NDA
if the application has not been approved. After NDA approval, the
withdrawal of a patent must be submitted to the Orange Book Staff
through the OGD Document Room and must specify the patent number, the
application number, and each product(s) approved in the application to
which the request applies. The Orange Book Staff subsequently will
forward a copy of the patent withdrawal to the NDA through the CDER
Central Document Room.
II.C. Patent Certification (Proposed Sec. Sec. 314.50(i) and
314.94(a)(12))
II.C.1. Method-of-Use Patents (Proposed Sec. Sec. 314.50(i)(1)(iii)
and 314.94(a)(12)(iii))
We are proposing to revise Sec. Sec. 314.50(i)(1)(iii) and
314.94(a)(12)(iii) to clarify that a 505(b)(2) or ANDA applicant that
is not seeking approval for any indications or other conditions of use
that are covered by a method-of-use patent for the listed drug(s)
relied upon or RLD, respectively, and has omitted corresponding
labeling from its proposed product may submit a statement under section
505(b)(2)(B) or 505(j)(2)(A)(viii), respectively, instead of a patent
certification with respect to any method-of-use claims. The proposed
addition of the phrase ``or other conditions of use'' to Sec. Sec.
314.50(i)(1)(iii) and 314.94(a)(12)(iii) reflects that a method-of-use
patent that claims a use other than an indication may be submitted for
listing in the Orange Book and may be the subject of a statement under
section 505(b)(2)(B) or 505(j)(2)(A)(viii) with an accompanying
labeling carve-out. This proposed revision is intended to conform with
current Agency practice.
II.C.2. Method-of-Manufacturing Patents (Proposed Deletion of
Sec. Sec. 314.50(i)(2) and 314.94(a)(12)(iv))
The current regulations in Sec. Sec. 314.50(i)(2) and
314.94(a)(12)(iv) state that a 505(b)(2) or ANDA applicant,
respectively, is not required to make a patent certification with
respect to any patent that claims only a method of manufacturing the
drug product (method-of-manufacturing patent). This has been
incorrectly interpreted by certain applicants to mean that a
manufacturer could elect to submit such a patent for listing. In 2003,
Sec. 314.53(b) was amended to state, among other things, that process
patents (i.e., method-of-manufacturing patents) must not be submitted
to FDA (68 FR 36676 at 36679). Therefore, we are proposing that current
Sec. Sec. 314.50(i)(2) and 314.94(a)(12)(iv) be removed (and reserved)
to ensure consistency and clarity in our regulations.
II.C.3. Licensing Agreement (Proposed Sec. 314.50(i)(3))
We are proposing to revise Sec. 314.50(i)(3) regarding licensing
agreements to remove the references to an ``immediate effective date''
and clarify that the patent owner with whom the applicant has a
licensing agreement may consent to approval of the 505(b)(2)
application (if otherwise justified) as of a specific date. These
proposed revisions reflect that there may be barriers to approval other
than the patent that is the subject of the licensing agreement. In
addition, the proposed revision acknowledges that a patent owner may
consent to approval as of a specific date.
This proposed revision does not alter the current requirements for
a 505(b)(2) (or ANDA) applicant that submits a paragraph IV
certification to a patent that claims the listed drug relied upon and
for which the applicant has a licensing agreement with the patent owner
(see proposed Sec. Sec. 314.50(i)(3) and 314.94(a)(12)(v)). A
505(b)(2) or ANDA applicant must comply with the statutory requirements
for sending notice of paragraph IV certification under section
505(b)(3) and (j)(2)(B) of the FD&C Act, respectively, with respect to
each listed patent for which it has submitted a paragraph IV
certification notwithstanding the applicant's statement that it has
been granted a patent license.
[[Page 6831]]
II.D. Notice of Paragraph IV Certification (Proposed Sec. Sec. 314.52
and 314.95)
II.D.1. Timing of Notice
A 505(b)(2) or ANDA applicant submitting a paragraph IV
certification is required to give notice of the patent challenge to the
holder of the NDA for the listed drug(s) relied upon or RLD,
respectively, and each owner of the patent that is the subject of the
certification within a specified timeframe (see section 505(b)(3) and
(j)(2)(B) of the FD&C Act). We are proposing to revise our regulations
to clearly delineate the two limitations on the timeframe within which
notice can be provided to the NDA holder and each patent owner of a
paragraph IV certification to a listed patent: (1) The date before
which notice may not be given and (2) the date by which notice must be
given. The MMA amended the FD&C Act to establish the date by which
notice of a paragraph IV certification must be given to the NDA holder
and each patent owner. Table 5 summarizes the proposed changes related
to the timing of providing notice of a paragraph IV certification.
Table 5--Highlights of Proposed Changes Regarding Timing of Notice of
Paragraph IV Certification \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Sending the notice (Sec. Sec. 314.52(b) Sending the notice (Sec.
and 314.95(b)) Sec. 314.52(b)(1) and
(b)(2) and 314.95(b)(1) and
(b)(2))
505(b)(2) applicant must send Except as provided
notice required by Sec. 314.52(a) when in Sec. 314.52(d), a
it receives from FDA an acknowledgment 505(b)(2) applicant must
letter stating that its 505(b)(2) send notice required by
application has been filed. Sec. 314.52(a) on or
after the date it receives
from FDA a paragraph IV
acknowledgment letter, but
not later than 20 days
after the date of the
postmark on the paragraph
IV acknowledgment letter.
Any required notice
is invalid if it is sent
before the 505(b)(2)
applicant's receipt of a
paragraph IV acknowledgment
letter. The applicant will
not have complied with Sec.
314.52(b) until it sends
valid notice.
ANDA applicant must send notice Except as provided
required by Sec. 314.95(a), when it in Sec. 314.95(d), an
receives from FDA an acknowledgment ANDA applicant must send
letter stating that its ANDA is notice required by Sec.
sufficiently complete to permit a 314.95(a) on or after the
substantive review. date it receives from FDA
an acknowledgment letter or
a paragraph IV
acknowledgment letter, but
not later than 20 days
after the date of the
postmark on the
acknowledgment letter or
paragraph IV acknowledgment
letter.
Any required notice
is invalid if it is sent
before the ANDA applicant's
receipt of an
acknowledgment letter or a
paragraph IV acknowledgment
letter, or before the first
working day after the day
the patent is published in
the list. The applicant
will not have complied with
Sec. 314.95(b) until it
sends valid notice.
The 20-day clock
begins on the day after the
date of the postmark on the
paragraph IV acknowledgment
letter. When the 20th day
falls on Saturday, Sunday,
or a Federal holiday, the
20th day will be the next
day that is not a Saturday,
Sunday, or Federal holiday.
Sending the notice (Sec. Sec. 314.52(b) Sending the notice (Sec.
and 314.95(b)) Sec. 314.52(b)(3) and
314.95(b)(3)
At the same time, the 505(b)(2) At the same time
or ANDA applicant must amend its the 505(b)(2) or ANDA
application to include a statement applicant sends the notice
certifying that notice of paragraph IV required by Sec.
certification has been provided to each 314.52(a) or Sec.
person identified under Sec. 314.52(a) 314.95(a), respectively, it
or Sec. 314.95(a), respectively, and must submit an amendment to
that notice met the content requirement its 505(b)(2) application
under Sec. 314.52(c) or Sec. that includes a statement
314.95(c), respectively. certifying that the notice
of paragraph IV
certification has been
provided to each person
under Sec. 314.52(a) or
Sec. 314.95(a),
respectively, and that
notice met the content
requirement under Sec.
314.52(c) or Sec.
314.95(c), respectively.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.D.1.a. Date before which notice may not be given. We are
proposing to clarify the text of our regulations to reflect our
longstanding practice that notice of a paragraph IV certification may
not be sent by a 505(b)(2) or ANDA applicant unless and until we have
notified the applicant that its application has been filed or received,
as appropriate, in an acknowledgment letter or a paragraph IV
acknowledgment letter (see proposed Sec. Sec. 314.52(b)(1) and
314.95(b)(1)).
Sections 314.52(b) and 314.95(b) currently require that a 505(b)(2)
and ANDA applicant, respectively, send notice of a paragraph IV
certification when it receives from FDA an acknowledgment letter
stating that the application is sufficiently complete to permit a
substantive review. An NDA, including a 505(b)(2) application, is
deemed sufficiently complete to permit a substantive review if it is
filed by the 60th day after submission (see Sec. 314.101(a)(1) and
proposed Sec. 314.101(a)(2)). An ANDA is received when FDA has made a
threshold determination that the ANDA is substantially complete and has
sent the ANDA applicant an acknowledgment letter or paragraph IV
acknowledgment letter (see Sec. 314.101(b)). We previously have
explained that notice of a paragraph IV certification is to be sent
only after the 505(b)(2) or ANDA applicant has received acknowledgment
from FDA that its application has been determined to be acceptable for
review because such notice subjects the 505(b)(2) or ANDA applicant to
the risk that it will be sued for patent infringement (see
``Abbreviated New Drug Application Regulations''; proposed rule (54 FR
28872; July 10, 1989) (1989 proposed rule); see also 35 U.S.C.
271(e)(2)). The receipt of notice of a paragraph IV certification by a
patent owner or the NDA holder (or their representatives) begins a 45-
day period within which the NDA holder or patent owner must initiate a
patent infringement action against the 505(b)(2) or ANDA applicant in
order to obtain, in certain cases, a statutory 30-month stay of
approval of the application while the patent infringement litigation is
pending (section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act).
The FD&C Act requires that a notice of paragraph IV certification
must state
[[Page 6832]]
that the 505(b)(2) application or ANDA containing the certification
``has been submitted'' (see section 505(b)(3)(D)(i) and
(j)(2)(B)(iv)(I) of the FD&C Act). As we noted in the preamble to the
1989 proposal to implement the Hatch-Waxman Amendments, however,
``[t]he statute and legislative history of Title I [of the Hatch-Waxman
Amendments] demonstrate that Congress did not intend incomplete
application submissions to trigger legal action by a patent owner or
approved application holder'' (1989 proposed rule, 54 FR 28872 at
28887). By requiring that a 505(b)(2) application has been filed or an
ANDA has been received before notice of a paragraph IV certification
can be given, we ensure that the NDA holder and patent owner do not
needlessly expend resources to initiate litigation with respect to an
application that is incomplete and therefore may not be reviewed by the
Agency (see 1989 proposed rule, 54 FR 28872 at 28887 and 1994 final
rule, 59 FR 50338 at 50349-50350). Accordingly, our current regulations
require that a 505(b)(2) or ANDA applicant's notice of a paragraph IV
certification must include a statement that FDA has filed the NDA (in
the case of a 505(b)(2) application) or has received the ANDA (see
Sec. Sec. 314.52(c)(1) and 314.95(c)(1)).
Despite the language in our existing regulations and the preamble
to the 1989 proposed rule, we have continued to receive inquiries from
the public regarding whether notice of paragraph IV certification may
be sent before the filing of a 505(b)(2) application or receipt of an
ANDA. Some have expressed uncertainty after enactment of the MMA
because the FD&C Act requires that notice be sent ``not later than 20
days after the date of the postmark on the notice with which [FDA]
informs the applicant'' that its 505(b)(2) application or ANDA has been
filed, without explicitly establishing a date earlier than which notice
may not be provided (see section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I)
of the FD&C Act).
We are proposing to amend Sec. Sec. 314.52(b) and 314.95(b) by
revising and redesignating the current text as paragraphs (b)(1) and
(b)(3) and adding a new paragraph (b)(2). Proposed Sec. Sec.
314.52(b)(2) and 314.95(b)(2) state that any notice sent before the
receipt of an FDA acknowledgment letter or paragraph IV acknowledgment
letter is invalid (and thus does not trigger either the 45-day period
in which the NDA holder and each patent owner may initiate a patent
infringement action and obtain a 30-month stay or the beginning of any
related 30-month period) and will not be considered to comply with the
FD&C Act's notice requirement until valid notice is sent. We also are
proposing to revise Sec. 314.95(b)(2) to state that any notice sent
before the first working day after the day the patent is published in
the Orange Book (the list) is invalid and will not be considered to
comply with the FD&C Act's notice requirement (see discussion in
section II.D.1.b.ii).
An applicant that prematurely sends notice of a paragraph IV
certification must resend notice within the required timeframe in order
to satisfy the notice requirement of the FD&C Act and, in the case of a
first applicant, qualify for 180-day exclusivity. To help ensure that
notices of paragraph IV certifications are not sent prematurely, we
also are proposing to amend Sec. Sec. 314.52(c)(3) and 314.95(c)(3)
to require that each 505(b)(2) or ANDA applicant include, in any notice
of paragraph IV certification related to its application, a statement
that it has received an acknowledgment letter or paragraph IV
acknowledgment letter. We recognize that this proposed requirement may
have the effect of delaying the provision of notice of paragraph IV
certification by a 505(b)(2) applicant (but not an ANDA applicant) by
approximately 2 weeks after the 505(b)(2) application is filed, because
an NDA is considered filed 60 days after submission, but our proposed
definition of a ``paragraph IV acknowledgment letter'' for a 505(b)(2)
application is the filing communication that is generally mailed by the
74th day after the date of submission of the 505(b)(2) application in
accordance with the performance goal established under the current
reauthorization of the prescription drug user fee program in FDASIA
(see section II.D.3.b). We recognize that this would potentially delay
the initiation of patent infringement litigation by an NDA holder or
patent owner and any corresponding 30-month stay of approval of the
505(b)(2) application by approximately 2 weeks. We invite comment on
this approach to premature notice of a paragraph IV certification for a
505(b)(2) application, especially with respect to notice sent after a
505(b)(2) application is filed (60th day after submission) and before a
paragraph IV acknowledgment letter (generally sent by the 74th day
after submission) is received.
There have been some instances in which an applicant seeks to
submit an amendment containing a paragraph IV certification to its
505(b)(2) application or ANDA prior to filing or receipt of the
application as described in Sec. 314.101(a) and (b), respectively, and
receipt of an acknowledgment letter or a paragraph IV acknowledgment
letter. For example, an applicant may seek to amend its ANDA to add a
new strength of the drug product (see Sec. 314.95(d)(3)). We are
proposing to revise Sec. Sec. 314.52(d)(2) and 314.95(d)(2) to clarify
that an applicant submitting an amendment containing a paragraph IV
certification must comply with the timeframes set forth in Sec. Sec.
314.52(b) and 314.95(b) and wait until it has received an
acknowledgment letter or a paragraph IV acknowledgment letter before
sending notice of its paragraph IV certification to the NDA holder and
each patent owner. This approach ensures that a notice of paragraph IV
certification is not sent before we have accepted for substantive
review the underlying application to which the notice relates (i.e.,
before we have filed the 505(b)(2) application or received the ANDA).
As one Federal district court observed in upholding FDA's
interpretation of the statute in this scenario, ``[i]f an ANDA
applicant could send Paragraph IV notice when amending an ANDA that has
not yet been accepted as received, the applicant could accelerate the
timing provisions and litigation process well beyond the framework that
Congress intended'' (SB Pharmco Puerto Rico, Inc. v. Mutual
Pharmaceutical Co., 552 F. Supp. 2d 500, 510 (E.D. Pa.), appeal
dismissed, 2008 U.S. App. LEXIS 27672 (Fed. Cir. 2008) (holding that
notice of a paragraph IV certification sent concurrent with submission
of an amendment to an ANDA that had not yet been accepted for filing
``was not valid or timely'' under section 505(j)(2)(B)(ii)(II) of the
FD&C Act)).
Thus, if an ANDA applicant submits an amendment containing a
paragraph IV certification before it has received an acknowledgment
letter or a paragraph IV acknowledgment letter advising that the ANDA
has been received for substantive review, the applicant is required to
send notice of its paragraph IV certification within 20 days after the
date of the postmark on the acknowledgment letter or paragraph IV
acknowledgment letter, as applicable. It is important to note that the
relevant date for purposes of determining first applicant eligibility
for 180-day exclusivity based upon submission of a paragraph IV
certification contained in an amendment is the date of submission of
the amendment (i.e., the date on which the amendment was officially
received (date-stamped) by the OGD Document Room) even though the
acknowledgment letter or paragraph IV acknowledgment letter may state
that the ANDA was received for substantive review on the date on which
the original ANDA was submitted (i.e., the date on
[[Page 6833]]
which the ANDA was officially received (date-stamped) by the OGD
Document Room) or, in the case of an ANDA that OGD initially refused to
receive under Sec. 314.101(d) or (e), the date on which the
deficiencies were resolved.
II.D.1.b. Date by which notice must be given. The MMA amended the
FD&C Act to require that 505(b)(2) and ANDA applicants provide notice
of a paragraph IV certification to the NDA holder and each patent owner
in accordance with the following timeframes:
If the paragraph IV certification is included in an
original 505(b)(2) application or ANDA, or in an amendment to such
application that is submitted before the applicant receives an
acknowledgment letter or paragraph IV acknowledgment letter, not later
than 20 days after the date of the postmark on the notice from FDA
informing the applicant that its application has been filed or received
(see section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act), or
If the paragraph IV certification is included in any other
amendment or in a supplement, at the time the applicant submits the
amendment or supplement (see section 505(b)(3)(B)(ii) and
505(j)(2)(B)(ii)(II) of the FD&C Act).
II.D.1.b.i. Determining the timeframe for sending notice after
receipt of an acknowledgment letter or a paragraph IV acknowledgment
letter. We are proposing to revise Sec. Sec. 314.52(b)(1) and
314.95(b)(1) to require that an applicant must send notice of a
paragraph IV certification contained in a 505(b)(2) application or ANDA
on or after the date on which it receives an acknowledgment letter or a
paragraph IV acknowledgment letter, but not later than 20 days after
the date of the ``postmark'' (see proposed definition below) on the
acknowledgment letter or paragraph IV acknowledgment letter. As
discussed in sections II.A.2.u and II.A.2.y, we are proposing a broader
definition of the term ``postmark'' and, as applied to paragraph IV
acknowledgment letters for 505(b)(2) applications, an alternate
interpretation of the term ``postmark'' to reflect current OND practice
regarding the mailing of filing communications. For purposes of
proposed Sec. 314.52(b) and (c) only, the ``date of the postmark'' on
the paragraph IV acknowledgment letter for a 505(b)(2) application is
considered to be 4 calendar days after the date on which the filing
communication is signed by the signatory authority (generally the
Division Director or designee in OND) unless OND sends the filing
communication to the applicant via electronic transmission. If OND
sends the filing communication via electronic transmission, then our
proposed definition of ``postmark'' in Sec. 314.3(b) would apply. We
recognize that issuance of the filing communication within 14 days
after the 60-day filing date described in Sec. 314.101(a)(1) and
(a)(2) represents a performance goal under the current reauthorization
of the prescription drug user fee program in FDASIA. Accordingly, an
applicant that has submitted a 505(b)(2) application containing a
paragraph IV certification and has received neither a refuse-to-file
letter within 60 days nor a filing communication within 74 days after
FDA receives the 505(b)(2) application should contact FDA to request
issuance of the filing communication. We invite comment on whether an
alternate approach should be taken. With reference to an acknowledgment
letter or a paragraph IV acknowledgment letter for an ANDA, we
recognize that there may be scenarios in which the postmark on the
envelope containing an acknowledgment letter or a paragraph IV
acknowledgment letter is illegible or inadvertently absent. We invite
comment on the interpretation of the term ``postmark'' in the context
of an acknowledgment letter or a paragraph IV acknowledgment letter for
a 505(b)(2) application or an ANDA, and whether our regulations should
be amended to define differently the specific date on which the 20-day
notice period begins.
The MMA does not specify how the 20-day period for providing notice
of a paragraph IV certification is to be calculated. We are proposing
in Sec. Sec. 314.52(b)(1) and 314.95(b)(1) to calculate this notice
period in the same way that we calculate the 45-day period within which
each patent owner and NDA holder may initiate a patent infringement
action (which may, if other applicable requirements are satisfied,
trigger a 30-month stay of approval of a 505(b)(2) application or ANDA)
following receipt of notice of a paragraph IV certification (see Sec.
314.107(f)). Specifically, we propose that the first day of the 20-day
period begin on the day after the date of the postmark on the
acknowledgment letter or paragraph IV acknowledgment letter. The 20-day
period is proposed to include all calendar days, except that if the
20th day falls on a Saturday, Sunday, or Federal holiday, the last day
of the 20-day period will be considered to be the next day that is not
a Saturday, Sunday, or Federal holiday. This approach reflects the most
conservative interpretation of the statute and is the calculation
method currently used by most ANDA applicants.
There will be no regulatory benefit or consequence for applicants
based on when they provide notice of a paragraph IV certification
contained in an original application, as long as notice is provided
within the 20-day timeframe required by the MMA. An ANDA applicant that
does not comply with the statutory timeframe in section
505(j)(2)(B)(ii)(I) and (j)(2)(B)(ii)(II) of the FD&C Act for providing
notice of its paragraph IV certification will be subject to
administrative consequences (see section II.D.5).
II.D.1.b.ii. Determining the timeframe for sending notice of a
paragraph IV certification upon submission of an amendment or
supplement. We are proposing to revise Sec. Sec. 314.52(d) and
314.95(d) to implement section 505(b)(3)(B)(i), (b)(3)(B)(ii),
(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act and for the
efficient enforcement of the FD&C Act. Our proposed revisions clarify
the applicable timeframe in which a 505(b)(2) or ANDA applicant must
send notice of a paragraph IV certification submitted in an amendment
or supplement to its 505(b)(2) application or ANDA, respectively. We
are proposing to revise and redesignate the current text of Sec. Sec.
314.52(d) and 314.95(d) as paragraph (d)(1) to accommodate the proposed
inclusion of additional paragraphs to Sec. Sec. 314.52(d) and
314.95(d). Table 6 summarizes the proposed changes related to the
timing of providing notice of paragraph IV certification(s) submitted
in an amendment or supplement to a 505(b)(2) application or ANDA.
Table 6--Highlights of Proposed Changes Regarding Timing of Notice of
Paragraph IV Certification in an Amendment or Supplement \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Amendment to an application or an Amendment or supplement to a
abbreviated application (Sec. Sec. 505(b)(2) application or an
314.52(d) and 314.95(d)) ANDA (Sec. Sec.
314.52(d)(1) and
314.95(d)(1))
[[Page 6834]]
If an application or abbreviated After receipt of an
application is amended to include the acknowledgment letter or
certification described in Sec. Sec. paragraph IV acknowledgment
314.50(i) or 314.94(a)(12)(i)(A)(4), letter:
respectively, the applicant must send the If an applicant
notice required by Sec. Sec. 314.52(a) submits an amendment or
or 314.95(a), respectively, at the same supplement to its 505(b)(2)
time the amendment is submitted to FDA application or ANDA that
includes a paragraph IV
certification, the
applicant must send notice
required by Sec.
314.52(a) or Sec.
314.95(a), respectively, at
the same time the amendment
is submitted to FDA.
Notice of
paragraph IV
certification is
required regardless of
whether notice already
has been provided for
another paragraph IV
certification contained
in the application or in
an amendment or
supplement to the
application.
Amendment to a 505(b)(2)
application or an ANDA
(Sec. Sec. 314.52(d)(2)
and 314.95(d)(2))
Before receipt of an
acknowledgement letter or
paragraph IV acknowledgment
letter:
If an applicant
submits a paragraph IV
certification in an
amendment to a 505(b)(2)
application or ANDA, the
applicant must send
notice required by Sec.
314.52(a) or Sec.
314.95(a), respectively,
in accordance with the
procedures in Sec.
314.52(b) or Sec.
314.95(b).
If an ANDA
applicant timely
provides notice of
paragraph IV
certification in
accordance with Sec.
314.95(b), FDA will base
its determination of
whether the applicant is
a first applicant on the
date of submission of
the amendment containing
the paragraph IV
certification.
Amendment to a 505(b)(2)
application or an ANDA
(Sec. Sec. 314.52(d)(3)
and 314.95(d)(3))
An applicant that
submits an amendment or
supplement to its 505(b)(2)
application or ANDA to seek
approval of a new strength
must provide notice of any
paragraph IV certification
in accordance with Sec.
Sec. 314.52(d)(1) and
(d)(2) or Sec. Sec.
314.95(d)(1) and (d)(2), as
applicable.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
We are proposing to revise Sec. Sec. 314.52(d) and 314.95(d)
(redesignated as Sec. Sec. 314.52(d)(1) and 314.95(d)(1),
respectively) to require that an applicant send notice of a paragraph
IV certification contained in an amendment to an application that has
been received for substantive review or in a supplement to an approved
application at the same time that the amendment or supplement is
submitted to FDA. Our proposed revisions clarify the requirement in our
current regulations for an applicant to send notice of a paragraph IV
certification at the same time that the amendment is submitted to FDA
by distinguishing between: (1) Amendments submitted after the
application has been received for substantive review as indicated by
the receipt of an acknowledgment letter (if, as to an ANDA, the
original application did not contain a paragraph IV certification) or
paragraph IV acknowledgment letter and (2) amendments submitted before
an application has been received for substantive review (see proposed
Sec. Sec. 314.52(d)(2) and 314.95(d)(2) and section II.D.1.b.i.). The
MMA amended the FD&C Act to require that notice of a paragraph IV
certification contained in a supplement to an approved 505(b)(2)
application or ANDA be sent at the same time that the supplement is
submitted to FDA, and our proposed revision to Sec. Sec. 314.52(d)(1)
and 314.95(d)(1) incorporates this requirement (see section
505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act).
In proposed Sec. Sec. 314.52(d)(1) and 314.95(d)(1), we reiterate
the statutory requirement that notice of a paragraph IV certification
in an amendment or supplement must be provided regardless of whether
the applicant has already given notice with respect to another
paragraph IV certification contained in the 505(b)(2) application or
ANDA or in an amendment or supplement to the 505(b)(2) application or
ANDA. The phrase ``another paragraph IV certification'' may refer to a
previous paragraph IV certification to a different listed patent for
the listed drug relied upon or RLD or, for certain amendments and
supplements (see section II.F), a previous paragraph IV certification
to the same listed patent. For example, if an ANDA applicant submitted
a paragraph IV certification to the '246 patent (a listed patent
claiming the drug product for the listed drug relied upon) in its
original application, and subsequently submitted an amendment to its
pending ANDA to change the formulation, the ANDA applicant would be
required to provide a new patent certification to the '246 patent (see
proposed Sec. 314.96(d)(1) and section II.F.1). If this ANDA applicant
submitted a paragraph IV certification to the '246 patent in its
amendment, the ANDA applicant would be required to send notice of its
second paragraph IV certification to the '246 patent to the NDA holder
and each patent owner at the same time the amendment to the ANDA is
submitted to FDA.
If an applicant submits an amendment containing a paragraph IV
certification to its 505(b)(2) application or ANDA before the applicant
has received an acknowledgment letter (if, as to an ANDA, the original
application did not contain a paragraph IV certification) or a
paragraph IV acknowledgment letter, proposed Sec. Sec. 314.52(d)(2)
and 314.95(d)(2) require that the applicant send notice of its
paragraph IV certification in accordance with the procedures described
in Sec. Sec. 314.52(b) and 314.95(b), respectively. In this
circumstance, the 505(b)(2) or ANDA applicant must send notice of the
paragraph IV certification contained in
[[Page 6835]]
its amendment on or after the date it receives an acknowledgment letter
or paragraph IV acknowledgment letter, but not later than 20 days after
the date of the postmark on the letter. This requirement reflects our
longstanding policy that notice of a paragraph IV certification may not
be sent unless and until we have notified the applicant that its
application has been filed or received, as appropriate (see section
II.D.1.a).
It should be noted that a paragraph IV certification submitted in
an amendment after the 505(b)(2) application or ANDA is submitted but
before the applicant receives a paragraph IV acknowledgment letter is
considered part of the original 505(b)(2) application or ANDA solely
for the purpose of determining the appropriate timeframe for sending
notice of paragraph IV certification. The availability of a 30-month
stay for patent infringement litigation initiated within the statutory
timeframe in response to a paragraph IV certification submitted in an
amendment to a 505(b)(2) application or an ANDA continues to be
determined by whether the patent at issue was filed with FDA before the
date on which the original 505(b)(2) application or ANDA (excluding an
amendment or supplement) was submitted (see section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act; see also proposed Sec. 314.107(b)(2)
and section II.M.2.b). For purposes of determining an ANDA applicant's
eligibility for 180-day exclusivity and the date from which a first
ANDA applicant's compliance with section 505(j)(5)(D)(i)(IV) of the
FD&C Act is assessed, the date of the submission of the paragraph IV
certification is the date on which the amendment was submitted. An
amendment seeking approval for a different strength of a drug product
thus may have a different submission date than the original ANDA
submission for purposes of evaluating an ANDA applicant's eligibility
for 180-day exclusivity for that new drug product and the date from
which a first ANDA applicant's compliance with section
505(j)(5)(D)(i)(IV) of the FD&C Act is assessed.
Proposed Sec. Sec. 314.52(d)(3) and 314.95(d)(3) require that an
applicant that submits an amendment or supplement to a 505(b)(2)
application or ANDA that contains a paragraph IV certification and
seeks approval for a different strength of the drug product must adhere
to the timing requirements for notice in Sec. Sec. 314.52(d)(1) or
(d)(2) and 314.95(d)(1) or (d)(2), as applicable. Unlike other
amendments and supplements to a 505(b)(2) application or ANDA, an
amendment or supplement seeking approval of a different strength may
refer to a different listed drug than the listed drug identified in the
original 505(b)(2) application or ANDA (see section 505(b)(4)(B) and
(j)(2)(D)(ii) of the FD&C Act). Accordingly, we have separately
described this type of amendment or supplement to clarify applicable
regulatory requirements.
There are a few situations in which the relationship between an
acknowledgment letter or paragraph IV acknowledgment letter and the
timing of notice for a paragraph IV certification contained in an
amendment or supplement to a 505(b)(2) application or ANDA may seem
complicated. For example, in the case of a 505(b)(2) or ANDA applicant
that submits an original application containing a paragraph III
certification to a listed patent and receives an acknowledgment letter
(as distinguished from a paragraph IV acknowledgment letter) indicating
that the 505(b)(2) application or ANDA has been received for
substantive review, if the applicant subsequently submits an amendment
containing a paragraph IV certification to a listed patent, the
applicant need not wait to receive a paragraph IV acknowledgment letter
before sending notice in accordance with Sec. 314.52(d)(1) or Sec.
314.95(d)(1).
Also, we note that FDA may send an acknowledgment letter for
certain types of supplements (e.g., a supplement to an ANDA seeking
approval for a new strength of a drug product; a 505(b)(2) supplement
to an NDA seeking approval for a new indication, new dosage regimen,
new route of administration, or a change from prescription use to OTC
status for all conditions of use). However, this practice would not
alter the 505(b)(2) or ANDA applicant's statutory obligation to send
notice of a paragraph IV certification at the time the supplement is
submitted to FDA (and not at the time the paragraph IV acknowledgment
letter for the supplement may be received).
We interpret the requirement in proposed Sec. 314.52(d)(1) or
Sec. 314.95(d)(1) to send notice of a paragraph IV certification at
the same time that the amendment or supplement to the application is
submitted to FDA to mean that notice to the NDA holder and each patent
owner must be sent on the same day that the amendment or supplement to
the application is submitted to FDA. It should be noted that the
controlling date for purposes of first applicant eligibility is the
date on which the amendment or supplement to the ANDA containing a
paragraph IV certification is submitted (i.e., officially received
(date-stamped) by the OGD Document Room) as long as notice is timely
provided in accordance with the statute. Due to a technical difference
in the method by which FDA determines the date of submissions to FDA
(using a date of receipt rule) and the date on which an applicant sends
notice of a paragraph IV certification to the NDA holder and each
patent owner (using a date of mailing rule), these dates may differ.
For example, Applicant A submits an amendment containing a paragraph IV
certification to its ANDA on August 2 and sends notice of the paragraph
IV certification to the NDA holder and each patent owner on that same
day. The amendment to the ANDA is date-stamped by the OGD Document Room
on August 3. Applicant A has complied with the statutory requirement to
send notice of its paragraph IV certification at the same time the
amendment or supplement to the ANDA is submitted despite the difference
in the date on which the amendment was officially received and the date
on which the notice of paragraph IV certification was sent because both
the amendment and notice(s) were actually sent on the same day.
If an ANDA applicant does not provide notice of a paragraph IV
certification on the same day that an amendment or supplement is
submitted, FDA will consider the paragraph IV certification to be
effective only as of the date that the applicant has both submitted the
amendment or supplement containing the paragraph IV certification and
sent the notice (see Purepac Pharmaceutical Co. v. Thompson, 354 F.3d
877 (D.C. Cir. 2004)).
To qualify as a first applicant eligible for 180-day exclusivity
under section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act, an applicant
must, among other things, submit a paragraph IV certification on the
``first day on which a substantially complete application containing a
[paragraph IV certification] is submitted.'' Because daily electronic
updates to the Orange Book generally do not occur until the afternoon
(Eastern Standard Time), the opportunity to be a first applicant with
respect to a patent that is newly listed in the Orange Book (i.e., to
submit an amendment to the ANDA containing a paragraph IV certification
and send notice of the paragraph IV certification on that same day)
could be affected by, among other things, the time zone in which the
ANDA applicant resides. To ensure that all ANDA applicants
(irrespective of time zone) have a reasonable opportunity to be a first
applicant with respect to a newly listed patent, we are proposing that
any notice of paragraph
[[Page 6836]]
IV certification is invalid if it is sent before the first working day
after the day the patent is listed in the Orange Book (see proposed
Sec. Sec. 314.95(b)(2) and 314.94(a)(12)(viii)(C)(1)(ii), discussed in
section II.E.4). The term ``working day'' has the meaning provided in
21 CFR 1.377 (``any day from Monday through Friday, excluding Federal
holidays''). This approach is intended to promote equity among ANDA
applicants and reduce the burden on industry and on the Agency
associated with serial submissions of amendments and multiple notices
of paragraph IV certifications related to a newly-issued patent. When a
new patent is issued by the PTO, the NDA holder has 30 days within
which to submit the patent information to FDA for listing. An ANDA
applicant does not know if or when the patent may be submitted to FDA,
and when it is submitted, there may be a delay in the patent's
appearance in the Orange Book. Therefore, if an ANDA applicant
reasonably believes a patent could be listed for an RLD, it will often
submit a paragraph IV certification to FDA and send notice to the NDA
holder and patent owner each day during the 30-day period after
issuance of the new patent. ANDA applicants have adopted this practice
in an attempt to satisfy the certification and notice requirements on
the first date on which the patent is listed in the Orange Book and
thus qualify as a first applicant. FDA's proposal is intended to
eliminate the need for these burdensome serial certifications.
The following example illustrates our approach: The NDA holder
submits Form FDA 3542 to the Office of Generic Drugs, Document Room,
Attention: Orange Book Staff, within 30 days after issuance of the '123
patent claiming the drug product Litigatolol. Form FDA 3542 is date-
stamped by the OGD Document Room on Friday, August 5 and listed in the
Orange Book, which is updated at 3 p.m. Eastern Standard Time on that
date. Applicant B and Applicant C have submitted ANDAs for Litigatolol
and have received acknowledgment letters indicating that their ANDAs
have been received for substantive review. Applicant B is located in
California and submits an amendment to its ANDA containing a paragraph
IV certification to the '123 patent and sends notice to the NDA holder
and each patent owner late in the afternoon, Pacific Time, on Friday,
August 5. Applicant C is located in New Jersey and would have been
unable to submit an amendment to its ANDA containing a paragraph IV
certification to the '123 patent and send notice to the NDA holder and
each patent owner before the end of the working day on Friday, August
5. Applicant C submits the amendment and sends notice on Monday, August
8. Prior to these amendments, no ANDA had contained a paragraph IV
certification to a patent listed for Litigatolol. Applicant B
prematurely submitted its amendment containing a paragraph IV
certification, and its notice of paragraph IV certification is invalid
because it was sent before the first full working day after the patent
is listed in the Orange Book. Only Applicant C has submitted the first
substantially complete ANDA containing a paragraph IV certification for
purposes of first applicant eligibility.
It should be noted that if there is a delay between FDA's receipt
of new patent information and publication of the patent information in
the Orange Book, the actual date of publication of the patent
information in the Orange Book provides the date from which the
validity of the ANDA applicant's notice of paragraph IV certification
will be assessed for purposes of first applicant eligibility (compare
section II.D.3 regarding determination of a 505(b)(2) or ANDA
applicant's patent certification obligations and the availability of a
30-month stay based on patent information in FDA's possession).
II.D.1.c. Certification of provision of notice. We are proposing to
amend Sec. Sec. 314.52(b) and 314.95(b) by revising and redesignating
certain text as new paragraph (b)(3). Proposed Sec. Sec. 314.52(b)(3)
and 314.95(b)(3) describe the current requirement for 505(b)(2) and
ANDA applicants, respectively, to amend their applications at the time
that they provide notice of a paragraph IV certification to include a
statement certifying that notice has been provided to the NDA holder
and each patent owner as required by Sec. Sec. 314.52(a) and 314.95(a)
and has met the content requirements for notice of a paragraph IV
certification as described in Sec. Sec. 314.52(c) and 314.95(c). We
are proposing to clarify that a copy of the notice of paragraph IV
certification itself does not need to be submitted to FDA in the
amendment.
We describe acceptable methods for delivery of notice of paragraph
IV certification and documentation of timely delivery and receipt of
such notice in section II.D.4.
II.D.2. Notice Required for All Paragraph IV Certifications
The MMA requires applicants submitting 505(b)(2) applications and
ANDAs to provide notice for all paragraph IV certifications submitted
to FDA on or after August 18, 2003, regardless of whether the applicant
had previously given notice of a paragraph IV certification contained
in its application or an amendment or supplement to the application
(see section 505(b)(3)(B) and (j)(2)(B)(ii) of the FD&C Act).
We are proposing to require a 505(b)(2) or ANDA applicant to
provide a new notice of paragraph IV certification to a patent for
which it previously had provided notice if the applicant submits an
amendment or supplement to the 505(b)(2) application or ANDA for
certain changes to the proposed product that should be accompanied by a
new patent certification (see section II.F).
II.D.3. Contents of Notice
We are proposing to revise Sec. Sec. 314.52(c) and 314.95(c)
regarding the contents of notice of a paragraph IV certification to
incorporate requirements added by the MMA and to support the efficient
enforcement of our regulations. We note, however, that the Agency
neither assesses the adequacy of the contents of a 505(b)(2) or ANDA
applicant's notice of paragraph IV certification nor the applicant's
stated basis for certifying that a listed patent is invalid,
unenforceable, or will not be infringed by its proposed drug product.
In our final rule implementing the patent and exclusivity provisions of
the Hatch-Waxman amendments, we stated that ``the agency does not have
the expertise or the desire to become involved in issues concerning
patent law and sufficiency of notice. . . . Disputes involving the
sufficiency of the notice [i.e., the detailed statement of the factual
and legal basis behind the applicant's opinion that the patent is
invalid, unenforceable, or not infringed] must be resolved by the
applicant, patent owner, and holder of the approved application rather
than by action on the part of FDA'' (59 FR 50338 at 50349, October 3,
1994).
We also are revising Sec. Sec. 314.52(c) and 314.95(c) to require
the 505(b)(2) or ANDA applicant to cite section 505(b)(3)(D) and
(j)(2)(B)(iv), respectively, as amended by the MMA, in the notice of
paragraph IV certification.
Table 7 summarizes the proposed changes related to content of a
notice of paragraph IV certification.
[[Page 6837]]
Table 7--Highlights of Proposed Changes Regarding Content of a Notice of
Paragraph IV Certification \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Content of a notice (Sec. Sec. Content of a notice (Sec.
314.52(c)) and 314.95(c)) Sec. 314.52(c)) and
314.95(c))
The 505(b)(2) or ANDA applicant The 505(b)(2) or
must cite section 505(b)(3)(B) or ANDA applicant must cite
505(j)(2)(B)(ii) of the FD&C Act, as section 505(b)(3)(D) or
appropriate, and the notice must also 505(j)(2)(B)(iv) of the
include, but not be limited to, the FD&C Act, as appropriate,
following information: and the notice must also
include, but is not limited
to, the following
information:
--(1) A statement that a 505(b)(2) --(1) A statement that a
application submitted by the 505(b)(2) application
applicant has been filed by FDA; or a that contains any
statement that FDA has received an required BA or BE data
ANDA submitted by the applicant has been submitted by
containing any required the applicant and filed
bioavailability (BA) or by FDA; or a statement
bioequivalence (BE) data or that FDA has received an
information. ANDA submitted by the
applicant containing any
required BA or BE data
or information.
--(2) The NDA or ANDA number. --(2) The NDA or ANDA
number.
--(3) The established name, if any, of --(3) A statement that
the proposed drug product. the applicant has
--(4) The active ingredient, strength, received the
and dosage form of the proposed drug acknowledgment letter or
product. paragraph IV
acknowledgment letter
for the 505(b)(2)
application or ANDA.
--(5) The patent number and expiration --(4) The established
date, as submitted to the Agency or name, if any, of the
as known to the applicant, of each proposed drug product.
patent alleged to be invalid, --(5) The active ingredient,
unenforceable, or not infringed. strength, and dosage form
--(6) A detailed statement of the of the proposed drug
factual and legal basis of the product.
applicant's opinion that the patent --(6) The patent number and
is not valid, unenforceable, or will expiration date of each
not be infringed. patent on the list alleged
--(7) If the applicant does not reside to be invalid,
or have a place of business in the unenforceable, or not
U.S., the name and address of an infringed.
agent in the U.S. authorized to --(7) A detailed statement
accept service of process for the of the factual and legal
applicant. basis of the applicant's
opinion that the patent is
not valid, unenforceable,
or will not be infringed.
--(8) If the applicant
alleges that the patent
will not be infringed and
may later decide to file a
civil action for
declaratory judgment in
accordance with section
505(c)(3)(D) and
505(j)(5)(C) of the FD&C
Act, then the notice must
be accompanied by an offer
of confidential access to
the 505(b)(2) application
or ANDA for the sole and
limited purpose of
evaluating possible
infringement of the patent
that is the subject of the
paragraph IV certification.
--(9) If the applicant
does not reside or have
a place of business in
the U.S., the name and
address of an agent in
the U.S. authorized to
accept service of
process for the
applicant.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.D.3.a. Statement that any required bioavailability or
bioequivalence studies for a 505(b)(2) application have been submitted.
The MMA amended the FD&C Act to require that the notice of paragraph IV
certification for a 505(b)(2) application include a statement that ``an
application that contains data from bioavailability or bioequivalence
studies'' has been submitted to FDA (section 505(b)(3)(D)(i) of the
FD&C Act). This statutory provision parallels the content requirements
for notice of paragraph IV certification for an ANDA (see section
505(j)(2)(B)(iv)(I) of the FD&C Act). Consistent with our previous
implementation of the statutory requirement for ANDAs in Sec.
314.95(c), proposed Sec. 314.52(c)(1) requires that a notice of a
paragraph IV certification for a 505(b)(2) application state that data
from ``any required bioavailability or bioequivalence studies''
(emphasis added) have been submitted. This qualifier reflects that FDA
may exercise its scientific judgment to determine what bioavailability
and bioequivalence studies may be needed for certain 505(b)(2)
applications and ANDAs (see, e.g., Sec. 314.54(a)(1) and (a)(2)
(citing Sec. Sec. 314.50(d)(3) and 320.21(a)(2) and (f)); compare
Sec. 320.21(b)(2)).
A 505(b)(2) application may seek to rely upon non-product-specific
published literature or other studies necessary for approval for which
the applicant has no right of reference or use. This type of 505(b)(2)
application generally would not require studies showing relative
bioavailability or bioequivalence because the 505(b)(2) application is
not relying upon the Agency's finding of safety and/or effectiveness
for a listed drug. In the absence of a listed drug, there is not likely
to be a specific drug for use as a comparator in a relative
bioavailability or bioequivalence study. However, such a 505(b)(2)
application must establish that reliance on the studies described in
the literature is scientifically appropriate. Further, a 505(b)(2)
application that did not rely upon a listed drug would not require a
patent certification or statement, and thus there would be no occasion
for a notice of paragraph IV certification.
II.D.3.b. Statement confirming receipt of an acknowledgment letter
or a paragraph IV acknowledgment letter. We are proposing to revise
Sec. Sec. 314.52(c)(3) and 314.95(c)(3) to add a new requirement for
505(b)(2) and ANDA applicants, respectively, to facilitate compliance
with and enforcement of section 505(b)(3)(B)(i), (b)(3)(B)(ii),
(j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act regarding the
timing of notice of paragraph IV certification. Proposed Sec. Sec.
314.52(c)(3) and 314.95(c)(3) require a 505(b)(2) and ANDA applicant,
respectively, to include a statement in its notice of paragraph IV
certification that the applicant has received an acknowledgment letter
or a paragraph IV acknowledgment letter for its 505(b)(2) application
or ANDA. This requirement is intended to ensure that a notice of
paragraph IV certification is not sent before FDA has determined that
the 505(b)(2) application or ANDA containing the certification is
acceptable for substantive review and has issued an acknowledgment
letter or a paragraph IV acknowledgment letter (see section II.D.1.a).
II.D.3.c. Documentation that paragraph IV certification was
submitted and notice was sent only for patents listed in the Orange
Book. We are proposing to revise Sec. Sec. 314.52(c)(6) and
314.95(c)(6) to specify that notice of a paragraph IV certification
(and therefore the underlying paragraph IV certification as well) must
only be sent for a patent that is listed in the Orange Book for the
listed drug(s) relied upon
[[Page 6838]]
for a 505(b)(2) application or for the RLD for an ANDA. We are
proposing to add the phase ``on the list'' to proposed Sec. Sec.
314.52(c)(6) and 314.95(c)(6) to qualify the patents for which a notice
of paragraph IV certification must be sent.
As discussed in section II.D.4.b, we are proposing to require an
ANDA applicant to include a dated printout of the Orange Book entry for
the RLD that includes the patent that is the subject of the notice of
paragraph IV certification in its amendment certifying that notice of
paragraph IV certification has been sent and documenting that notice
has been received (see proposed Sec. 314.95(e)). A 505(b)(2) applicant
may elect to submit a copy of the Orange Book patent listing for the
listed drug(s) relied upon with its 505(b)(2) application, amendment,
or supplement containing a paragraph IV certification to describe the
applicant's understanding of the most current patent information listed
in the Orange Book at the time of submission. We note, however, that a
505(b)(2) or ANDA applicant's patent certification obligations and the
availability of a 30-month stay under section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act are determined based on patent
information in FDA's possession, even if such information is not
accurately listed in the Orange Book (see Teva Pharms., USA, Inc. v.
Leavitt, 548 F.3d 103, at 105 (D.C. Cir. 2008) (``FDA insists reality
matters'')).
In addition, we are proposing to delete the phrase ``as submitted
to the agency or as known to the applicant'' from Sec. Sec.
314.52(c)(6) and 314.95(c)(6), as this phrase is over-inclusive. It
does not accurately describe the universe of patents for which a
paragraph IV certification may be submitted and thus is inapplicable to
the content requirements for notice of a paragraph IV certification.
Although an applicant may submit a certification pursuant to section
505(b)(2)(A)(i) or 505(j)(2)(A)(vii)(I) of the FD&C Act (``paragraph I
certification'') with respect to patent information that has not been
filed with FDA and is not listed in the Orange Book, such a patent
could not be the basis for a paragraph IV certification.
II.D.3.d. Offer of confidential access accompanying notice. The MMA
established conditions under which a 505(b)(2) or ANDA applicant may
bring a declaratory judgment action to obtain ``patent certainty''
(i.e., obtain a judicial determination of noninfringement, invalidity,
or unenforceability) with respect to a listed patent for which it has
given notice of a paragraph IV certification but has not been sued by
the NDA holder or any patent owner within the statutory timeframe (see
section 505(c)(3)(D) and (j)(5)(C) of the FD&C Act). As a precondition
to filing an action for declaratory judgment to establish patent
noninfringement (as distinguished from patent invalidity or
unenforceability), the applicant must provide a document offering the
NDA holder and each patent owner confidential access to the 505(b)(2)
application or ANDA for the sole and limited purpose of assessing
patent noninfringement (see section 505(c)(3)(D)(i)(III) and
(j)(5)(C)(i)(III) of the FD&C Act). Because this offer of confidential
access, if made, is required to accompany the notice of paragraph IV
certification, we are proposing to revise Sec. Sec. 314.52(c) and
314.95(c) to reference the statutory requirement for an offer of
confidential access (see section 505(c)(3)(D)(i)(I)(cc) and
(j)(5)(C)(i)(I)(cc) of the FD&C Act). Our proposed regulations do not
otherwise address the offer of confidential access because the process
for seeking a declaratory judgment does not involve FDA.
II.D.4. Documentation of Timely Sending and Receipt of Notice
We are proposing to revise Sec. Sec. 314.52(e) and 314.95(e) to
clarify the requirements for submission of an amendment to a 505(b)(2)
application or ANDA, respectively, containing documentation of timely
sending of notice of paragraph IV certification and confirmation of
receipt of same by the NDA holder and each patent owner. In addition,
we are proposing to revise Sec. Sec. 314.52 and 314.95 to expand the
list of acceptable delivery methods that may be used to send notice of
paragraph IV certification to the NDA holder and each patent owner.
These proposed revisions are intended to facilitate compliance with the
statutory requirements regarding timing of notice of paragraph IV
certification and related regulatory provisions.
Table 8 summarizes the proposed changes regarding documentation of
timely sending and receipt of notice of paragraph IV certification:
Table 8--Highlights of Proposed Changes Regarding Documentation of
Timely Sending and Receipt of Notice of Paragraph IV Certification \1\
------------------------------------------------------------------------
Current regulations Proposed revisions to regulations
------------------------------------------------------------------------
Notice of certification (Sec. Sec. Notice of certification (Sec. Sec.
314.52(a) and 314.95(a)) 314.52(a) and 314.95(a))
505(b)(2) or ANDA 505(b)(2) or ANDA
applicant must send notice of applicant must send notice of
paragraph IV certification by paragraph IV certification by
registered or certified mail, registered or certified mail,
return receipt requested, to each return receipt requested, or by a
patent owner and the NDA holder. designated delivery service, to
each patent owner and the NDA
holder.
505(b)(2) or ANDA
applicant may send notice by an
alternative method only if FDA has
agreed in advance that the method
will produce an acceptable form of
documentation.
Documentation of receipt of notice Documentation of timely sending and
(Sec. Sec. 314.52(e) and receipt of notice (Sec. Sec.
314.95(e)) 314.52(e) and 314.95(e))
Applicant must amend its Applicant must amend its
505(b)(2) application or ANDA to 505(b)(2) application or ANDA to
document the date of receipt of provide documentation of the date
the notice of paragraph IV of receipt of the notice of
certification by each patent owner paragraph IV certification by each
and NDA holder provided the patent owner and NDA holder
notice. provided the notice.
Applicant must include a --FDA will accept as adequate
copy of the return receipt or documentation of the date of
other similar evidence of the date receipt a return receipt,
the notification was received. signature proof of delivery by a
--FDA will accept as adequate designated delivery service, or a
documentation of the date of letter acknowledging receipt by
receipt a return receipt or a the person provided notice.
letter acknowledging receipt by
the person provided the notice.
An applicant may rely on --Amendment must be submitted to
another form of documentation only FDA within 30 days after the last
if FDA has agreed to such date on which notice was received
documentation in advance. by a patent owner or NDA holder.
[[Page 6839]]
Amendment also must
include adequate documentation
that notice was sent on a date
that complies with the timeframe
required by Sec. 314.52(b) or
(d) or Sec. 314.95(b) or (d), as
applicable.
--FDA will accept a copy of the
registered mail receipt, certified
mail receipt, or receipt from a
designated delivery service, as
adequate documentation of the date
of delivery.
An ANDA applicant's
amendment must include a dated
printout of the Orange Book entry
for the RLD that includes the
patent that is the subject of the
paragraph IV certification.
An applicant may rely on
another form of documentation only
if FDA has agreed in advance.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.D.4.a. Acceptable methods of sending notice of paragraph IV
certification. A 505(b)(2) or ANDA applicant currently is required to
send notice of a paragraph IV certification to the NDA holder and each
patent owner by registered or certified mail, return receipt requested,
unless FDA agrees in advance to another method of delivery (see
Sec. Sec. 314.52(a) and (e) and 314.95(a) and (e)). We are proposing
to revise Sec. Sec. 314.52(a) and (e) and 314.95(a) and (e) to provide
applicants with the option of sending notice of paragraph IV
certification by a designated delivery service, as defined in proposed
Sec. Sec. 314.52(g)(1) and 314.95(g)(1). Section 505(b)(2) and ANDA
applicants often request permission to send notice of a paragraph IV
certification by a major commercial delivery service instead of the
U.S. Postal Service (for example, to send notice of a paragraph IV
certification to a patent owner who resides outside of the United
States). Because we routinely grant these requests, we are proposing to
amend our regulations to provide the option to all 505(b)(2) and ANDA
applicants to send notice of paragraph IV certification by the U.S.
Postal Service or a designated delivery service. We propose to define a
``designated delivery service'' in Sec. Sec. 314.52(g)(1) and
314.95(g)(1) to mean any delivery service provided by a trade or
business that the Agency determines: (1) Is available to the general
public throughout the United States; (2) records electronically to its
database, kept in the regular course of its business, or marks on the
cover in which any item referred to in this section is to be delivered,
the date on which such item was given to such trade or business for
delivery; and (3) provides overnight or 2-day delivery service
throughout the United States.
This proposed definition is adapted from definition of ``designated
delivery service'' in 26 U.S.C. 7502(f)(2) (governing timely mailing
treated as timely filing and paying by the IRS). As noted in proposed
Sec. Sec. 314.52(g)(2) and 314.95(g)(2), FDA will periodically issue
guidance describing designated delivery services that meet these
criteria.
Our proposal to revise Sec. Sec. 314.52(a) and (e) and 314.95(a)
and (e) to provide applicants with the option of sending notice of
paragraph IV certification by a designated delivery service, as defined
in proposed Sec. Sec. 314.52(g)(1) and 314.95(g)(1), differs from an
earlier proposal to provide additional methods of sending notice of
paragraph IV certification (see ``New Drugs for Human Use;
Clarification of Requirements for Patent Holder Notification; Proposed
Rule'' 63 FR 11174; March 6, 1998) (Patent Holder Notification proposed
rule). The Patent Holder Notification proposed rule would have
permitted a 505(b)(2) or ANDA applicant to send notice of paragraph IV
certification ``by mail or personal delivery'' (including overnight
delivery service, electronic mail, and facsimile) if the applicant
obtained a verification of receipt. We received comments objecting to
certain aspects of the Patent Holder Notification Proposed Rule--in
particular, notice by electronic methods of delivery such as electronic
mail or facsimile--and withdrew the proposed rule (see ``New Drugs for
Human Use; Clarification of Requirements for Patent Holder
Notification; Withdrawal'' 65 FR 12154; March 8, 2000) (Withdrawal of
Patent Holder Notification proposed rule). With respect to notification
by overnight delivery service, two comments on the Patent Holder
Notification proposed rule supported this alternate method of delivery
if a signed verification of receipt of notice by the NDA holder or each
patent owner was provided (see Docket No. FDA-1997-P-0417-0011 and FDA-
1997-P-0417-0012, available at http://www.regulations.gov). Another
comment objected to notification by overnight delivery service because
receipt of bulk deliveries (containing multiple envelopes and packages)
to large corporations is acknowledged by a single signature. This
commenter expressed concern that an overnight delivery service envelope
containing a notice of paragraph IV certification may not ensure timely
receipt by a responsible person. Given that receipt of notice of
paragraph IV certification begins a statutory 45-day period within
which a patent infringement action must be filed to obtain, under
certain circumstances, a 30-month stay, a signature acknowledging
receipt of the specific envelope was preferred by this commenter (see
Docket No. FDA-1997-P-0417-0010, available at http://www.regulations.gov).
In light of the frequency with which FDA receives requests to send
notice by overnight delivery services, we invite comment on our current
proposal to provide applicants with the option of sending notice of
paragraph IV certification by a designated delivery service, as defined
in proposed Sec. Sec. 314.52(g)(1) and 314.95(g)(1).
We also are proposing to add Sec. Sec. 314.52(a)(4) and
314.95(a)(4) and revise Sec. Sec. 314.52(e) and 314.95(e) to clarify
that a 505(b)(2) or ANDA applicant may send notice of paragraph IV
certification by an alternative method (i.e., a method other than
registered or certified mail, return receipt requested, or a designated
delivery service) only if FDA has agreed in advance that the method
will produce an acceptable form of documentation.
In addition, we are proposing to revise the introductory text of
Sec. 314.52(a) to refer to each patent that claims the listed drug or
drugs relied upon or that claims a use for such listed drug or drugs
and for which the applicant submits a paragraph IV certification. This
revision is proposed
[[Page 6840]]
for clarity and does not represent a substantive change.
II.D.4.b. Amendment documenting timely sending and confirmation of
receipt of notice of paragraph IV certification. We are proposing to
revise Sec. Sec. 314.52(e) and 314.95(e) to facilitate implementation
of section 505(b)(3)(B)(i), (b)(3)(B)(ii), (j)(2)(B)(ii)(I), and
(j)(2)(B)(ii)(II) of the FD&C Act and for the efficient enforcement of
the FD&C Act.
A 505(b)(2) or ANDA applicant that has submitted one or more
paragraph IV certifications currently must submit an amendment to its
application documenting the date on which notice of paragraph IV
certification was received by the NDA holder and each patent owner (see
Sec. Sec. 314.52(e) and 314.95(e)). As discussed in section II.D.1.b,
the MMA amended the FD&C Act to require that a 505(b)(2) and ANDA
applicant provide notice of a paragraph IV certification in accordance
with the timeframes described in section 505(b)(3)(B)(i),
(b)(3)(B)(ii), (j)(2)(B)(ii)(I), and (j)(2)(B)(ii)(II) of the FD&C Act
(see proposed Sec. Sec. 314.52(b) and (d) and 314.95(b) and (d)). Our
proposed revisions to Sec. Sec. 314.52(e) and 314.95(e) require a
505(b)(2) and ANDA applicant, respectively, to establish compliance
with this statutory requirement by also submitting in its amendment
documentation that the notice of paragraph IV certification was sent on
a date that complies with the timeframe required by Sec. 314.52(b) or
(d) or Sec. 314.95(b) or (d), as applicable. For administrative
efficiency, we are proposing to require that a 505(b)(2) or ANDA
applicant submit the amendment containing documentation of timely
sending and receipt of notice of paragraph IV certification within 30
days after the last date on which notice was received by a person
described in Sec. 314.52(a) or Sec. 314.95(a), respectively.
The proposed requirement for documentation that notice of paragraph
IV certification was timely sent can be satisfied by submitting a copy
of the registered mail receipt or certified mail receipt issued by the
U.S. Postal Service that bears a postmark documenting the date of
mailing or by submitting a copy of the receipt from a designated
delivery service, as defined in proposed Sec. Sec. 314.52(g) and
314.95(g). With respect to documentation of the date of receipt of
notice of paragraph IV certification, we are proposing to revise
Sec. Sec. 314.52(e) and 314.95(e) to include acceptance of signature
proof of delivery by a designated delivery service as adequate
documentation. A single document may be adequate to document both
timely sending and receipt of notice of paragraph IV certification if
it contains the information required by proposed Sec. Sec. 314.52(e)
and 314.95(e).
In addition, we are proposing to require that ANDA applicants
include in their amendment a dated printout of the Orange Book entry
for the RLD that includes the patent that is the subject of the notice
of paragraph IV certification. This requirement is intended to ensure
that a paragraph IV certification that may qualify an ANDA applicant
for 180-day exclusivity is submitted only for a listed patent and is
not prematurely or inappropriately sent before the first working day
after the day the patent is listed in the Orange Book (see proposed
Sec. Sec. 314.95(b)(2) and 314.94(a)(12)(viii)(C)(1)(ii)).
The following example illustrates our approach: The NDA holder
timely submits Form FDA 3542 to the Office of Generic Drugs, Document
Room, Attention: Orange Book Staff, at 4 p.m., Eastern Standard Time,
on the 30th day after issuance of the '456 patent claiming the drug
product Procrastinadipine. Form FDA 3542 is date-stamped by the Office
of Generic Drugs, Document Room on Friday, October 1 and listed in the
Orange Book on the afternoon of Monday, October 4. Applicant D and
Applicant E have submitted ANDAs for Procrastinadipine and each has
received an acknowledgment letter indicating that its ANDA has been
received for substantive review.
Applicant D is aware that the '456 patent was issued by the PTO on
September 1 and understands that for the '456 patent to be timely filed
under section 505(c)(2) of the FD&C Act, the NDA holder must file the
patent information with FDA no later than October 1. Applicant D
submits an amendment to its ANDA containing a paragraph IV
certification to the '456 patent and sends notice to the NDA holder and
each patent owner on October 1 in an effort to have submitted the first
substantially complete ANDA containing a paragraph IV certification to
a patent listed for Procrastinadipine. However, Applicant D is unable
to submit the required printout (see proposed Sec. 314.95(b)(2)) of
the Orange Book entry for the RLD that includes the patent that is the
subject of the paragraph IV certification because the '456 patent has
not yet been listed in the Orange Book. Applicant E submits on Tuesday,
October 5 (i.e., the first working day after the day the patent is
listed in the Orange Book) an amendment to its ANDA containing a
paragraph IV certification to the '456 patent and the required printout
of the Orange Book entry and sends notice to the NDA holder and each
patent owner on that same day.
Prior to these amendments, no ANDA had contained a paragraph IV
certification to a patent listed for Procrastinadipine. Applicant D's
notice of paragraph IV certification is premature and thus invalid
because the '456 patent had not yet been listed in the Orange Book.
Only Applicant E has submitted the first substantially complete ANDA
containing a paragraph IV certification for purposes of first applicant
eligibility.
II.D.5. Administrative Consequence for Late Notice
The MMA does not specify a consequence for 505(b)(2) or ANDA
applicants that do not send notice of a paragraph IV certification
within the timeframe required by the FD&C Act (i.e., within 20 days
after the date of the postmark on the paragraph IV acknowledgment
letter or on the date that an amendment or supplement containing a
paragraph IV certification is submitted to FDA). In response to our
Request for MMA Comments, we received comments suggesting that we
create an administrative consequence for late notice (see, e.g., PhRMA
MMA Comment at 1 to 2). In light of the importance of the timing of
sending notice of paragraph IV certification to the statutory scheme,
we agree that it is appropriate to propose an administrative
consequence for ANDA applicants who are late in providing notice.
After considering several suggestions for administrative
consequences, including those submitted to us in response to our
Request for MMA Comments, we are proposing to address ANDA applicants
that fail to timely provide notice of a paragraph IV certification by
moving forward the date of submission of the ANDA by the number of days
beyond the required time frame that the applicant delayed in sending
its notice (see proposed Sec. 314.101(b)(4)). Consequently, an ANDA
applicant may lose its first applicant status and thus its eligibility
for 180-day exclusivity as a result of providing late notice (see
section 505(j)(5)(B)(iv) of the FD&C Act), if another applicant submits
a substantially complete ANDA containing a paragraph IV certification
on the same first day and provides timely notice. Also, an ANDA
applicant that fails to timely provide notice of paragraph IV
certification may experience a delay in the review queue for its ANDA
consistent with the revised date of submission. We note that this
proposed administrative consequence
[[Page 6841]]
would not reduce the 30-month timeframe set forth in section
505(j)(5)(D)(i)(I)(aa)(BB) and (j)(5)(D)(i)(IV) of the FD&C Act in the
forfeiture calculus for a first applicant; rather, the 30-month period
would begin on the revised date of submission.
We believe that the proposed administrative consequence for ANDA
applicants appropriately balances the purposes served by the
requirement for timely notice of paragraph IV certifications with the
legislative goal of speeding the availability of lower cost
alternatives to approved drugs. Certain options we considered as
alternatives did not seem to provide as measured a balance. For
example, we considered deeming paragraph IV certifications for which
notice had been provided after the statutory timeframe to not be
``lawfully maintained'' (see section 505(j)(5)(B)(iv)(bb) of the FD&C
Act). Under this interpretation, however, an ANDA applicant would
certainly lose its eligibility for 180-day exclusivity as a result of
sending late notice, regardless of the amount of time its notice was
delayed (e.g., even if its notice were one day late). We decline to
adopt this approach because it seems disproportionately punitive.
We are not proposing a similar consequence for 505(b)(2) applicants
that fail to timely provide notice of a paragraph IV certification
because 505(b)(2) applicants are not eligible for 180-day exclusivity
and we are unable to extend the review clock as an administrative
consequence for an NDA (including a 505(b)(2) application) subject to
the Prescription Drug User Fee Act Reauthorization Performance Goals
and Procedures (see http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm; see also 21 CFR 314.100). As
described below, we considered other possible administrative
consequences for any 505(b)(2) applicants that fail to provide notice
of a paragraph IV certification within the statutory timeframe;
however, we are declining to propose an administrative consequence at
this time.
The implications of late notice of a paragraph IV certification by
a 505(b)(2) applicant differ from those of an ANDA applicant that may
otherwise be eligible for 180-day exclusivity. A 505(b)(2) application
that contains a paragraph IV certification could not be approved until
the 505(b)(2) applicant had provided notice of its paragraph IV
certification to the NDA holder and each patent owner and the
respective 45-day periods for each recipient of notice had expired
without the filing of a legal action for patent infringement (see Sec.
314.107(f)(2)). A 505(b)(2) applicant that provides late notice of a
paragraph IV certification risks that the NDA holder or patent owner
will file an action for patent infringement within the 45-day period
after notice, and that any resultant 30-month stay will delay approval
by a period of time commensurate with the 505(b)(2) applicant's delay
in providing notice of its paragraph IV certification. We considered
the suggestion, submitted in response to our Request for MMA Comments,
that we ``creat[e] an automatic regulatory presumption which could be
used by the court hearing the patent infringement action that the ANDA
or 505(b)(2) applicant `failed to reasonably cooperate in expediting
the action' within the meaning of [section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act]'' (see PhRMA MMA Comment at 2).
However, we decline to propose this approach because it is not
necessary to properly implement the statutory goal of adequate notice
and opportunity to defend certain intellectual property rights prior to
approval.
II.E. Amended Patent Certifications (Proposed Sec. Sec. 314.50(i)(6)
and 314.94(a)(12)(viii))
We are proposing to revise Sec. Sec. 314.50(i)(6) and
314.94(a)(12)(viii) regarding submission of amended patent
certifications by 505(b)(2) and ANDA applicants, respectively, to
reflect revisions to the FD&C Act made by the MMA and for the efficient
enforcement of the FD&C Act. A 505(b)(2) or ANDA applicant would be
required to submit an amended patent certification to provide, for
example, a certification to a recently issued patent listed by the NDA
holder after submission of a 505(b)(2) application or ANDA that relies
upon the listed drug, or to change its certification to a patent for
which the applicant had previously submitted a patent certification. As
discussed in this section of the document, submission of an amended
patent certification also would be required for a reissued patent and
for a revision to a prior certification in the event that a patent or
patent information has been withdrawn from listing in the Orange Book.
We are proposing to revise the introductory text of Sec.
314.94(a)(12)(viii) to remove the provision that restricts an ANDA
applicant from amending a paragraph IV certification to a paragraph III
certification in certain circumstances. Currently, Sec.
314.94(a)(12)(viii) provides that an ANDA applicant that has submitted
a paragraph IV certification may not amend its patent certification to
a paragraph III certification (delaying approval until the date on
which such patent will expire) if a patent infringement action has been
filed against another applicant that had submitted a paragraph IV
certification. The current regulation provides that an ANDA applicant
is permitted to amend its patent certification to a paragraph III
certification in these circumstances only if the Agency has determined
that no applicant is entitled to 180-day exclusivity or the patent
expired while patent infringement litigation was pending or before the
end of the 180-day exclusivity period. We have determined, however,
that it is not necessary to restrict submission of an amended patent
certification under these circumstances because 180-day exclusivity
does not extend beyond patent expiry. Accordingly, an applicant that
amended its paragraph IV certification to a paragraph III certification
would not be eligible for approval until patent expiration and thus
would not undermine a first applicant's 180-day exclusivity as to that
patent. The MMA specifically provides that a first applicant's 180-day
exclusivity would, in any event, terminate upon expiration of all of
the patents as to which the applicant submitted a paragraph IV
certification qualifying it for 180-day exclusivity (see section
505(j)(5)(D)(i)(VI) of the FD&C Act; see also Sec.
314.94(a)(12)(viii)).
There are several circumstances in which amending to a paragraph
III certification is appropriate, including when an applicant is no
longer seeking approval before the patent expires or when required by
the terms of a settlement agreement between parties in patent
infringement litigation. This proposal would facilitate amendment of
paragraph IV certifications to paragraph III certifications in such
circumstances.
We also are proposing to revise Sec. Sec. 314.50(i)(6)(i) and
314.94(a)(12)(viii) to require that a 505(b)(2) or ANDA applicant
submit an amended patent certification as an amendment to its pending
application (including a supplemental 505(b)(2) application or
supplemental ANDA (see Sec. Sec. 314.70(i) and 314.97(c),
respectively)) and not by letter. This requirement will facilitate
appropriate management of amended patent certifications.
Table 9 summarizes the proposed changes regarding amended patent
certifications:
[[Page 6842]]
Table 9--Highlights of Proposed Changes Regarding Amended Patent
Certifications\1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Amended Certifications (Sec. Sec. Amended Certifications (Sec.
314.50(i)(6) and 314.94(a)(12)(viii)) Sec. 314.50(i)(6) and
314.94(a)(12)(viii))
Amended patent certification must Amended patent
be submitted as an amendment to a pending certification must be
505(b)(2) application or ANDA or by submitted as an amendment
letter to an approved application. to the 505(b)(2)
application or ANDA and may
no longer be submitted by
letter.
Amended Certifications (Sec. Amended Certifications (Sec.
314.94(a)(12)(viii) only) 314.94(a)(12)(viii) only)
ANDA applicants restricted from Deletion of
amending a paragraph IV certification to restriction on ANDA
a paragraph III certification in certain applicants from amending a
circumstances when another ANDA applicant paragraph IV certification
has been sued for patent infringement. to a paragraph III
certification.
After a Finding of Infringement (Sec. After a Finding of
Sec. 314.50(i)(6)(i) and Infringement (Sec. Sec.
314.94(a)(12)(viii)(A)) 314.50(i)(6)(i) and
314.94(a)(12)(viii)(A))
Change from
paragraph IV certification
to paragraph III
certification required
after a final judgment is
entered finding the patent
to be infringed.
Provision applies
if patent infringement
action initiated within 45
days of receipt of notice
of paragraph IV
certification.
Change from
paragraph IV certification
to paragraph III
certification required
after court enters final
decision from which no
appeal has been or can be
taken, or signs settlement
order or consent decree
with a finding of
infringement (unless the
patent also is found
invalid). An applicant may
instead provide a statement
under Sec.
314.50(i)(1)(iii) or Sec.
314.94(a)(12)(iii) with
respect to a method-of-use
patent if the 505(b)(2)
application or ANDA is
amended such that the
applicant is no longer
seeking approval for a
method of use claimed by
the patent.
Provision applies
if patent infringement
action initiated after
receipt of notice of
paragraph IV certification,
irrespective of whether the
action is brought within
the 45-day period.
After Removal of a Patent from the List After Request to Remove a
(Sec. Sec. 314.50(i)(6)(ii) and Patent or Patent
314.94(a)(12)(viii)(B)) Information from the List
If a patent is removed from the (Sec. Sec.
list, any applicant with a pending 314.50(i)(6)(ii) and
application (including a tentatively 314.94(a)(12)(viii)(B))
approved application with a delayed If the list
effective date) who has made a reflects that an NDA holder
certification with respect to such patent has requested that a patent
must amend its certification. be removed from the list
A patent that is the subject of a and:
lawsuit under Sec. 314.107(c) shall not --no ANDA applicant is
be removed from the list until FDA eligible for 180-day
determines either that no delay in exclusivity based on a
effective dates of approval is required paragraph IV certification
under that section as a result of the to that patent, the patent
lawsuit, that the patent has expired, or will be removed and any
that any such period of delay in applicant with a pending
effective dates of approval is ended. 505(b)(2) application or
Applicant must submit a ``no ANDA (including a
relevant patents'' certification or, if tentatively approved
other relevant patents claim the drug, 505(b)(2) application or
must amend the patent certification to ANDA) who has certified to
refer only to those relevant patents. that patent must submit an
amendment to withdraw the
certification.
--one or more first
applicants are eligible for
180-day exclusivity based
on a paragraph IV
certification to that
patent, the patent shall
remain listed until any 180-
day exclusivity is
extinguished.
If one or more
first applicants are
eligible for 180-day
exclusivity based on a
paragraph IV certification
to a patent that has been
reissued, then the first
applicant must submit a
paragraph IV certification
to the reissued patent
within 30 days of listing
to have lawfully maintained
its paragraph IV
certification for purposes
of eligibility for 180-day
exclusivity.
A 505(b)(2)
applicant is not required
to provide or maintain a
certification to a patent
that remains listed only
for purposes of a first
applicant's 180-day
exclusivity.
After any
applicable 180-day
exclusivity period has
ended, the patent will be
removed and any pending
ANDA (including a
tentatively approved ANDA)
that contains a
certification to the patent
must be amended to withdraw
the certification.
If removal of a
patent from the list
results in no patents
listed for the listed
drug(s) identified in the
505(b)(2) application or
ANDA, the applicant must
submit an amended
certification reflecting
that there are no listed
patents.
Late submission of patent information Untimely filing of patent
(Sec. Sec. 314.50(i)(4) and information (Sec. Sec.
314.94(a)(12)(vi)) 314.50(i)(4) and
314.94(a)(12)(vi))
If a patent on the listed (see Table 3)
drug is issued and the NDA holder for
the listed drug does not submit the
required information on the patent
within 30 days of patent issuance, an
applicant who submitted a 505(b)(2)
application or an ANDA for that drug
that contained an appropriate patent
certification before the submission
of the patent information is not
required to submit an amended
certification.
[[Page 6843]]
An applicant whose 505(b)(2)
application or ANDA is submitted
after a late submission of patent
information, or whose pending
505(b)(2) application or ANDA was
previously submitted but did not
contain an appropriate patent
certification at the time of the
patent submission, must submit a
certification under (Sec.
314.50(i)(1)(i) or Sec.
314.94(a)(12)(i) or a statement under
Sec. 314.50(i)(1)(iii) or Sec.
314.94(a)(12)(iii) as to that patent.
Patents Claiming the Drug Substance, Drug Patents Claiming the Drug
Product, or Method of Use (Sec. Sec. Substance, Drug Product, or
314.50(i)(1)(i)(A) and Method of Use (Sec. Sec.
314.94(a)(12)(i)(A)) 314.50(i)(1)(i)(A) and
314.94(a)(12)(i)(A))
A 505(b)(2) application and (No substantive
ANDA are required to contain a patent revisions)
certification or statement for each ............................
patent issued by the PTO that, in the ............................
opinion of the applicant and to the ............................
best of its knowledge, claims the ............................
listed drug relied upon or RLD or ............................
that claims an approved use for such ............................
drug for which the applicant is Other Amendments (Sec. Sec.
seeking approval and for which 314.50(i)(6)(iii)(A)(2)
information is required to be filed and
under section 505(b) and (c) of the 314.94(a)(12)(viii)(C)(1)(i
FD&C Act and Sec. 314.53. i))
Except as provided
in Sec. Sec.
314.50(i)(4) and
(i)(6)(iii)(B) and
314.94(a)(12)(vi) and
(a)(12)(viii)(C)(2)), an
applicant must submit a
patent certification or
statement if, after
submission of the 505(b)(2)
application or ANDA, a new
patent is issued by the PTO
that, in the opinion of the
applicant and to the best
of its knowledge, claims
the listed drug or RLD or
that claims an approved use
for such drug and for which
information is required to
be filed under section
505(b) and (c) of the FD&C
Act and Sec. 314.53.
For a paragraph IV
certification, the
certification must not be
submitted earlier than the
first working day after the
day the patent is published
in the list.
Other Amendments (Sec. Sec. Other Amendments (Sec. Sec.
314.50(i)(6)(iii)(A) and 314.50(i)(6)(iii)(A)(1)
314.94(a)(12)(viii)(C)(1)) and
314.94(a)(12)(viii)(C)(1)(i
))
[Amended patent certification [Upon patent
required upon patent expiration under expiration, FDA will
existing requirement for submission consider the 505(b)(2) or
of amended certification if, at any ANDA applicant to have
time before approval, the submitted constructively changed its
certification is no longer accurate.] patent certification to a
paragraph II
certification.]
Other Amendments (Sec. Sec. Other Amendments (Sec. Sec.
314.50(i)(6)(iii)(B) and 314.50(i)(6)(iii)(B) and
314.94(a)(12)(viii)(C)(2)) 314.94(a)(12)(viii)(C)(2))
An applicant is not required An applicant is not
to amend a submitted certification in required to submit a
response to patent information supplement to change a
submitted after approval of the submitted certification in
505(b)(2) application or ANDA (unless response to patent
a patent certification is required information submitted after
with a supplement to the 505(b)(2) approval of the 505(b)(2)
application or ANDA). application or ANDA (unless
a patent certification is
required with a supplement
to the 505(b)(2)
application or ANDA).
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.E.1. Amended Patent Certifications After a Finding of Infringement
We are proposing to amend Sec. Sec. 314.50(i)(6)(i) and
314.94(a)(12)(viii)(A) to reflect changes to the FD&C Act made by the
MMA that clarify the requirements for a 505(b)(2) or ANDA applicant,
respectively, to amend their paragraph IV certification after a
judicial finding of patent infringement. As further discussed in
section II.M, the MMA amended section 505(c)(3)(C) and (j)(5)(B)(iii)
of the FD&C Act to specify the types of court decisions that will
terminate a 30-month stay of approval, given that many patent
infringement actions previously had been concluded without a ``final
judgment'' regarding infringement being entered by a court. With
respect to a 505(b)(2) or ANDA applicant that had submitted a paragraph
IV certification resulting in a patent infringement action, the FD&C
Act provides that if, before the expiration of the 30-month stay of
approval, the district court hearing the patent infringement action
decides that the patent has been infringed and the district court's
judgment is either not appealed or is affirmed on appeal, the 505(b)(2)
application or ANDA may be approved on the date specified by the
district court that is not earlier than the date of expiration of the
patent (including any patent extension) and of any applicable
exclusivity (see section 505(c)(3)(C)(ii)(II) and
(j)(5)(B)(iii)(II)(bb) of the FD&C Act and 35 U.S.C. 271(e)(4)(A)).
We are proposing to amend Sec. Sec. 314.50(i)(6)(i) and
314.94(a)(12)(viii)(A) to require that a 505(b)(2) and ANDA applicant,
respectively, submit an amendment to change its paragraph IV
certification to a paragraph III certification (stating that the patent
will expire on a specific date) or, if appropriate, to a statement
under section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act if a
``court enters a final decision from which no appeal has been or can be
taken'' that the patent at issue has been infringed. After a final
court decision of patent infringement from which no appeal has been or
can be taken, a 505(b)(2) or ANDA applicant can no longer lawfully
maintain a paragraph IV certification that the patent is invalid or
will not be infringed by the manufacture, use, or sale of the drug for
which the 505(b)(2) application or ANDA has been submitted (see, e.g.,
Mylan Labs., Inc. v. Thompson, 389 F.3d 1272, 1281 (D.C. Cir. 2004)
(concluding that after the district court's finding of patent validity
and infringement, the ANDA applicant's paragraph IV certification was
``at variance with the legal reality'' and ``no longer accurate'')).
These proposed revisions to Sec. Sec. 314.50(i)(6)(i) and
[[Page 6844]]
314.94(a)(12)(viii)(A) reflect a change to the current text requiring a
505(b)(2) or ANDA applicant to amend its paragraph IV certification if
a ``final judgment'' has been entered finding the patent to be
infringed.
Proposed Sec. Sec. 314.50(i)(6)(i) and 314.94(a)(12)(viii)(A) also
would require a 505(b)(2) and ANDA applicant, respectively, to submit
an amendment to change its paragraph IV certification to a paragraph
III certification or, if appropriate, to a statement under section
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act if a court signs a
settlement order or consent decree in the action that includes a
finding that the patent is infringed, unless the final decision,
settlement order or consent decree also finds the patent to be invalid.
For a first ANDA applicant, submission of an amendment that changes the
paragraph IV certification that qualified the applicant for 180-day
exclusivity to a paragraph III certification or a statement under
section 505(j)(2)(A)(viii) of the FD&C Act has implications for
continuing eligibility for 180-day exclusivity (see section
505(j)(5)(D)(i)(III) of the FD&C Act). We note, however, that if a
settlement is reached without a finding of patent infringement or
invalidity, then a paragraph IV certification may continue to be
appropriate. For example, if the 505(b)(2) or ANDA applicant is granted
a patent license such that the applicant would be permitted to obtain
approval and commence marketing prior to patent expiration, the
505(b)(2) or ANDA applicant would maintain its paragraph IV
certification with respect to the patent at issue and should submit an
amendment pursuant to proposed Sec. Sec. 314.50(i)(3) and
314.94(a)(12)(v) to advise the Agency of the patent licensing
agreement. Such an amendment must include a written statement by the
applicant that it has been granted a patent license and a written
statement from the patent owner confirming the licensing agreement and
consenting to approval of the application as of a specific date (see
proposed Sec. Sec. 314.50(i)(3) and 314.94(a)(12)(v)).
We are proposing to apply the requirement that a 505(b)(2) or ANDA
applicant must submit an amendment to change its paragraph IV
certification to a paragraph III certification or, if appropriate, to a
statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C
Act after a judicial finding of patent infringement irrespective of
whether the patent infringement action was brought within 45 days of
receipt of the notice of paragraph IV certification (see proposed
Sec. Sec. 314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)). A patent
infringement action initiated outside of the 45-day period following
receipt of a notice of paragraph IV certification is not eligible for a
30-month stay of approval while the patent infringement litigation is
pending (see Sec. 314.107(b)(3)). However, the rationale for an
amended patent certification in the event that the patent is found
valid and infringed applies with equal force to a legal action for
infringement of a listed patent that was brought outside of the 45-day
period (see 35 U.S.C. 271(e)(4)). Thus, we are proposing to remove the
phrase ``within 45 days of the receipt of notice sent under [Sec.
314.52 or Sec. 314.95, respectively]'' from the description of the
patent infringement action to which Sec. Sec. 314.50(i)(6)(i) and
314.94(a)(12)(viii)(A) apply. This proposed revision would clarify, for
example, that the approval of a 505(b)(2) application or ANDA that
contained a paragraph IV certification but was not subject to a 30-
month stay still may be delayed by the intervening grant of pediatric
exclusivity under section 505A(b)(1)(B) of the FD&C Act after a
judicial finding of infringement of the patent for which the paragraph
IV certification had been submitted (see Mylan Labs., Inc. v. Thompson,
332 F. Supp. 2d 106 (D.D.C.), aff'd, 389 F.3d 1272 (D.C. Cir. 2004);
see also proposed Sec. 314.107(b)(4) and (e)(1)(vi)).
As explained in proposed Sec. Sec. 314.50(i)(6)(i) and
314.94(a)(12)(viii)(A), an applicant may change its paragraph IV
certification for a method-of-use patent to a statement under section
505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C Act only if the
applicant amends its 505(b)(2) application or ANDA, respectively, such
that the applicant is no longer seeking approval for a method of use
claimed by the patent (see Sec. Sec. 314.50(i)(1)(iii) and
314.94(a)(12)(iii)).
II.E.2. Amended Certifications After Request by the NDA Holder To
Remove a Patent or Patent Information From the List
We are proposing to revise Sec. Sec. 314.50(i)(6)(ii) and
314.94(a)(12)(viii)(B) to clarify the circumstances and timeframe in
which a 505(b)(2) or ANDA applicant, respectively, must submit an
amended patent certification to its 505(b)(2) application or ANDA after
an NDA holder has requested removal of a patent or patent information
from the list (``patent delisting''). These proposed revisions also
describe our current practice regarding patent delisting as it relates
to the eligibility of one or more first ANDA applicants for 180-day
exclusivity.
An NDA holder may request removal of a patent or patent information
from the list in accordance with a court order or on its own
initiative, if it determines that the patent or patent information no
longer meets the statutory criteria for listing (see section 505(b)(1)
and (c)(2) of the FD&C Act). Since April 18, 2008, FDA has identified
in the Orange Book (the list) those patents for which an NDA holder has
withdrawn the patent and submitted a request for removal of the patent
from the list. We are proposing to revise Sec. Sec. 314.50(i)(6)(ii)
and 314.94(a)(12)(viii)(B) to state that if an NDA holder has requested
removal of a patent or patent information from the list, the patent or
patent information will be removed if no ANDA applicant has submitted a
paragraph IV certification to the patent or no ANDA applicant is
eligible for 180-day exclusivity. Upon removal of the patent or patent
information from the list, any applicant with a pending 505(b)(2)
application or ANDA (including a tentatively approved 505(b)(2)
application or ANDA) must submit an amendment to its application to
withdraw its certification to the patent.
However, if an NDA holder has requested removal of a patent or
patent information from the list and one or more first ANDA applicants
are eligible for 180-day exclusivity, FDA will not remove the patent or
patent information from the list until we have determined that no first
applicant still is eligible for 180-day exclusivity (see section
505(j)(5)(D) of the FD&C Act regarding forfeiture of 180-day
exclusivity) or the 180-day exclusivity is extinguished (see proposed
Sec. Sec. 314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B)). Otherwise, if
the NDA holder withdrew the patent or patent information for which a
first ANDA applicant had submitted the certification that qualified it
for 180-day exclusivity and FDA immediately removed the patent or
patent information from the list, the first applicant would be required
to withdraw its patent certification and could not ``lawfully
maintain'' its paragraph IV certification (as the ANDA would no longer
be considered to be one containing a paragraph IV certification) (see
section 505(j)(5)(B)(iv)(II)(bb) and (j)(5)(D)(i)(III) of the FD&C
Act). In addition, if FDA immediately removed a patent or patent
information from the list upon the NDA holder's request when one or
more first applicants were eligible for 180-day exclusivity, it could
result in ANDA applicants withdrawing corresponding patent
certifications
[[Page 6845]]
prematurely and thus undermining a first applicant's 180-day
exclusivity. We also are proposing to revise the heading for Sec. Sec.
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) by replacing the phrase
``after removal of a patent'' with ``after request to remove a patent
or patent information'' to emphasize that FDA will not remove a patent
or patent information from the list until we have determined that no
first applicant is eligible for 180-day exclusivity.
An NDA holder's withdrawal of a patent or patent information is
implicitly an acknowledgment that the standard for patent listing set
forth in section 505(b) and (c) of the FD&C Act can no longer be met.
Nevertheless, a patent for which the NDA holder has requested removal
may remain listed for 180-day exclusivity purposes. For a patent that
remains listed for purposes of 180-day exclusivity after an NDA holder
has withdrawn the patent or patent information and requested that FDA
remove the patent or patent information from the list, the requirements
for providing a patent certification will differ between 505(b)(2)
applicants and ANDA applicants. A 505(b)(2) applicant is neither
eligible for nor blocked by 180-day generic drug exclusivity.
Accordingly, we are proposing to revise Sec. 314.50(i)(6)(ii) to
exempt a 505(b)(2) applicant from the requirement to provide or
maintain a certification to a patent that is identified in the Orange
Book as remaining listed only for purposes of a first applicant's 180-
day generic drug exclusivity. Because one or more ANDA applicants may
be eligible for 180-day exclusivity, ANDA applicants are required to
provide an appropriate patent certification to each patent listed in
the Orange Book (except as provided in Sec. 314.94(a)(12)(vi)),
including to a patent that is listed with a notation indicating that
the NDA holder has requested removal of the patent or patent
information from the Orange Book. Once FDA has determined that no first
applicant is eligible for 180-day exclusivity, or such exclusivity is
extinguished, and has removed the patent information from the Orange
Book, an ANDA applicant must submit an amendment to its pending ANDA to
withdraw the certification.
We are proposing to delete the statement in current Sec. Sec.
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) regarding the timing of
removal of a patent or patent information that is the subject of a
patent infringement lawsuit under Sec. 314.107(c). This statement
would be replaced by the broader criterion, discussed earlier in this
section, that a patent will not be removed from the list until FDA has
determined that any 180-day exclusivity is extinguished. This proposed
revision reflects our current practice.
We also are proposing to add a statement to emphasize that if a
505(b)(2) or ANDA applicant submits an amendment to withdraw a
paragraph IV certification, the 505(b)(2) application or ANDA will no
longer be considered to be one containing a paragraph IV certification
to the patent. In addition, we are proposing a conforming revision to
Sec. 314.94(a)(12)(viii) to clarify that once an amendment is
submitted to change a certification, the ANDA will no longer be
considered to contain the prior certification. This is consistent with
the Agency's practice for amended patent certifications for 505(b)(2)
applications (see Sec. 314.50(i)(6)).
Finally, we are proposing to relocate within Sec. Sec.
314.50(i)(6)(ii) and 314.94(a)(12)(viii)(B) and revise the current
statement regarding submission of an amended patent certification after
removal of a patent from the list. This proposed revision is intended
to clarify rather than substantively change our current requirements.
If removal of a patent from the list results in there being no patents
listed for the listed drug(s) identified in the 505(b)(2) application
or the RLD identified in the ANDA, the applicant must submit an amended
certification under Sec. 314.50(i)(1)(ii) or Sec. 314.94(a)(12)(ii),
as appropriate, to reflect that there are no listed patents. We note,
however, that if a 505(b)(2) or ANDA applicant fails to submit an
amended patent certification after removal of a patent from the list,
the Agency will consider the 505(b)(2) or ANDA applicant to have
constructively withdrawn its patent certification to the delisted
patent (compare Ranbaxy Labs. Ltd. v. FDA, 307 F. Supp. 2d 15, 21
(D.D.C.), aff'd, 2004 U.S. App. LEXIS 8311 (D.C. Cir. 2004); see also
section II.E.4). With respect to any patents that remain listed for the
listed drug(s) identified in the 505(b)(2) application or for the RLD
identified in the ANDA, it is expected that the applicant would
maintain an accurate patent certification consistent with current
regulatory requirements (see Sec. Sec. 314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C)). We seek comment on this approach.
II.E.3. Amended Certifications Upon Patent Reissuance
In section II.B.1.e, we describe certain proposed revisions to our
regulations to clarify our requirements regarding an NDA holder's
submission of patent information related to reissued patents. Because
the listing of a reissued patent may require submission of an amended
patent certification by a 505(b)(2) or ANDA applicant under our current
regulations, we are describing in this section of the document an
applicant's patent certification obligations with respect to a reissued
patent.
Sections 314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) require that
a 505(b)(2) and ANDA applicant submit an amended patent certification
if, at any time before approval of the 505(b)(2) application or ANDA,
the applicant learns that the submitted certification is no longer
accurate. As a general rule, we require a 505(b)(2) or ANDA applicant
to provide an appropriate patent certification or statement with
respect to a reissued patent, unless either the original patent or the
reissued patent was not timely filed by the NDA holder for listing in
the Orange Book (see Sec. Sec. 314.50(i)(4) and 314.94(a)(12)(vi)). As
noted in section II.B.1.e, if a 505(b)(2) or ANDA applicant is not
required to provide a patent certification or statement to the original
patent because it was untimely filed (and late-listed as to the pending
505(b)(2) application or ANDA), the 505(b)(2) or ANDA applicant would
not be required to provide a patent certification or statement to the
reissued patent even if timely filed following reissuance.
We require a 505(b)(2) or ANDA applicant to provide an amended
patent certification or statement to the reissued patent, even though a
patent certification or statement may already have been submitted for
the original patent, because the scope of claims may be narrowed or, in
certain circumstances, broadened upon reissuance of the patent (see 35
U.S.C. 251). A change in the scope of the patent claims may result in
the reissued patent being listed in the Orange Book with a revised
designation by the NDA holder regarding whether the patent claims the
drug substance, drug product, and/or a method of use, or the reissued
patent may be listed with a revised use code. Accordingly, submission
of an amendment to a pending 505(b)(2) application or ANDA is necessary
to provide an appropriate patent certification or statement to the
reissued patent, even if the type of patent certification (e.g., a
paragraph III certification) does not differ from that submitted for
the original patent.
If an ANDA applicant submitted a paragraph IV certification to the
original listed patent and continues to opine that the reissued patent
is invalid or will not be infringed by the manufacture, use, or sale of
the drug for which the application is submitted, then we are
[[Page 6846]]
proposing that the applicant must submit an amendment to its pending
ANDA that contained a paragraph IV certification to the reissued patent
within 30 days of the date of listing of the reissued patent in the
Orange Book to lawfully maintain its paragraph IV certification for
purposes of eligibility for 180-day exclusivity (see proposed Sec.
314.94(a)(12)(viii)(B)). Both 505(b)(2) and ANDA applicants are
required to provide notice of the paragraph IV certification to the
reissued patent and comply with other applicable regulatory
requirements at the time of submission of the amendment containing the
paragraph IV certification. We seek comment on this proposal.
An amended patent certification to the reissuance of an original
patent for which a paragraph IV certification previously was submitted
may have implications for the 30-month stay provisions of the FD&C Act:
If a 505(b)(2) or ANDA applicant submitted a paragraph IV
certification to the original patent and a patent infringement action
was initiated within 45 days of its notice of the paragraph IV
certification to the original patent, the resulting 30-month stay would
not be affected solely by reissuance of the patent, recertification,
and renotification and would continue subject to Sec. 314.107.
If a 505(b)(2) or ANDA applicant submitted a statement
under section 505(b)(2)(B) or section 505(j)(2)(A)(viii) of the FD&C
Act, respectively, or a paragraph III certification to the original
patent and subsequently submitted a paragraph IV certification to the
reissued patent, a 30-month stay would be available if a patent
infringement action was initiated within 45 days of its notice of the
paragraph IV certification to the reissued patent.
If a 505(b)(2) or ANDA applicant had previously submitted
a paragraph IV certification to the original patent and no patent
infringement action was initiated within 45 days of receipt of notice,
no subsequent patent infringement action with respect to the reissued
patent can give rise to a 30-month stay.
This approach reflects our proposal to treat the original patent and
the reissued patent as a ``single bundle'' of patent rights, albeit
patent rights that have changed with reissuance, such that the patent
information listed for the reissued patent would have been submitted
under 505(b)(1) or 505(c)(2) of the FD&C Act at the time of listing of
the original patent for purposes of section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act. Although we recognize that a reissued
patent may have a broadened scope of claims if applied for within 2
years from the grant of the original patent (see 35 U.S.C. 251), our
proposal to consider the original patent and reissued patent together
for purposes of administering the patent certification requirements of
the FD&C Act and any 30-month stay of approval or 180-day exclusivity
that relates to a paragraph IV certification is intended to provide a
consistent and predictable approach to implementation of the FD&C Act.
If FDA were to propose a different approach to the availability of a
30-month stay based on a paragraph IV certification to a reissued
patent with broadened claims, the implementation of such an approach
would require resources and patent expertise that FDA currently does
not possess and would be inconsistent with the Agency's ministerial
role in patent listing. In any event, we do not expect that the
scenario described here will occur frequently.
An amended patent certification to the reissuance of an original
patent for which a paragraph IV certification previously was submitted
also may have implications for the 180-day exclusivity provisions of
the FD&C Act. As described previously in this section of the document,
if a one or more first ANDA applicants is eligible for 180-day
exclusivity based on a paragraph IV certification to the original
patent and the patent is reissued, the first ANDA applicant would be
required to submit a paragraph IV certification to the reissued patent
within 30 days of listing to be considered by FDA to have lawfully
maintained its paragraph IV certification for purposes of section
505(j)(5)(B)(iv)(II)(bb) and (j)(5)(D)(i)(III) of the FD&C Act. We note
that the original patent, which qualified the first applicant for 180-
day exclusivity, would remain listed in the Orange Book until FDA
determined that any 180-day exclusivity is extinguished. Consistent
with our current practice regarding requests for patent delisting, the
original patent that qualified a first applicant for 180-day
exclusivity also would remain listed in the Orange Book even if the
scope of the reissued patent is narrowed such that the patent is no
longer eligible for listing pursuant to section 505(b)(1) or 505(c)(2)
of the FD&C Act and the NDA holder has requested, as required, that the
patent be delisted from the Orange Book (see proposed Sec.
314.53(f)(2) and section II.B.4.b). Given that FDA will continue to
list a patent that qualified a first applicant for 180-day exclusivity
under specified circumstances even if the patent has been withdrawn by
the NDA holder on its own initiative or after a judicial finding of
invalidity or unenforceability, the fact that the original patent
technically is surrendered upon reissuance is not relevant to FDA's
assessment of a first applicant's continued eligibility for 180-day
exclusivity. However, in recognition of the surrender of the original
patent upon reissuance, we require a first applicant to maintain a
paragraph IV certification to the reissued patent. If a first applicant
submitted only a paragraph III certification or a 505(j)(2)(A)(viii)
statement to the reissued patent, we would consider the first applicant
to have amended or withdrawn its paragraph IV certification to the
patent for which it qualified for 180-day exclusivity under section
505(j)(5)(D)(i)(III) of the FD&C Act.
If no applicant had submitted a paragraph IV certification to the
original patent, the first ANDA applicant to submit a paragraph IV
certification to the reissued patent could be eligible for 180-day
exclusivity, if no other applicant already has qualified as a first
applicant based on an earlier paragraph IV certification to another
listed patent. However, if a first applicant who qualifies as such
based on a paragraph IV certification to the original patent forfeits
180-day exclusivity, 180-day exclusivity would not be available to a
subsequent applicant that submitted a paragraph IV certification to the
reissued patent (see section 505(j)(5)(D)(iii)(II) of the FD&C Act).
II.E.4. Other Amended Certifications
Sections 314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) require a
505(b)(2) and ANDA applicant, respectively, to amend a submitted
certification if, at any time before approval of the application, the
applicant learns that the submitted certification is no longer
accurate. In Dr. Reddy's Labs., Inc. v. Thompson, the district court
held that our regulations ``imposing a duty upon ANDA applicants to
assure its certifications are accurate until the date of final approval
is supported by [the] . . . express FDA authority [in section
505(j)(4)(J) and (K) of the FD&C Act]'' (302 F. Supp. 2d 340, 355
(D.N.J. 2003)) (see also section 505(e) of the FD&C Act).
Over the years, many 505(b)(2) and ANDA applicants have neglected
to amend a previously submitted patent certification after the patent
has expired. The Agency's longstanding position has been that a patent
is relevant for purposes of 180-day exclusivity determinations ``until
the end of the term of the patent or applicable 180-day
[[Page 6847]]
exclusivity period, whichever occurs first'' (1994 final rule, 59 FR
50338 at 50348). Section 505(j)(5)(D)(i)(VI) of the FD&C Act, added by
the MMA, is consistent with FDA's longstanding position that 180-day
exclusivity is extinguished upon expiration of the patent(s) on which
exclusivity is based (see Docket No. FDA-2004-N-0062-0006 (comment
submitted by PhRMA) at 5, available at http://www.regulations.gov).
Accordingly, we are proposing to codify our longstanding position
that if an applicant that previously submitted a paragraph III
certification, a paragraph IV certification, or a statement under
section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act with respect to
a listed patent fails to amend its patent certification to a paragraph
II certification upon patent expiration, the Agency will consider the
505(b)(2) or ANDA applicant to have constructively changed its patent
certification to a paragraph II certification (see, e.g., Ranbaxy Labs.
Ltd. v. FDA, 307 F. Supp. 2d 15, 21 (D.D.C.), aff'd, 2004 U.S. App.
LEXIS 8311 (D.C. Cir. 2004) (finding that upon patent expiration an
ANDA applicant's paragraph IV certifications ``became invalid, and
either converted as a matter of law to Paragraph II certifications or
became inaccurate, thereby creating both an obligation on [the ANDA
applicant's] . . . part to amend its ANDAs to reflect patent expiry and
an inability on the part of the FDA to approve the ANDAs in their
inaccurate form'')). This approach also will clarify that any pediatric
exclusivity will delay approval of a 505(b)(2) application or ANDA upon
patent expiry under section 505A(b)(1)(B) and (c)(1)(B) of the FD&C
Act, regardless of whether an applicant has amended its certification
to a paragraph II certification.
We also are proposing to amend Sec. Sec. 314.50(i)(6)(iii)(A) and
314.94(a)(12)(viii)(C)(1) by revising and redesignating the current
text as paragraph (1) and paragraph (i), respectively, and adding a new
paragraph (2) and paragraph (ii) to expressly codify the requirement
for a 505(b)(2) and ANDA applicant to submit a patent certification to
a newly issued patent. Proposed Sec. Sec. 314.50(i)(6)(iii)(A)(2) and
314.94(a)(12)(viii)(C)(1)(ii) state that, except as provided in
Sec. Sec. 314.50(i)(4) and (i)(6)(iii)(B) and 314.94(a)(12)(vi) and
(a)(12)(viii)(C)(2)), an applicant must submit a patent certification
or statement if, after submission of the 505(b)(2) application or ANDA,
a new patent is issued by the PTO that, in the opinion of the applicant
and to the best of its knowledge, claims the listed drug or RLD or that
claims an approved use for such drug and for which information is
required to be filed under section 505(b) and (c) of the FD&C Act and
Sec. 314.53.
A 505(b)(2) and ANDA applicant currently are required to submit a
patent certification or statement for each patent issued by the PTO
that, in the opinion of the applicant and to the best of its knowledge,
claims the listed drug or RLD or that claims an approved use for such
drug for which the applicant is seeking approval and for which
information is required to be filed under section 505(b) and (c) of the
FD&C Act and Sec. 314.53. Although the general requirement to submit a
patent certification to a newly issued patent is established by
Sec. Sec. 314.50(i)(1)(i)(A) and 314.94(a)(12)(i)(A) and implicit in
the exceptions for late submission of patent information, we are
proposing to expressly codify the requirement to submit a patent
certification to a newly issued patent in the section of the
regulations directed to amended patent certification.
As discussed in section II.D.1.b.ii, we are proposing that a patent
certification or statement by an ANDA applicant must not be submitted
earlier than the first working day after the day the patent is
published in the Orange Book (see proposed Sec.
314.94(a)(12)(viii)(C)(1)(ii)). Thus, for a paragraph IV certification,
the certification must not be submitted earlier than the first working
day after the day the patent is published in the Orange Book. This
proposal is intended to discourage burdensome serial submissions of
paragraph IV certifications and ensure that all ANDA applicants
(irrespective of time zone) have a reasonable opportunity to be a first
applicant with respect to a newly listed patent (see also proposed
Sec. 314.95(b)(2)).
In addition, we are proposing to revise Sec. Sec.
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C) to technically correct,
but not substantively change, the reference to the lack of a
requirement to ``amend'' a submitted patent certification after
approval of a 505(b)(2) application or ANDA, respectively. We are
proposing to correct this statement to indicate that an applicant is
not required to submit a supplement solely to change a submitted patent
certification after approval of the application. This revision also
reflects that any changes to an application after approval would be
made in a supplement to the application and not in an amendment, as the
current regulation describes.
II.F. Patent Certification Requirements for Amendments and Supplements
to 505(b)(2) Applications and ANDAs (Proposed Sec. Sec. 314.60,
314.70, 314.96, and 314.97)
We are proposing to add Sec. Sec. 314.60(f), 314.70(i), 314.96(d),
and 314.97(c) to clarify and augment the patent certification
requirements for amendments and supplements described in Sec. Sec.
314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C). Proposed Sec. Sec.
314.60(f) and 314.96(d) would require an applicant to also submit a
patent certification described in Sec. Sec. 314.50(i) or
314.94(a)(12), as appropriate, if approval is sought for any of the
following types of amendments to an original 505(b)(2) application or
ANDA: (1) To add a new indication or other condition of use; (2) to add
a new strength; (3) to make other than minor changes in product
formulation; or (4) to change the physical form or crystalline
structure of the active ingredient.
Currently, an applicant that submits an amendment to a pending
505(b)(2) application or supplement or a pending ANDA or supplement is
required to amend its patent certification if, at any time before
approval, the applicant learns that the previously submitted patent
certification is no longer accurate with respect to the pending
application or supplement, as amended (see Sec. Sec. 314.50(i)(6)(iii)
and 314.94(a)(12)(viii)(C), respectively, and section II.E.4). For
example, an amendment to change the formulation of a proposed product
in a 505(b)(2) application or ANDA would require a revised patent
certification if, in the applicant's opinion and to the best of its
knowledge, the new formulation would infringe a listed patent for which
it previously had filed a paragraph IV certification.
Some NDA holders have expressed concern that a 505(b)(2) or ANDA
applicant may change its proposed product in an amendment to a pending
application, but not update its patent certification to correspond to
the proposed product as changed by the amendment. For example, in 2003,
FDA received a citizen petition submitted on behalf of Biovail
Corporation requesting, among other things, that FDA require submission
of a new patent certification upon amendment of the chemistry,
manufacturing, and controls section of an ANDA (Docket No. FDA-2003-P-
0519 (Biovail Petition), available at http://www.regulations.gov; see
also PhRMA comment to Docket No. FDA-2002-N-0279-0061 at 9 to 10,
available at http://www.regulations.gov). The
[[Page 6848]]
Biovail Petition recognized that even if the ANDA (or 505(b)(2))
applicant continued to assert that a paragraph IV certification was the
appropriate patent certification for the changed product, the factual
and legal basis of the applicant's opinion that the patent will not be
infringed may have changed in light of the changes in product
formulation (see Biovail Petition at 4 to 5). Biovail maintained that
``[r]equiring a new patent certification whenever the CMC portion of an
ANDA is amended will allow the NDA holder and patent owner to ensure
that the impact of the amendment on patent infringement issues is
addressed promptly'' (Supplement to Biovail Petition at 1).
We agree that certain changes to a proposed product submitted in a
505(b)(2) application or ANDA should be accompanied by a new patent
certification (see section II.F.2). To address these concerns and
further clarify our requirements for submission of new patent
certifications with an amendment to a 505(b)(2) application or ANDA, we
are proposing to add Sec. Sec. 314.60(f) and 314.96(d). If an
applicant submits an amendment to a 505(b)(2) application or ANDA for
any of the categories of changes described in these provisions and does
not submit a new patent certification, the applicant will be required
to verify that the proposed change described in the amendment is not
the type of change for which a new patent certification is required
(e.g., the proposed formulation change meets the criteria for a
``minor'' formulation change). We seek comment on this proposal.
We also are proposing to add Sec. Sec. 314.70(i) and 314.97(c),
and make conforming revisions to Sec. Sec. 314.50(i)(6)(iii)(B) and
314.94(a)(12)(viii)(C)(2), to clarify our requirements for submission
of new patent certifications with a supplement to a 505(b)(2)
application or ANDA. Proposed Sec. Sec. 314.70(i) and 314.97(c) would
require an applicant to also submit a patent certification described in
Sec. 314.50(i) or 314.94(a)(12), as appropriate, if approval is sought
for either of the following types of supplements to a 505(b)(2)
application or ANDA: (1) To add a new indication or other condition of
use or (2) to add a new strength.
FDA is not proposing to require a patent certification with a
supplement to change the formulation or to change the physical form or
crystalline structure of the active ingredient of a product approved in
a 505(b)(2) application or ANDA. It is not necessary for FDA to use its
limited resources to require patent certifications under these
circumstances because the NDA holder for a listed drug and any patent
owner can monitor postapproval changes in the formulation or active
ingredient of a marketed drug product and address any patent-related
concerns without the involvement of FDA. With respect to NDA
supplements, it should be noted that these patent certification
requirements apply to 505(b)(2) supplements, irrespective of whether
the original application to which the supplement was submitted was
approved as a stand-alone 505(b)(1) application or a 505(b)(2)
application. A supplement to a 505(b)(2) application of the type
described in proposed Sec. 314.70(i) is generally a 505(b)(2)
supplement.
Table 10 summarizes the proposed changes related to patent
certification requirements for amendments and supplements to 505(b)(2)
applications and ANDAs:
Table 10--Highlights of Proposed Changes Regarding Patent Certification
Requirements for Amendments and Supplements to 505(b)(2) Applications
and ANDAs \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Amended certifications--Other amendments Amended certifications--
(Sec. Sec. 314.50(i)(6)(iii), Other amendments (Sec.
314.94(a)(12)(viii)(C)) Sec. 314.50(i)(6)(iii),
314.94(a)(12)(viii)(C))
Except as otherwise provided, Except as otherwise
an applicant must amend a submitted provided, an applicant must
certification if, at any time before amend a submitted
approval of the 505(b)(2) application certification if, at any
or ANDA, the applicant learns that time before approval of the
the submitted certification is no 505(b)(2) application or
longer accurate. ANDA, the applicant learns
that the submitted
certification is no longer
accurate.
Patent certification
requirements (Sec. Sec.
314.60(f) and 314.96(d)).
Except as provided
below, an amendment to a
505(b)(2) application or
ANDA is required to contain
patent certifications
described in Sec. Sec.
314.50(i) or 314.94(a)(12),
respectively, if approval
is sought for any of the
following types of
amendments or supplements:
--(1) To add a new
indication or other
condition of use;
--(2) to add a new
strength;
--(3) to make other than
minor changes in product
formulation; or
--(4) to change the
physical form or
crystalline structure of
the active ingredient.
Patent certification
requirements (Sec. Sec.
314.70(i) and 314.97(c)).
Except as provided
below, a supplement to a
505(b)(2) application or
ANDA is required to contain
patent certifications
described in Sec. Sec.
314.50(i) or 314.94(a)(12),
respectively, if approval
is sought for either of the
following types of
supplements:
--(1) To add a new
indication or other
condition of use; or
--(2) to add a new
strength.
A supplement to a
505(b)(2) application that
seeks approval to add a new
indication or other
condition of use is
required to contain patent
certifications described in
Sec. 314.50(i) only for
patents that are identified
as claiming an approved
use. If the method-of-use
patent is identified as
also claiming the drug
substance or drug product,
the patent certification
also must address the drug
substance and/or drug
product claims.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
[[Page 6849]]
We invite comment on this proposal and whether a new patent
certification should be required with the submission of other types of
amendments or supplements to a 505(b)(2) application or ANDA that may
change the drug product in a manner that could be protected by patent.
II.F.1. Types of Amendments or Supplements for Which Patent
Certification is Required
II.F.1.a. Amendments or supplements to add a new indication or
other condition of use. Proposed Sec. Sec. 314.60(f)(1),
314.70(i)(1)(i), 314.96(d)(1), and 314.97(c)(1) require a 505(b)(2) or
ANDA applicant to submit a new patent certification with an amendment
or supplement to add a new indication or other condition of use for the
drug product that is the subject of the 505(b)(2) application or ANDA.
Although most requests for approval of a different indication or
condition of use by a 505(b)(2) applicant could not be made as an
amendment to the 505(b)(2) application (see Separate Marketing
Application Guidance at 4 to 5), there are certain scenarios in which
an applicant may submit an amendment to a 505(b)(2) application (or
ANDA) for a new indication or other condition of use. For example, a
505(b)(2) or ANDA applicant seeking approval for a drug product for
which the indication has changed from prescription status to OTC use
for the listed drug relied upon or RLD, as applicable, would be
required to submit a new patent certification with an amendment or
supplement to the application. These patent certification requirements
are currently encompassed by Sec. Sec. 314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C). Proposed Sec. Sec. 314.60(f)(1),
314.70(i)(1)(i), 314.96(d)(1), and 314.97(c)(1) would parallel the
requirements for submission of patent information by an NDA applicant
seeking approval of a supplement to add a new indication or other
condition of use (see proposed Sec. 314.53(d)(2)(ii)).
Currently, an applicant is required to submit a patent
certification or statement with a 505(b)(2) supplement that seeks
approval for a new indication or other condition of use (``efficacy
supplement''). We are proposing to reduce the current patent
certification requirements with respect to a supplement to a 505(b)(2)
application that seeks approval for a new indication or other condition
of use. Proposed Sec. 314.70(i)(2) states that a supplement to a
505(b)(2) application that only seeks approval to add a new indication
or other condition of use is required to contain patent certifications
described in Sec. 314.50(i) only for patents that are identified as
claiming an approved use. This proposed change preserves the NDA
holder's intellectual property rights without requiring the 505(b)(2)
applicant to submit a duplicative certification to patents listed in
the Orange Book for the listed drug relied upon that have not been
identified by the NDA holder as claiming a method of use and would not
be implicated by the efficacy supplement. We note, however, that if a
method-of-use patent is identified as also claiming the drug substance
or drug product, a statement under section 505(b)(2)(B) of the FD&C Act
would not be sufficient. The 505(b)(2) applicant's patent certification
also must address the drug substance and/or drug product claims in the
patent.
II.F.1.b. Amendments or supplements to add a new strength or change
an existing strength. Proposed Sec. Sec. 314.60(f)(2),
314.70(i)(1)(ii), 314.96(d)(2), and 314.97(c)(2) would codify our
current requirements with respect to an applicant's submission of a new
patent certification with an amendment or supplement to add a new
strength for the drug product that is the subject of the 505(b)(2)
application or ANDA. As noted in section II.A.2.q, it is our
longstanding practice to regard different strengths of a drug product
as different drug products (see Apotex, Inc. v. Shalala, 53 F. Supp. 2d
454 (D.D.C.), aff'd, 1999 U.S. App. LEXIS 29571 (D.C. Cir. 1999)).
II.F.1.c. Amendments to make other than minor changes in product
formulation. Proposed Sec. Sec. 314.60(f)(3) and 314.96(d)(3) would
require a 505(b)(2) or ANDA applicant to submit a new patent
certification with an amendment to make other than minor changes in the
formulation of the drug product that is the subject of the original
505(b)(2) application or ANDA. This enhanced patent certification
requirement is intended to facilitate ongoing compliance with section
505(b)(2)(A) and (j)(2)(A)(vii) of the FD&C Act. An applicant that
submits a 505(b)(2) application or ANDA containing a paragraph IV
certification to a listed patent must reevaluate whether the patent
certification continues to be accurate after a change to the
formulation of the proposed product submitted in an amendment to the
505(b)(2) application or ANDA. By requiring a new patent certification
and, with respect to a paragraph IV certification, a new notice of
paragraph IV certification to be sent at the same time the amendment
for the change in formulation is submitted to FDA, we aim to uphold the
legislative balance of the Hatch-Waxman Amendments that facilitates the
availability of generic drug products while protecting innovator
intellectual property rights. We seek comment on this proposal.
This requirement would apply to all amendments to change the
formulation of a proposed product in an original 505(b)(2) application
or ANDA, except for minor changes in product formulation that FDA would
regard as resulting in essentially the same product. A new patent
certification would not be required if the new formulation in the
amendment is qualitatively (Q1) the same as the previous formulation
(i.e., contains all of the same inactive ingredients) and
quantitatively (Q2) essentially the same (i.e., each inactive
ingredient differs by no more than plus or minus 5 percent from the
previous formulation). These limits correspond to the Agency's policy
on products that generally can be regarded as essentially the same
(see, e.g., draft guidance for industry entitled ``Bioavailability and
Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local
Action'' (April 2003) at 8, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070111.pdf;
compare Sec. 314.70(b)(2)(i)), and thus a change within these limits
would not be likely to affect an applicant's patent certification.
These limits also are similar to ``Level 1'' changes (those that are
unlikely to have any detectable impact on formulation quality and
performance) in components and composition of a drug product under the
Agency's Scale-Up and Postapproval Changes guidance (see guidance for
industry entitled ``Immediate Release Solid Oral Dosage Forms; Scale-Up
and Postapproval Changes: Chemistry, Manufacturing, and Controls, In
Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation''
(November 1995) at 6 to 8, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070636.pdf).
It should be noted that an applicant seeking approval for an ANDA
for a product intended for parenteral, ophthalmic, otic, or topical use
must submit information to show that the proposed product contains the
same inactive ingredients in the same concentration as the RLD, subject
to exceptions specified in Sec. 314.94(a)(9)(iii) through (a)(9)(v).
Additional regulatory considerations related to changes to the
formulation of a drug product proposed in an
[[Page 6850]]
amendment to an ANDA are discussed in section II.G.1 to II.G.2 and
II.L.
II.F.1.d. Amendments to change the physical form or crystalline
structure of the active ingredient. Proposed Sec. Sec. 314.60(f)(4)
and 314.96(d)(4) would require a 505(b)(2) or ANDA applicant to submit
a new patent certification with an amendment to change the physical
form (e.g., different waters of hydration, solvates, and amorphous
forms) or crystalline structure of the active ingredient of the drug
product that is the subject of the 505(b)(2) application or ANDA. For
example, a new patent certification would be required for an amendment
to an ANDA that includes a change to the physical form of the active
ingredient to conform with the physical form(s) of the active
ingredient described in a final USP monograph.
These patent certification requirements apply to changes to the
active ingredient that may be submitted as an amendment to a 505(b)(2)
application or ANDA and do not alter the Agency's policy regarding the
types of different active ingredients (e.g., different salts, esters,
and complexes of the same active moiety) that should be submitted in a
separate application (see Separate Marketing Application Guidance; see
also section II.G.3 to II.G.4). We note that the Agency has long
considered different polymorphs to be the ``same active ingredient''
and pharmaceutical equivalents (see section 1.7 of the preface to the
Orange Book (33rd Edition, 2013, at xv).
II.F.2. Requirements for Notice of Paragraph IV Certifications and
Implications for 180-Day Exclusivity
There are additional regulatory considerations related to the
submission of a paragraph IV certification by an applicant required to
submit a new patent certification with its amendment or supplement to a
505(b)(2) application or ANDA. As a preliminary matter, we note that
notice is required for all paragraph IV certifications, irrespective of
whether the applicant previously provided notice of paragraph IV
certification to the same patent or to another patent claiming the
listed drug relied upon or RLD (see section 505(b)(3)(B) and
(j)(2)(B)(ii) of the FD&C Act). If patent infringement litigation has
been initiated in response to a previous notice of paragraph IV
certification, a new paragraph IV certification submitted with an
amendment or supplement to the 505(b)(2) application or ANDA still
requires formal notice in accordance with Sec. Sec. 314.52 and 314.95.
The new notice of paragraph IV certification must contain the
information required by section 505(b)(3)(D) and (j)(2)(B)(iv) of the
FD&C Act and Sec. Sec. 314.52(c) and 314.95(c), updated to correspond
to the proposed product as changed by the amendment or supplement. For
example, the detailed statement of the factual and legal basis of the
applicant's opinion that the patent is invalid, unenforceable, or will
not be infringed by its proposed product must be updated, as necessary,
by the 505(b)(2) or ANDA applicant to reflect the changes proposed in
the amendment or supplement. The notice of paragraph IV certification
also must clarify whether the amendment or supplement contains any
required bioavailability or bioequivalence data that was necessary to
support the proposed change to the 505(b)(2) application or ANDA.
With respect to any listed patent challenged by the applicant in an
amendment or supplement to the 505(b)(2) application or ANDA for which
the NDA holder or patent owner initiated patent infringement litigation
within the statutory timeframe in response to notice of paragraph IV
certification, the availability of a 30-month stay will depend upon
whether the NDA holder filed information on the patent at issue with
FDA prior to the date of submission of the 505(b)(2) application or the
date of submission of the ANDA (which FDA later determined to be
substantially complete) that refers to the listed drug claimed by the
patent (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act).
Accordingly, a 30-month stay may result from initiation of a patent
infringement action in response to a second notice of paragraph IV
certification provided at the time of submission of an amendment or
supplement to a 505(b)(2) application or ANDA if the patent was listed
prior to the date of submission of the original 505(b)(2) application
or ANDA and, for example, the infringement action was warranted by the
change proposed in the amendment or supplement.
A first applicant that submits an amendment to its pending ANDA or
a supplement would be considered to have lawfully maintained a
paragraph IV certification to the patent upon which eligibility for
180-day exclusivity was based if the amendment or supplement is
accompanied by another paragraph IV certification to the patent and
notice of paragraph IV certification is sent in accordance with Sec.
314.95(d).
II.G. Amendments or Supplements to a 505(b)(2) Application for a
Different Drug and Amendments or Supplements to an ANDA That Reference
a Different Listed Drug (Proposed Sec. Sec. 314.60, 314.70, 314.96,
314.97)
The MMA added section 505(b)(4)(A), (b)(4)(B), (j)(2)(D)(i), and
(j)(2)(D)(ii) to the FD&C Act, which generally prohibit the submission
of certain types of changes in an amendment or a supplement to a
505(b)(2) application or an ANDA, respectively. We interpret these
provisions in the context of the MMA's amendment of section
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act to restrict the
availability of a 30-month stay of approval in certain circumstances
involving amendments and supplements to a 505(b)(2) application or ANDA
and seek comment on this approach.
Section 1101(a)(1)(A) of the MMA amended section 505(j) of the FD&C
Act to generally prohibit an ANDA applicant from amending or
supplementing 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 FDA]'' (section 505(j)(2)(D)(i) of the
FD&C Act). The textual reference in the statute to ``seek approval of a
drug referring to a different listed drug'' is clearly understood in
the context of section 505(j) of the FD&C Act and FDA's regulatory
scheme for the approval of ANDAs. An applicant that submits an ANDA for
a duplicate of a listed drug is required to identify and rely upon the
listed drug designated by FDA as the RLD (see Sec. 314.94(a)(3)). An
applicant also may petition FDA to request permission to submit an ANDA
that differs from a selected listed drug in route of administration,
dosage form, or strength, or that has one different active ingredient
in a combination drug product (see section 505(j)(2)(C) of the FD&C
Act). Accordingly, we are proposing to add Sec. Sec. 314.96(c) and
314.97(b) to state that an ANDA applicant may not amend or supplement
an ANDA to seek approval of a drug referring to listed drug that is
different from the RLD identified in the ANDA. An ANDA applicant that
seeks to refer to a listed drug different from the RLD identified in
the initial ANDA must submit a new ANDA (see section 505(j)(2)(D)(i) of
the FD&C Act; see also section II.G.1 to II.G.2 of this document).
Section 1101(b)(1)(A) of the MMA amended section 505(b) of the FD&C
Act to generally prohibit an applicant from amending or supplementing
``an application referred to in [section
[[Page 6851]]
505(b)(2)] to seek approval of a drug that is a different drug than the
drug identified in the application as submitted to the Secretary.''
Although section 1101(a) and (b) of the MMA are parallel in structure,
the statutory text restricting an applicant from amending or
supplementing a 505(b)(2) application in certain circumstances differs
from the corresponding restrictions for ANDAs. Section 505(b)(4)(A)
prohibits an amendment or a supplement ``to seek approval of a drug
that is a different drug'' (emphasis added) while section
505(j)(2)(D)(i) prohibits an amendment or supplement to an ANDA ``to
seek approval of a drug referring to a different listed drug''
(emphasis added).
The MMA also amended section 505(c)(3)(C) and (j)(5)(B)(iii) of the
FD&C Act to permit a 30-month stay of approval of a 505(b)(2)
application or ANDA only with respect to patents for which the NDA
holder submitted information to FDA prior to the date of submission of
the 505(b)(2) application or the date of submission of the ANDA (which
FDA later determines to be substantially complete) that refers to the
listed drug claimed by the patent. The ``date on which the application
. . . was submitted'' specifically excludes the date of submission of
an amendment or supplement to a 505(b)(2) application or ANDA. Given
this limitation on the patents that may give rise to a 30-month stay,
the MMA may have created an incentive for a 505(b)(2) or ANDA applicant
to seek approval for a change to a drug, or to reference a different
listed drug, through an amendment or a supplement, rather than by
submitting a new application. To address this concern, section
505(b)(4)(A) and (j)(2)(D)(i) of the FD&C Act ensure that 505(b)(2) and
ANDA applicants do not use the amendment or supplement process to evade
the possibility of a 30-month stay of approval that otherwise would
have applied if the 505(b)(2) applicant sought approval for a drug that
is a different drug or if the ANDA applicant sought to refer to a
different RLD in the original 505(b)(2) application or ANDA,
respectively. Accordingly, we interpret section 505(b)(4)(A) of the
FD&C Act in a manner that is consistent with the statutory text,
accomplishes the statutory goal of preserving a meaningful opportunity
for a single 30-month stay, and reflects, to the extent feasible,
Congress' expressed intent to preserve rather than disrupt FDA
processes regarding submission of amendments and supplements to
505(b)(2) applications and ANDAs.
We propose that a drug will be considered a ``different drug'' for
purposes of section 505(b)(4)(A) of the FD&C Act if it has been
modified to have a different active ingredient, different route of
administration, or different dosage form. Similarly, a drug will be
considered to be a different drug if it has been modified to have
different excipients that require either a separate clinical study to
establish safety or effectiveness or, for topical products, that
requires a separate in vivo demonstration of bioequivalence (see
proposed Sec. Sec. 314.60(e) and 314.70(h)). Consistent with FDA's
``bundling'' policy in effect at the time of enactment of the MMA, an
applicant may not seek approval for these types of changes to a drug
through an amendment or supplement to the 505(b)(2) application; the
applicant is required to submit a new 505(b)(2) application (see draft
guidance for industry entitled ``Submitting Separate Marketing
Applications and Clinical Data for Purposes of Assessing User Fees''
(describing FDA's bundling policy at the time of enactment of the MMA
in 2003); see also Separate Marketing Applications Guidance). These
changes to a drug product are significant enough that it is reasonable
to assume that one or more patents for the listed drug might be
implicated by the change and, if an action for patent infringement is
brought in response to a paragraph IV certification to a listed patent,
an opportunity for 30-month stay would be appropriate. Thus, FDA has
concluded that these modifications to a drug would make the drug a
``different drug'' for purposes of section 505(b)(4)(A) of the FD&C
Act. An applicant seeking marketing approval for a drug that has been
modified in these ways must submit a separate marketing application for
the different drug product, and not an amendment or supplement.
We considered possible alternative interpretations of the phrase
``to seek approval of a drug that is a different drug'' in section
505(b)(4)(A) of the FD&C Act. The narrowest reading of this text would
preclude the submission of an amendment or a supplement to a 505(b)(2)
application for any change (including labeling changes and
manufacturing changes) that would arguably render the proposed product
a ``different drug'' than the drug identified in the original
submission of the application. If labeling changes, for example, could
not be made through an amendment or a supplement to a 505(b)(2)
application, each such change would require the submission of a
separate 505(b)(2) application, with related regulatory and
administrative burdens, and user fee and review cycle implications. We
did not adopt this reading because it would have resulted in an
unwarranted departure from FDA's previous practice for handling such
changes.
In applying section 505(b)(4)(A) of the FD&C Act, we initially
interpreted the phrase ``drug that is a different drug'' in section
505(b)(4)(A) in a manner that was influenced by and intended to be
consistent with the phrase ``drug referring to a different listed
drug'' in section 505(j)(2)(D)(i) of the FD&C Act. Under this
interpretation, an applicant was not permitted to amend or supplement a
505(b)(2) application to seek approval of a drug that relied on the
Agency's finding of safety and/or effectiveness for a listed drug that
was different from the listed drug(s) identified in the original
submission of the application. This approach assumed that the
difference in phrasing between section 505(b)(4)(A) and (j)(2)(D)(i) of
the FD&C Act was simply intended to reflect the different statutory
frameworks for 505(b)(2) applications and ANDAs. This interpretation
also was intended to ensure that a 505(b)(2) applicant did not
circumvent the 30-month stay provisions of the FD&C Act by amending or
supplementing a 505(b)(2) application to identify a new or additional
listed drug upon which it relied for approval.
We found our initial approach to be overly restrictive in practice,
however, as this interpretation required withdrawal and resubmission of
a 505(b)(2) application to identify a new or additional listed drug
even where there were no patents listed in the Orange Book for the new
or additional listed drug, and thus there was no possibility of a 30-
month stay.
Accordingly, we are proposing a narrower interpretation that is
guided by Congress' expressed view that these provisions are intended
to ``reflect the FDA's current practice regarding those changes and
variations to both innovator and generic drugs that may be approved
under amendments and supplements to previously filed NDAs and ANDAs . .
.'' (see Conference Report on H.R. 1, November 20, 2003, at H12099).
Our interpretation of section 505(b)(4)(A), (b)(4)(B),
(j)(2)(D)(i), and (j)(2)(D)(ii) of the FD&C Act seeks to preserve the
legislative balance of the Hatch-Waxman Amendments with respect to
facilitating the availability of drug products that meet the statutory
requirements for approval while protecting innovator intellectual
property rights (and allowing for an early resolution of any patent
infringement litigation). We seek
[[Page 6852]]
comment on this proposal and potential alternatives to maintain the
intended balance.
In the Federal Register of November 4, 2004 (69 FR 64314), FDA
announced the availability of a draft guidance for industry, issued as
required by section 505(j)(2)(D)(iii) of the FD&C Act, that defined the
term ``listed drug'' for purposes of section 505(j)(2)(D) with respect
to amendments and supplements to an ANDA (see draft guidance for
industry entitled ``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'' (October 2004), available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072887.pdf) (Draft
Guidance on Listed Drugs). In the Draft Guidance on Listed Drugs, we
advised that our definition of the term ``listed drug'' is set forth in
Sec. 314.3, and that we did not intend to amend that definition to
implement section 505(j)(2)(D) of the FD&C Act. Although minor
revisions to the definition of listed drug are proposed in this
rulemaking (see section II.A.2.s), these proposed revisions do not
substantively alter the definition for purposes of section 505(j)(2)(D)
of the FD&C Act. We note that different strengths of an approved drug
product continue to be regarded as different listed drugs. However, the
FD&C Act expressly permits an applicant to amend or supplement a
505(b)(2) application or ANDA to seek approval of a different strength
(see section 505(b)(4)(B) and (j)(2)(D)(ii) of the FD&C Act).
Table 11 summarizes the proposed changes related to amendments or
supplements to a 505(b)(2) application or ANDA:
Table 11--Highlights of Proposed Changes Regarding Amendments or
Supplements to a 505(b)(2) Application or ANDA \1\
------------------------------------------------------------------------
Current regulations Proposed revisions to regulations
------------------------------------------------------------------------
[No corresponding regulation]..... Amendments and Supplements--
Different drug (Sec. Sec.
314.60(e) and 314.70(h))
Applicant may not amend a
505(b)(2) application to seek
approval of a drug that is a
different drug from the drug in the
original submission of the
505(b)(2) application.
Applicant may not
supplement a 505(b)(2) application
to seek approval of a drug that is
a different drug from the drug in
the approved 505(b)(2) application.
For purposes of this
section, a drug is a different drug
if it has been modified to have a
different active ingredient,
different route of administration,
different dosage form, or
difference in excipients that
requires either a separate clinical
study to establish safety or
effectiveness or, for topical
products, that requires a separate
in vivo demonstration of
bioequivalence.
Approval of a different
drug must be requested in a new
505(b)(2) application.
Notwithstanding the
limitations described above, an
applicant may amend or supplement
the 505(b)(2) application to seek
approval of a different strength.
[No corresponding regulation]..... Amendments and Supplements--
Different listed drug (Sec. Sec.
314.96(c) and 314.97(b))
Applicant may not amend an
ANDA to seek approval of a drug
referring to a listed drug that is
different from the RLD identified
in the ANDA.
--Applies if, at any time before
ANDA approval, a different listed
drug approved in an NDA is
pharmaceutically equivalent to the
product in the ANDA and is
designated as an RLD.
--Applies if changes are proposed in
an amendment to the ANDA such that
the proposed product is a
pharmaceutical equivalent to a
different listed drug than the RLD
identified in the ANDA.
Applicant may not
supplement an ANDA to seek approval
of a drug referring to a listed
drug that is different from the
current RLD identified in the ANDA.
--Applies if changes are proposed in
a supplement to the ANDA such that
the proposed product is a
pharmaceutical equivalent to a
different listed drug than the RLD
identified in the ANDA.
A change of the RLD must be
submitted in a new ANDA.
Notwithstanding the
limitations described above, an
applicant may amend or supplement
the ANDA to seek approval of a
different strength.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.G.1. Amendments to an Unapproved ANDA (Proposed Sec. 314.96(c))
We are proposing to revise Sec. 314.96 regarding amendments to an
unapproved ANDA by adding paragraph (c) to implement section
505(j)(2)(D)(i) and (ii) of the FD&C Act. Proposed Sec. 314.96(c)
states that an applicant may not amend an ANDA to seek approval of a
drug referring to a listed drug that is different from the RLD
identified in the ANDA. Two examples in proposed Sec. 314.96(c)
illustrate the application of this provision.
II.G.1.a. Approval of a pharmaceutically equivalent drug product.
Proposed Sec. 314.96(c) states that if at any time before approval of
the ANDA, an NDA is approved for a drug product that is
pharmaceutically equivalent to the product in the pending ANDA and that
NDA is designated as an RLD, the applicant is not permitted to amend
its pending ANDA to reference the new RLD. This change must be
submitted in a new ANDA. As a preliminary matter, we note that the drug
product designated as an RLD may not necessarily be the drug product
identified in the Orange Book as the reference standard for
bioequivalence studies, for example, for drug product lines with
multiple strengths. An ANDA would not be ineligible for approval
because it relied upon an RLD that was not the reference standard or
because it relied upon one of two or more potential RLDs for a
pharmaceutically equivalent product. FDA's policy on designating an
additional RLD for multiple source products is set forth in the
preamble to the 1992 final rule and also described in the preface to
the Orange Book. In the 1992 final rule, we stated in relevant part:
``FDA recognizes that, for multiple source products, a product not
designated as the listed drug and not shown bioequivalent to the listed
drug may be shielded from direct generic competition. If an applicant
believes that there are sound reasons for designating another drug as a
reference listed drug, it should consult FDA'' (57 FR 17950 at 17958;
see also Letter to Robert W. Pollock, Lachman Consultant Services,
Inc., dated April 18, 2005, regarding Docket No. FDA-2004-P-0466
(requesting designation of DiaBeta as a second RLD for glyburide
tablets, 5
[[Page 6853]]
mg), available at http://www.regulations.gov).
The scenario described in proposed Sec. 314.96(c) arises, for
example, when an ANDA is submitted after the grant of a suitability
petition pursuant to section 505(j)(2)(C) of the FD&C Act for a new
dosage form, route of administration, or new active ingredient (in a
drug product containing more than one active ingredient) and another
applicant obtains approval of an NDA (including a 505(b)(2)
application) for the change described in the suitability petition
before the ANDA is approved. Under these circumstances, it is FDA's
longstanding position that an ANDA (including a tentatively approved
ANDA) can no longer reference the approved suitability petition and the
listed drug described therein as the basis for ANDA submission (see
Sec. Sec. 314.94(a)(3) and 314.127(a)(5), (a)(6), and (a)(12) and
section II.I). Prior to enactment of the MMA, an applicant with a
pending ANDA based upon an approved ``suitability petition'' (a
petitioned ANDA) could have amended its ANDA to change the basis for
submission (see Sec. 314.94(a)(3)) to a pharmaceutically equivalent
product that subsequently had been approved in an NDA and was
designated by FDA as the RLD. However, the plain language of section
505(j)(2)(D)(i) of the FD&C Act (added by the MMA) prohibits an ANDA
applicant from amending its ANDA to change the basis for submission to
a pharmaceutically equivalent product subsequently approved in an NDA.
Accordingly, for an ANDA applicant to obtain approval for a
pharmaceutically equivalent product, the applicant would be required to
submit a new ANDA that identifies the pharmaceutically equivalent
product as its basis for ANDA submission under Sec. 314.94 and meet
applicable statutory and regulatory requirements (see, generally,
discussion in the Letter from Janet Woodcock, M.D., Director, CDER, to
Mark S. Aikman, Pharm.D., Osmotica Pharmaceutical Corp., dated November
25, 2008, regarding Docket No. FDA-2008-P-0329, available at http://www.regulations.gov) (Venlafaxine ER Citizen Petition Response).
FDA's policy is scientifically justified because an NDA (either a
``stand-alone'' NDA or 505(b)(2) application) approved for the change
described in a suitability petition need not be bioequivalent to the
listed drug identified in the suitability petition. For example, a
505(b)(2) applicant may develop a different dosage form of a drug
product that is intentionally more bioavailable than a previously
approved product (see Sec. 314.54(b)). A 505(b)(2) applicant also may
have relied upon a different listed drug in support of its 505(b)(2)
application than the listed drug identified in the suitability
petition. By ensuring that an ANDA has clearly demonstrated
bioequivalence to a pharmaceutically equivalent drug product identified
as the RLD, we enhance the utility and accuracy of FDA's therapeutic
equivalence determinations. We previously have explained that ``this
approach reduces the potentially confusing proliferation of
pharmaceutically equivalent drug products that have not demonstrated
therapeutic equivalence, and ensures that ANDAs . . . will be
therapeutically equivalent and thus substitutable for the RLD''
(Venlafaxine ER Citizen Petition Response at 13).
FDA's requirement that an applicant with a pending ANDA must change
its basis for ANDA submission upon approval of an NDA for the same drug
product described in the suitability petition also is intended to
ensure that ANDA applicants do not circumvent the patent certification
requirements of section 505(j)(2)(A)(vii) and (j)(2)(A)(viii) of the
FD&C Act through the suitability petition process. Otherwise, if a
patent were listed for a drug product approved in an NDA and designated
as the RLD and a pending ANDA submitted pursuant to an approved
suitability petition were permitted to amend its application to refer
to the new RLD, even a single 30-month stay would not be available
should the NDA holder or patent owner initiate patent infringement
litigation within the statutory timeframe in response to a paragraph IV
certification for a patent listed after submission of the original ANDA
that FDA later determined to be substantially complete. In addition,
our policy appropriately protects any marketing exclusivity that has
been granted to the newly approved RLD.
The Agency has rejected the argument that a pending ANDA submitted
pursuant to an approved suitability petition may continue to reference
the listed drug identified in the suitability petition after a
pharmaceutically equivalent product has been approved in an NDA
(including a 505(b)(2) application) and is designated as the RLD (see
generally Venlafaxine ER Citizen Petition Response). This ``reflects
the Agency's judgment that considerations regarding an ANDA's limited
reliance on an approved suitability petition are outweighed by the need
for a clear determination of therapeutic equivalence for a generic drug
product and protection of intellectual property rights accorded an NDA
holder'' (Venlafaxine ER Citizen Petition Response at 9). In section
II.I, we describe our proposed revisions to Sec. 314.93(e) and (f) to
codify FDA's policy that the listed drug identified in an approved
suitability petition can no longer be the basis for submission for an
unapproved ANDA after a drug product is approved in an NDA for the
change described in the petition.
In the case of a first applicant that had been eligible for 180-day
exclusivity based on a paragraph IV certification to a patent listed in
the Orange Book for the listed drug described in the suitability
petition, we note that a new assessment of first applicant status would
begin upon submission of a new ANDA. This reflects the fact that any
ANDA that referenced the listed drug identified in the suitability
petition after approval of a pharmaceutically equivalent product could
not be approved. Further, an applicant that withdrew its ANDA would not
have lawfully maintained its paragraph IV certification and would no
longer be eligible for first applicant status.
II.G.1.b. Changes to the drug product proposed in the ANDA. The
second example in proposed Sec. 314.96(c) that illustrates the
application of this provision involves one or more changes proposed in
an amendment to an ANDA that would result in the proposed product being
a pharmaceutical equivalent to a different listed drug than the RLD
identified in the ANDA. This type of change must be submitted in a new
ANDA that identifies the pharmaceutically equivalent product as the new
RLD. In the Draft Guidance on Listed Drugs, we explained that ``[a]ll
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'' (Draft Guidance on Listed Drugs, at 3). This generally
conforms with Agency practice before passage of the MMA with respect to
certain types of changes (e.g., a change in the dosage form or a change
in the formulation that may significantly affect absorption of the
active drug ingredient or active moiety) that should be submitted as a
separate ANDA (see guidance for industry entitled ``Variations in Drug
[[Page 6854]]
Products that May Be Included in a Single ANDA'' (December 1998),
available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072892.pdf)
(Guidance on Drug Product Variations). For example, we noted
``[g]enerally, when there is a separate NDA as a RLD for a specific
drug product there should be a separate abbreviated application for
that NDA'' (Guidance on Drug Product Variations, at 2).
Proposed Sec. 314.96(c) clarifies that, notwithstanding these
restrictions on amendments to an ANDA, an applicant is permitted to
amend an ANDA to seek approval for a different strength of the drug
product (see section 505(j)(2)(D)(ii) of the FD&C Act). As discussed in
section II.A.2.bb, we interpret this exception for different strengths
of the drug product to include changes to the concentration or to the
total drug content of a parenteral drug product. We note that, unlike
original ANDAs, not all amendments are subject to a filing review by
the Office of Generic Drugs to determine whether the submission may be
formally received for substantive review. Accordingly, it is possible
that an ANDA applicant that submits an amendment not permitted by
statute may be informed late in the review process that the proposed
change to its ANDA must be submitted as a new ANDA. We encourage ANDA
applicants with questions about whether a proposed amendment to an ANDA
would be precluded by section 505(j)(2)(D)(i) of the FD&C Act to
contact the Office of Generic Drugs for further guidance.
II.G.2. Supplements to an ANDA (Proposed Sec. 314.97(b))
We are proposing to revise Sec. 314.97 regarding supplements by
designating the current text as paragraph (a) and by adding proposed
paragraph (b) to implement section 505(j)(2)(D)(i) and (ii) of the FD&C
Act. Proposed Sec. 314.97(b) explains that an applicant may not
supplement an ANDA to seek approval of a drug referring to a listed
drug that is different from the current RLD identified in the ANDA.
This restriction applies if changes are proposed in a supplement to the
ANDA that would result in the proposed product being pharmaceutically
equivalent to a different listed drug than the RLD identified in the
underlying ANDA. This type of change must be submitted in a new ANDA
that identifies the pharmaceutically equivalent product as the new RLD.
There are several types of changes that may be proposed in a
supplement to an ANDA that would result in the proposed product being
pharmaceutically equivalent to a different listed drug than the RLD
identified in the underlying ANDA. For example, the scenario described
in proposed Sec. 314.97(b) may arise if the RLD for the drug product
approved in an ANDA is subsequently changed from prescription use to
OTC status for some or all conditions of use of the drug product. An
ANDA holder for the drug product with the ``switched'' conditions of
use would be required to seek approval of the drug product for OTC use
because the FD&C Act does not permit a drug product to be marketed as
prescription and OTC for the same conditions of use at the same time
(see section 503(b) of the FD&C Act (21 U.S.C. 353(b)). However, if the
NDA holder for the RLD obtained approval of the switch from
prescription use to OTC status in a separate NDA (for example, if fewer
than all conditions of use were switched to OTC status), then the NDA
for OTC use would be considered a different RLD. Section
505(j)(2)(D)(i) of the FD&C Act does not permit an ANDA holder to refer
to a different RLD in a supplement (or, with respect to a pending ANDA,
an amendment) to its ANDA. This type of change must be submitted in a
new ANDA that identifies the different NDA for OTC use as the RLD.
We note, however, that an ANDA holder may submit a supplement that
seeks to demonstrate bioequivalence to a different listed drug when
there are multiple RLDs (see, e.g., Orange Book, 33rd Edition (2013) at
xx to xxi (Description of Special Situations--levothyroxine sodium)).
In this case, the submission of additional bioequivalence data in an
ANDA supplement is not for the purpose of seeking approval of a drug
referring to a different RLD, but rather to obtain an additional
therapeutic equivalence rating. This type of change may continue to be
submitted as a supplement to an ANDA.
Proposed Sec. 314.97(b) clarifies that, notwithstanding these
restrictions on supplements to an ANDA, an applicant is permitted to
supplement an ANDA to seek approval for a different strength of the
drug product (see section 505(j)(2)(D)(ii) of the FD&C Act). As
discussed in section II.G.1.b, we interpret this exception for
different strengths of the drug product to include changes to the
concentration or to the total drug content of a parenteral drug product
(see also section II.A.2.bb).
II.G.3. Amendments to an Unapproved 505(b)(2) Application (Proposed
Sec. 314.60(e))
We are proposing to revise Sec. 314.60 regarding amendments to an
unapproved 505(b)(2) application by adding proposed paragraph (e) to
implement section 505(b)(4)(A) and (b)(4)(B) of the FD&C Act. Proposed
Sec. 314.60(e) states that an applicant may not amend a 505(b)(2)
application to seek approval of a drug that is a different drug from
the drug in the original submission of the 505(b)(2) application. For
purposes of this section, a drug is a different drug if it has been
modified to have a different active ingredient, different route of
administration, different dosage form, or difference in excipients that
requires either a separate clinical study to establish safety or
effectiveness or, for topical products, that requires a separate in
vivo demonstration of bioequivalence.
II.G.3.a. Applications within the scope of section 505(b)(4)(A) of
the FD&C Act. Section 505(b)(4)(A) of the FD&C Act restricts certain
types of amendments and supplements to a 505(b)(2) application. We
interpret this statutory provision to apply to an NDA that was
submitted as a 505(b)(2) application and to an NDA that was submitted
as a stand-alone 505(b)(1) application but was misclassified by the
applicant. A stand-alone 505(b)(1) application would be misclassified
if, for example, the application relied, at least in part, on the
Agency's finding of safety and/or effectiveness for one or more listed
drugs or published literature. Such an NDA is considered to be a
505(b)(2) application even if the applicant failed to identify the
listed drug(s) in accordance with Sec. 314.54(a)(1)(iii) and comply
with applicable regulatory requirements. It would be inconsistent with
the statutory scheme, as amended by the MMA, to permit an applicant to
circumvent the restrictions on amendments to a 505(b)(2) application
and the potential implications for the availability of a 30-month stay
of approval pursuant to section 505(c)(3)(C) of the FD&C Act merely by
incorrectly characterizing the original submission as a stand-alone
505(b)(1) application.
We note, however, that reliance on a listed drug pursuant to
section 505(b)(2) of the FD&C Act generally assumes that the drug the
applicant is referencing is one for which it is not the application
holder and for which it would not have a right of reference or use.
Accordingly, an applicant that cross-references relevant studies in its
own previous
[[Page 6855]]
505(b)(2) application (i.e., studies that were conducted by or for the
applicant or to which the applicant has obtained a right of reference
or use) would not be a 505(b)(2) applicant as to those portions of its
previous 505(b)(2) application. However, an applicant may be relying,
in part, for approval of its current NDA upon the Agency's finding of
safety and/or effectiveness for a listed drug identified in its
previous 505(b)(2) application, to which it does not have a right of
reference or use. In this scenario, if an applicant continues to rely
upon the original listed drug for approval of its current NDA, then it
is a 505(b)(2) application and the applicant must identify the original
listed drug in accordance with Sec. 314.54 and comply with other
applicable regulatory requirements.
An applicant also may not amend a literature-based 505(b)(2)
application to seek approval of a drug that has been modified to have a
different active ingredient, different route of administration,
different dosage form, or difference in excipients that requires either
a separate clinical study to establish safety or effectiveness or, for
topical products, that requires a separate in vivo demonstration of
bioequivalence.
II.G.3.b. Proposed amendments subject to section 505(b)(4)(A) of
the FD&C Act. Proposed Sec. 314.60(e) provides that the statutory
restriction on amending a 505(b)(2) application to seek approval of a
drug that is a different drug from the drug in the original submission
of the 505(b)(2) application applies to any proposed amendment, even if
the amendment is submitted prior to the Agency's decision regarding
whether the 505(b)(2) application can be filed in accordance with Sec.
314.101(a). This standard is consistent with the MMA's amendments to
section 505(c)(3)(C) of the FD&C Act to limit the availability of a 30-
month stay of approval to patents for which the NDA holder submitted
information to FDA ``before the date on which the application
(excluding an amendment or supplement to the application) was
submitted.''
Under proposed Sec. 314.60, an applicant cannot amend a 505(b)(2)
application to seek approval for a drug that has been modified to have
a different active ingredient. This includes, but is not limited to, a
different salt, ester, or complex of the same active moiety (compare
section II.F.1.d). A change in the route of administration or dosage
form also cannot be made in an amendment to a 505(b)(2) application
unless the product is qualitatively (Q1) the same and quantitatively
(Q2) essentially the same as the proposed drug product in the original
505(b)(2) application for all routes of administration or dosage forms,
as applicable.
An applicant also cannot amend a 505(b)(2) application to seek
approval for a drug that has been modified to have a difference in
excipients that requires either a separate clinical study to establish
safety or effectiveness or, for topical products, that requires a
separate in vivo demonstration of bioequivalence (see Sec.
320.24(b)(4)). These proposed modifications would result in a different
drug for which approval must be requested in a new 505(b)(2)
application.
However, notwithstanding these restrictions on amendments to a
505(b)(2) application, an applicant is permitted to amend a 505(b)(2)
application to identify a new or additional listed drug upon which the
application relies for approval.
In addition, proposed Sec. 314.60(e) clarifies that an applicant
is permitted to amend a 505(b)(2) application to seek approval for a
different strength of the drug product (see section 505(b)(4)(B) of the
FD&C Act; see also sections II.A.2.bb and II.G.1.b of this document).
II.G.4. Supplements to a 505(b)(2) Application (Proposed Sec.
314.70(h))
We are proposing to revise Sec. 314.70 regarding supplements to an
approved 505(b)(2) application by adding proposed paragraph (h) to
implement section 505(b)(4)(A) and (b)(4)(B) of the FD&C Act. Proposed
Sec. 314.70(h) states that an applicant may not supplement a 505(b)(2)
application to seek approval of a drug that is a different drug from
the drug in the original submission of the 505(b)(2) application. For
purposes of this section, a drug is a different drug if it has been
modified to have a different active ingredient, different route of
administration, different dosage form, or difference in excipients that
requires either a separate clinical study to establish safety or
effectiveness or, for topical products, that requires a separate in
vivo demonstration of bioequivalence (see discussion in section
II.G.3.b). These proposed modifications would result in a different
drug for which approval must be requested in a new 505(b)(2)
application.
In addition, proposed Sec. 314.70(h) clarifies that,
notwithstanding these restrictions on supplements to a 505(b)(2)
application, an applicant is permitted to supplement a 505(b)(2)
application to seek approval for a different strength of the drug
product (see section 505(b)(4)(B) of the FD&C Act; see also sections
II.A.2.bb and II.G.1.b of this document).
We interpret section 505(b)(4)(A) of the FD&C Act to apply to the
submission of a 505(b)(2) supplement to an NDA approved through the
505(b)(2) pathway, irrespective of whether the original 505(b)(2)
application relied upon published literature or the Agency's finding of
safety and/or effectiveness for one or more listed drugs. However,
because the statutory text expressly applies to a supplement to a
505(b)(2) application, we do not interpret the restriction in section
505(b)(4)(A) to apply to a 505(b)(2) supplement to an NDA that received
approval as a stand-alone 505(b)(1) application unless an intervening
505(b)(2) supplement has been approved for that NDA (see Sec. 314.3(b)
(defining the term ``application'' to include all supplements to the
application)).
II.H. Procedure for Submission of an Application Requiring
Investigations for Approval of a New Indication for, or Other Change
From, a Listed Drug (Proposed Sec. 314.54)
We are proposing to revise Sec. Sec. 314.50(i), 314.54(a), and
314.125(b) to establish the requirement that an applicant identify a
pharmaceutically equivalent product, if already approved, as a listed
drug relied upon to support approval of a 505(b)(2) application.
FDA's longstanding policy has been that a 505(b)(2) applicant may
rely on FDA's finding of safety and/or effectiveness for a listed drug
only to the extent that the proposed product in the 505(b)(2)
application shares characteristics (e.g., active ingredient, dosage
form, route of administration, strength, indication, conditions of use)
in common with the listed drug. To the extent that the listed drug and
the drug proposed in the 505(b)(2) application differ, the 505(b)(2)
application must include sufficient data to demonstrate that the
proposed drug meets the statutory approval standard for safety and
effectiveness. The 505(b)(2) approval pathway is not intended for a
``duplicate'' of a listed drug that is eligible for approval in an
ANDA, and FDA would refuse to file such a 505(b)(2) application (see
Sec. 314.101(d)(9)). The Hatch-Waxman Amendments established a
specific abbreviated approval pathway for duplicates of a listed drug
in section 505(j) of the FD&C Act.
However, there are circumstances in which a proposed drug product
that is pharmaceutically equivalent to a listed drug (i.e., drug
products in the same dosage form and route(s) of
[[Page 6856]]
administration that contain the same amount of the same active drug
ingredient and that meet other applicable standards) is not eligible
for approval as an ANDA and must be submitted as an NDA. For example, a
proposed extended-release drug product may intentionally differ in its
pharmacokinetic profile from a listed drug that is also an extended-
release drug product such that the proposed product cannot meet the
bioequivalence requirement for ANDAs (see section 505(j)(2)(A)(iv) of
the FD&C Act; compare Sec. 314.54(b)). Certain drug products intended
for parenteral, ophthalmic, otic, or topical use may contain
differences in excipients that render the drug product ineligible for
submission in an ANDA (see Sec. 314.94(a)(9)(iii) to (a)(9)(v)). For
certain complex drug products, an applicant may be unable to
demonstrate ``sameness'' of the active ingredient as required for
submission of an ANDA (see section 505(j)(2)(A)(ii) of the FD&C Act). A
request for approval of a new indication for a pharmaceutically
equivalent drug product also is ineligible for submission as an ANDA.
These changes to a listed drug must be submitted in an NDA.
We have explained that a 505(b)(2) applicant may rely on FDA's
finding of safety and effectiveness for a listed drug ``only to the
extent that such reliance would be allowed under section 505(j) of the
act'' (1989 proposed rule, 54 FR 28872 at 28892). If a pharmaceutically
equivalent drug product has been approved before a 505(b)(2)
application is submitted, then we consider the 505(b)(2) applicant to
be implicitly relying on the approval of such drug product. We are
proposing to revise Sec. 314.54(a)(1)(iii) to require that the listed
drug or drugs identified as relied upon by a 505(b)(2) applicant must
include any approved drug product that: (1) Is pharmaceutically
equivalent to the drug product for which the 505(b)(2) application is
submitted and (2) was approved before the 505(b)(2) application was
submitted. This requirement is intended to help ensure that the
505(b)(2) pathway is not used to circumvent the statutory obligation
that would have applied if the proposed product was submitted as an
ANDA--namely, submission of a patent certification for a listed patent
that corresponds to the protected aspects of the pharmaceutically
equivalent listed drug (see draft guidance for industry entitled
``Applications Covered by Section 505(b)(2)'' (October 1999), available
at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079345.pdf) (``If
there is a listed drug that is the pharmaceutical equivalent of the
drug proposed in the 505(b)(2) application, the 505(b)(2) applicant
should provide patent certifications for the patents listed for the
pharmaceutically equivalent drug''). Clarifying revisions in proposed
Sec. 314.54(a)(1)(iii) and (a)(1)(vi) replace the reference to ``other
drugs'' with ``listed drug'' to conform with our longstanding policy
that an applicant may rely upon more than one listed drug to support
approval of a 505(b)(2) application. In addition, we are proposing to
replace the term ``reference listed drug'' in Sec. 314.54(b) with
``listed drug'' because the descriptor ``reference listed drug'' is a
term of art that applies to an ANDA. A 505(b)(2) application may rely
on FDA's finding of safety and/or effectiveness for one or more listed
drugs.
We also are proposing to add Sec. 314.50(i)(1)(i)(C) to require
that if, before the date of submission of the 505(b)(2) application,
there is an approved drug product that is pharmaceutically equivalent
to the drug product for which the 505(b)(2) application is submitted,
the applicant must submit an appropriate patent certification under
Sec. 314.50(i) with respect to each patent listed for the
pharmaceutically equivalent product that claims the drug substance or
drug product or that claims an approved use for such drug.
We are proposing a conforming revision to Sec. 314.125(b) to state
that we may refuse to approve a 505(b)(2) application based on the
applicant's failure to submit an appropriate patent certification or
statement with respect to each listed patent for a drug product that:
(1) Is pharmaceutically equivalent to the drug product for which the
505(b)(2) application is submitted and (2) was approved before the
505(b)(2) application was submitted. If FDA approves a pharmaceutically
equivalent product within the 60-day filing review period after a
505(b)(2) application is submitted, the 505(b)(2) applicant is not
required to identify the product as a listed drug relied upon or submit
a patent certification under Sec. 314.50(i) and FDA would not refuse
to file the application under Sec. 314.101(d)(9) based on the new
approval.
It also should be noted that the requirement to identify a
pharmaceutically equivalent product as a listed drug relied upon (and
to submit an appropriate patent certification or statement with respect
to each listed patent) does not apply if a pharmaceutically equivalent
product is approved while the 505(b)(2) application is pending.
We intend to promptly publish on FDA's Web site information
regarding the approval of new drug products to facilitate, among other
things, a 505(b)(2) applicant's compliance with proposed Sec.
314.54(a)(1)(iii) and (a)(1)(vi) and Sec. 314.50(i)(1)(i)(C).
II.I. Petition To Request a Change From a Listed Drug (Proposed Sec.
314.93)
We are proposing to amend Sec. 314.93 regarding petitioned ANDAs
to codify FDA's policy that the listed drug identified in an approved
suitability petition can no longer be the basis for submission for an
unapproved ANDA after a drug product is approved in an NDA for the
change described in the petition (see generally Venlafaxine ER Citizen
Petition Response). This proposed revision is intended to facilitate
implementation of section 505(j)(2)(D)(i) and (ii) of the FD&C Act and
complement proposed revisions to Sec. 314.96(c) regarding amendments
to an unapproved ANDA (see section II.F.1.a).
We are proposing to revise Sec. 314.93(f) regarding withdrawal of
approval of a suitability petition by redesignating the current text as
paragraph (f)(1) and by adding paragraph (f)(2). Proposed Sec.
314.93(f)(2) clarifies that if, after approval of a petition and before
approval of an ANDA submitted pursuant to the approved petition, a drug
product is approved in an NDA for the change described in the petition,
the petition and the listed drug identified in the petition can no
longer be the basis for ANDA submission, irrespective of whether FDA
has withdrawn approval of the petition. Because an ANDA applicant may
not amend its ANDA to change the basis for submission to the new RLD
(see section 505(j)(2)(D)(i) of the FD&C Act), a person seeking
approval for such drug product would be required to submit a new ANDA
that identifies the pharmaceutically equivalent RLD as the basis for
ANDA submission and comply with applicable statutory and regulatory
requirements.
We also are proposing to add Sec. 314.93(e)(1)(vi) to codify our
longstanding policy that FDA will not approve a suitability petition if
a drug product is approved in an NDA for the change described in the
petition. The suitability petition process is intended for a proposed
``drug product which is not identical to a listed drug in route of
administration, dosage form, and strength, or in which one active
ingredient is substituted for one of the active ingredients in a listed
combination drug'' (Sec. 314.93(b)). If a pharmaceutically equivalent
drug
[[Page 6857]]
product has been approved in an NDA, the ANDA applicant should refer to
the approved pharmaceutical equivalent designated by the Agency as the
RLD as its basis for ANDA submission. Throughout the pendency of review
of the ANDA, applicants should confirm that an NDA has not been
approved for the drug product described in the suitability petition.
Although FDA currently has the authority to withdraw approval of a
suitability petition after a drug product is approved in an NDA for the
change described in the petition, we note that it has been the Agency's
practice not to rescind approval of the petition under these
circumstances due to the administrative burden. We previously have
explained: ``we need not withdraw approval of the suitability petition
to implement our long-standing practice that the intervening approval
of an NDA for the product described by the suitability petition
precludes an ANDA applicant from referring to the suitability petition
and listed drug described therein as its basis for ANDA submission. Any
pending ANDA that referred to the suitability petition and the listed
drug described therein would not be eligible for approval, and any
newly submitted ANDA that sought to reference the suitability petition
instead of the RLD identified in the Orange Book would not be received
by the Agency'' (Venlafaxine ER Citizen Petition Response at 25). To
ensure that our regulations consistently reflect this policy, we are
proposing to add Sec. 314.127(a)(14) to state that FDA will refuse to
approve a petitioned ANDA if an NDA subsequently has been approved for
the change described in the suitability petition.
II.J. Filing an NDA and Receiving an ANDA (Proposed Sec. 314.101)
II.J.1. Notification of Filing of a 505(b)(2) Application or Receipt of
an ANDA
We are proposing to amend Sec. 314.101, with respect to 505(b)(2)
applications and ANDAs that contain a paragraph IV certification, to
facilitate implementation of the MMA's timing requirements for sending
notice of a paragraph IV certification and for efficient enforcement of
the FD&C Act.
Section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act
require a 505(b)(2) or ANDA applicant, respectively, to send notice of
a paragraph IV certification within 20 days after the date of the
postmark on the notice with which FDA informs the applicant that the
505(b)(2) application has been filed or the ANDA has been received (see
section II.D.1). Our proposed revisions to Sec. 314.101(a)(2) and
(b)(2) clarify that FDA will notify the applicant that the 505(b)(2)
application is regarded as filed or the ANDA is regarded as received,
respectively, by means of an acknowledgment letter or a paragraph IV
acknowledgment letter (see also section II.A.2.c and II.A.2.u).
We are proposing to revise Sec. 314.101(b)(1) and (b)(2) regarding
ANDAs to incorporate the statutory definition of a ``substantially
complete application,'' which was added by the MMA for purposes of
section 505(j)(5) of the FD&C Act (see section 505(j)(5)(B)(iv)(II)(cc)
of the FD&C Act and section II.A.2.cc of this document). Proposed Sec.
314.101(b)(1) states that receipt of an ANDA means that FDA has made a
threshold determination that the ANDA is substantially complete. We
also are proposing to revise proposed Sec. 314.101(b)(2) to clarify
that if an ANDA is determined to have been substantially complete as of
the date on which it was submitted, the date of submission is
considered to be the date of receipt. As noted in section II.A.2.cc,
our proposed replacement of the current standard ``sufficiently
complete to permit a substantive review'' with the phrase
``substantially complete application'' is not intended to alter the
meaning. Rather, we are seeking to consistently use defined terms
throughout our regulations.
We are proposing to amend Sec. 314.101(b)(3) to remove the method
of notification by which FDA will advise an ANDA applicant that FDA has
refused to receive the ANDA under Sec. 314.101(d) or (e). The
regulations currently state that FDA will ordinarily notify an ANDA
applicant by telephone; however, this does not accurately describe
FDA's current practice to inform the ANDA applicant in writing by
issuing a ``refuse to receive'' letter.
In proposed Sec. 314.101(b)(4), we establish an administrative
consequence for an ANDA applicant that fails to timely provide notice
of a paragraph IV certification as required by section 505(j)(2)(B)(ii)
of the FD&C Act and Sec. 314.95(b) and (d). If FDA determines that an
ANDA applicant did not send notice of a paragraph IV certification
within the timeframe described in Sec. 314.95(b) or (d), as
applicable, FDA will deem the date that the ANDA was submitted to be
delayed by the number of days by which the timeframe for sending notice
of a paragraph IV certification was exceeded. As discussed in section
II.D.5, an ANDA applicant that fails to provide timely notice of a
paragraph IV certification may, based upon the revised date on which
the ANDA was determined to have been received, lose its first applicant
status and thus its eligibility for 180-day exclusivity. In addition,
such an ANDA may be repositioned in the review queue consistent with
the revised date of ANDA submission.
II.J.2. Other Proposed Revisions
We are proposing several clarifying revisions to Sec. 314.101.
First, we are proposing to delete the reference to section 507 of the
FD&C Act in Sec. 314.101(d)(3). As discussed in section II.A.2.b,
FDAMA repealed section 507 of the FD&C Act under which marketing
applications, including abbreviated applications, for antibiotics had
been approved (see section 125 of FDAMA). Section 125(d) of FDAMA
provided that abbreviated applications for antibiotics previously
approved under section 507 of the FD&C Act would be deemed approved
under section 505(j) of the FD&C Act.
Second, we are proposing to replace the term ``application'' in
Sec. 314.101(d)(6) and (d)(7) with ``NDA and ANDA'' to clarify that
these provisions apply to ANDAs as well as NDAs. As discussed in
section II.A.2.b and II.A.2.i, we have proposed to incorporate the
commonly used acronyms NDA and ANDA in place of the terms application
and abbreviated application, as appropriate, throughout the sections of
part 314 and part 320 in this rulemaking. Proposed Sec. 314.101(d)(6)
states that FDA may refuse to file an NDA or may not consider an ANDA
to be received if the NDA or ANDA does not contain a statement for each
nonclinical laboratory study regarding compliance with the requirements
of part 58 of this chapter. This criterion is applicable to ANDAs as
well as NDAs. Nonclinical studies submitted in an ANDA may include, but
are not limited to, dissolution studies and ``dose-dumping'' studies.
Proposed Sec. 314.101(d)(7) provides that FDA may refuse to file an
NDA or may not consider an ANDA to be received if the NDA or ANDA does
not contain a statement for each clinical study regarding whether it
was conducted in compliance with the regulations in part 50 and part 56
of this chapter. Clinical studies submitted in an ANDA which may be
subject to the regulations in part 50 and part 56 of this chapter
include, for example, comparative clinical trials conducted for the
purpose of demonstrating bioequivalence (see Sec. 320.24(b)(4); see
also Sec. 314.94(a)(7)(iii)).
Third, we are proposing to replace the current text of Sec.
314.101(e)(2) with a
[[Page 6858]]
statement that FDA will refuse to file a 505(b)(2) application or will
consider an ANDA not to have been received if submission of a 505(b)(2)
application or an ANDA for the active moiety is not permitted under
Sec. 314.108(b)(2). This is not a substantive revision, as Sec.
314.108(b)(2) describes the conditions set forth in current Sec.
314.101(e)(2)(i) and (e)(2)(ii).
We also propose to add headings to certain paragraphs for
administrative convenience.
II.K. Approval of an NDA and ANDA (Proposed Sec. 314.105)
We are proposing to revise Sec. 314.105(a) and (d) regarding
approval of an NDA (including a 505(b)(2) application) and an ANDA to
remove the references to a ``delayed effective date'' and clarify that
an application is approved on the date of issuance of an approval
letter. These proposed revisions reflect current FDA practice and
policy with respect to approval letters. The Agency does not issue
approval letters with delayed effective dates. Rather, the Agency will
issue a tentative approval letter when an NDA or ANDA that is otherwise
eligible for approval cannot be approved due to unexpired patents,
certain circumstances related to patent litigation (see Sec.
314.107(b)(3) and (e)(1)(vi)), or various types of exclusivity (see
proposed Sec. 314.107(b)(1)(iii), (c) and (d)). ``Tentative approval''
is defined in proposed Sec. 314.3. We also have made conforming
revisions throughout this proposed rulemaking to replace references to
the ``effective date'' of an application with language reflecting our
current practice.
A drug product granted tentative approval is not an approved drug.
Prior to obtaining approval of a 505(b)(2) application or ANDA, the
applicant may be requested to submit updated labeling; chemistry,
manufacturing, and controls (CMC) data; a safety update; and any other
information necessary to ensure that the 505(b)(2) application or ANDA
meets the statutory and regulatory requirements for approval. For a
505(b)(2) application or ANDA to be approved, the applicant must
receive an approval letter from FDA (see proposed Sec. 314.107(b)(4)).
We note that an applicant with a tentatively approved 505(b)(2)
application or ANDA has a continuing obligation to amend its patent
certification or statement if, at any time before approval of the
505(b)(2) application or ANDA, the submitted certification is no longer
accurate (see proposed Sec. Sec. 314.50(i)(6) and
314.94(a)(12)(viii)). In the context of a tentatively approved
application, this obligation may apply, for example, if the NDA holder
for the listed drug relied upon or RLD timely submits new patent
information for a patent that claims the drug substance, drug product,
or a method of use after the 505(b)(2) application or ANDA has been
tentatively approved. In this scenario, the 505(b)(2) or ANDA applicant
would be required to submit an amendment to its tentatively approved
application with an appropriate patent certification or statement
regarding the newly listed patent.
The applicant with a tentatively approved application also may need
to update the draft product labeling to incorporate relevant revisions
to the labeling of the listed drug relied upon or RLD made after the
tentative approval of the 505(b)(2) application or ANDA, respectively.
This caveat is particularly relevant for an ANDA, which is required by
statute to have, among other things, the same labeling and conditions
of use as the RLD (see section 505(j)(2)(A)(i) and (j)(2)(A)(v) of the
FD&C Act; compare section 505(j)(10) of the FD&C Act), unless the ANDA
applicant is not seeking approval for an indication or other aspect of
labeling protected by patent or accorded exclusivity under section
505(j)(4)(D) of the FD&C Act (see Sec. 314.94(a)(8)(iv); see also
section 505(j)(2)(A)(viii) of the FD&C Act). In addition, a tentatively
approved ANDA for a drug product intended for parenteral, ophthalmic,
otic, or topical use that is required to contain the same inactive
ingredients in the same concentration as the RLD, subject to exceptions
specified in Sec. 314.94(a)(9)(iii) through (a)(9)(v), may be required
to modify its drug product and amend its ANDA to address certain
changes in the formulation of the RLD subsequent to tentative approval
unless FDA has made a determination that the RLD was not withdrawn from
sale for reasons of safety or effectiveness (see Sec. Sec. 314.122 and
314.161; see also discussion in section II.L).
In addition, we are proposing to revise Sec. 314.105(a) and (d) to
expressly state that FDA's tentative approval of a drug product is
based on information available to FDA at the time of the tentative
approval letter (i.e., information in the 505(b)(2) application or ANDA
and the status of current good manufacturing practices of the
facilities used in the manufacturing and testing of the drug product)
and is therefore subject to change on the basis of new information that
may come to FDA's attention.
Finally, it should be noted that a tentatively approved application
is subject to any applicable period of marketing exclusivity granted to
the listed drug relied upon (for a 505(b)(2) application) or RLD (for
an ANDA) after tentative approval. For example, approval of a
tentatively approved application may be delayed by the intervening
grant, pursuant to section 505A of the FD&C Act, of a period of
pediatric exclusivity to the NDA holder for the listed drug relied upon
or RLD after tentative approval of the 505(b)(2) application or ANDA,
respectively (see, e.g., Barr Labs., Inc. v. Thompson, 238 F. Supp. 2d
236 (D.D.C. 2002) (upholding FDA's determination that a 6-month period
of pediatric exclusivity that had attached to a listed patent for which
a paragraph III certification had been submitted applied to a
tentatively approved application)).
II.L. Refusal to Approve an NDA or ANDA (Proposed Sec. Sec. 314.125
and 314.127 and Related Provisions in Proposed Sec. Sec. 314.90 and
314.99)
We are proposing to revise Sec. Sec. 314.90 and 314.99 to clarify
the effect of FDA's grant of an applicant's request for waiver of a
requirement under Sec. Sec. 314.50 through 314.81 or Sec. Sec. 314.92
through 314.99, respectively. If FDA grants such a request, the
applicant's failure to comply with the requirement that is the subject
of the waiver request will not constitute a basis for refusal to
approve the NDA under Sec. 314.125 or the ANDA under Sec. 314.127, as
applicable. We also are proposing corresponding revisions to Sec. Sec.
314.125(b) and 314.127(a), which address permissive refusal to approve
an NDA and mandatory refusal to approve an ANDA, respectively. Proposed
Sec. 314.125(b) states that FDA may refuse to approve an NDA for any
of the following reasons listed, unless the requirement has been waived
pursuant to Sec. 314.90. Proposed Sec. 314.127(a) states that FDA
will refuse to approve an ANDA for a new drug under section 505(j) of
the FD&C Act for any of the following reasons listed, unless the
requirement has been waived pursuant to Sec. 314.99.
Sections 314.90 and 314.99 currently provide that an NDA or ANDA
applicant may ask FDA to waive any requirement that applies to the
applicant under Sec. Sec. 314.50 through 314.81 or Sec. Sec. 314.92
through 314.99, respectively. FDA has interpreted its waiver of a
submission requirement under these provisions to carry with it the
implicit waiver of any corresponding approval requirement under
Sec. Sec. 314.125 or 314.127. Otherwise, the waiver of a submission
requirement for an NDA or ANDA would be meaningless if there was a
parallel
[[Page 6859]]
requirement under Sec. Sec. 314.125 or 314.127, respectively, for
approval of the application.
The proposed revisions to Sec. Sec. 314.90 and 314.99, and
corresponding proposed revisions to proposed Sec. Sec. 314.125 and
314.127, codify FDA's approach to this issue. For example, FDA has
relied on Sec. 314.99(b) to grant a waiver of the requirement that the
formulation of a drug product intended for parenteral use contain the
same inactive ingredients in the same concentration as the RLD, with
limited exceptions for preservatives, buffers, and antioxidants, where
the formulation proposed by the ANDA applicant had previously been
approved by FDA as safe and effective. We note that FDA may not waive a
statutory requirement (see 1989 Proposed Rule, 54 FR 28872 at 28889).
II.M. Date of Approval of a 505(b)(2) Application or ANDA (Proposed
Sec. 314.107)
Section 314.107 establishes the earliest date on which a 505(b)(2)
application or ANDA may be approved in light of the statutory
provisions that can delay the approval of an application that is
otherwise eligible for approval. Approval of a 505(b)(2) application or
ANDA can be delayed by the marketing exclusivity granted to another
drug product under section 505(c)(3)(E) and (j)(5)(F) of the FD&C Act
(and, with respect to ANDAs, section 505(j)(5)(B)(iv) of the FD&C Act
for 180-day exclusivity) or pediatric exclusivity under section 505A of
the FD&C Act that may attach to a patent listed for a drug product.
Approval of a 505(b)(2) application or ANDA also can be delayed by a
30-month stay of approval should the NDA holder or patent owner
initiate patent infringement litigation within the statutory timeframe
in response to notice of a paragraph IV certification (see section
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). The MMA amended the
FD&C Act to alter the circumstances under which a 30-month stay of
approval can arise. The MMA also amended the FD&C Act to specify the
types of court actions that will terminate a 30-month stay of approval.
In addition, approval of a 505(b)(2) application or ANDA can be delayed
by a court order pursuant to 35 U.S.C. 271(e)(4)(A) ordering that the
application may be approved no earlier than the date specified
(irrespective of whether the injunction relates to a patent described
in Sec. 314.107(b)(3) (see proposed Sec. 314.107(b)(4) and
(e)(1)(vi)).
Table 12 summarizes the proposed changes related to the effect of
patent(s) on the listed drug with respect to the date of approval of a
505(b)(2) application or ANDA.
Table 12--Highlights of Proposed Changes Regarding the Effect of
Patent(s) on the Listed Drug \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Effect of patent on the listed drug (Sec. Effect of patent(s) on the
314.107(b)) listed drug (Sec.
314.107(b))
Introduction to criteria for Introduction to
determining date on which approval of a criteria that must be used
505(b)(2) application or ANDA will become to determine, for each
effective. relevant patent, the date
that patent will no longer
prevent approval.
The first possible
date of approval will be
calculated for each patent,
and the 505(b)(2)
application or ANDA may be
approved on the last
applicable date.
Multiple certifications (Sec.
314.107(b)(4))
If the applicant has submitted
certifications for more than one patent,
the date of approval will be calculated
for each certification, and the approval
will become effective on the last
applicable date.
Date of approval letter (Sec. Timing of approval based on
314.107(b)(1)) patent certification or
statement (Sec.
314.107(b)(1))
Except as provided in Sec. If none of the
314.107(b)(3), (b)(4), and (c), approval reasons in Sec. 314.125
will become effective on the date FDA or Sec. 314.127 for
issues an approval letter if the refusing to approve the
applicant certifies that: application apply, and none
(i) there are no relevant patents; or of the reasons in Sec.
(ii) the patent information has not been 314.107(d) for delaying
submitted to FDA; or approval apply, the
(iii) the relevant patent has expired; or 505(b)(2) application or
(iv) the relevant patent is invalid, ANDA may be approved--
unenforceable, or will not be infringed. (i) Immediately, if the
applicant certifies that:
(A) the patent information
has not been submitted to
FDA; or
(B) the relevant patent has
expired; or
(C) the relevant patent is
invalid, unenforceable, or
will not be infringed,
except as provided in Sec.
314.107(b)(3) and (c), and
the 45-day period provided
for in section 505(c)(3)(C)
and 505(j)(5)(B)(iii) of
the FD&C Act has expired;
or
(D) there are no relevant
patents.
(ii) Immediately, if the
applicant submits an
appropriate statement
explaining that a method-
of-use patent does not
claim an indication or
other condition of use
for which it is seeking
approval.
Patent expiration (Sec. 314.107(b)(2)) Timing of approval based on
patent certification or
statement (Sec.
314.107(b)(1)(iii))
If the applicant certifies that If the applicant
the relevant patent will expire on a certifies that the relevant
specified date (paragraph III patent will expire on a
certification), approval will become specified date (paragraph
effective on the specified date. III certification), a
505(b)(2) application or
ANDA otherwise eligible for
approval may be approved on
the specified date.
[No corresponding regulation] Patent information filed
after submission of
505(b)(2) application or
ANDA (Sec. 314.107(b)(2))
If an NDA holder
submits patent information
for a listed drug after the
date on which a 505(b)(2)
application or ANDA relying
on such drug was submitted
to FDA, the 505(b)(2) or
ANDA applicant must submit
an amended patent
certification or statement
in accordance with Sec.
Sec. 314.50(i)(4) and
(i)(6) and
314.94(a)(12)(vi) and
(a)(12)(viii).
[[Page 6860]]
If the applicant
submits a paragraph IV
certification to the newly-
listed patent information
and complies with the
notice requirements of Sec.
314.52 or Sec. 314.95,
the 505(b)(2) application
or ANDA may be approved
immediately upon submission
of documentation of receipt
of notice of paragraph IV
certification.
The 45-day period
provided for in section
505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C
Act does not apply.
Disposition of patent litigation (Sec. Disposition of patent
314.107(b)(3)(i)) litigation (Sec.
314.107(b)(3)(i))
(A) Except as provided in Sec. (A) Except as
314.107(b)(3)(ii) through (b)(3)(iv), if provided in Sec.
--applicant submits a paragraph IV 314.107(b)(3)(ii) through
certification; and (b)(3)(viii), if, with
--patent owner or its representative or respect to patents for
the exclusive patent licensee brings suit which required information
for patent infringement within 45 days of was submitted before the
receipt by the patent owner of the notice date on which the 505(b)(2)
of paragraph IV certification, application or ANDA was
submitted to FDA (excluding
an amendment or
supplement),
--applicant submits a
paragraph IV certification;
and
Approval may be made effective 30 months --patent owner or the
after the date of the receipt of the exclusive patent licensee
notice of paragraph IV certification by brings suit for patent
the patent owner or by the exclusive infringement within 45 days
licensee (or their representatives) of receipt of the notice of
unless the court has extended or reduced paragraph IV certification,
the period; or 505(b)(2) application, or
(B) If the patented drug product ANDA may be approved 30
qualifies for 5-year exclusivity, and months after the later of
the date of the receipt of
the notice of certification
by any owner of the listed
patent or by the NDA holder
who is an exclusive patent
licensee (or their
representatives) unless the
court has extended or
reduced the period; or
(B) If the patented
drug product qualifies for
5-year exclusivity, and--
patent owner or its
representative or the
exclusive patent licensee
brings suit for patent
infringement during the 1-
year period beginning 4
years after the date the
patented drug was approved
and within 45 days of
receipt by the patent owner
of the notice of paragraph
IV certification,
Approval may be made
effective at the expiration
of 7\1/2\ years from the
date of NDA approval for
the patented drug product.
--patent owner or its
representative or the
exclusive patent licensee
brings suit for patent
infringement during the 1-
year period beginning 4
years after the date the
patented drug was approved
and within 45 days of
receipt of the notice of
paragraph IV certification,
the 505(b)(2) application or
ANDA may be approved at the
expiration of 7\1/2\ years
from the date of NDA
approval for the patented
drug product.
Disposition of patent litigation (Sec. Disposition of patent
314.107(b)(3)(ii)-(b)(3)(iv)) litigation (Sec.
314.107(b)(3)(ii)-(b)(3)(vi
ii)
If before the expiration of the 30-month If before the expiration of
period, or 7\1/2\ years where applicable: the 30-month period, or 7\1/
2\ years where applicable:
(ii) the court issues a final (ii) the district
order that the patent is invalid, court decides that the
unenforceable, or not infringed, patent is invalid,
approval may be made effective on: unenforceable, or not
--the date the court enters judgment; infringed (including any
(iii) the court issues a substantive determination
final order or judgment that the that there is no cause of
patent has been infringed, approval action for patent
may be made effective on: infringement or
--the date the court determines that invalidity), the 505(b)(2)
the patent will expire or otherwise application or ANDA may be
orders approved on:
(iv) the court grants a --(A) the date on which the
preliminary injunction prohibiting court enters judgment
the applicant from engaging in the reflecting the decision; or
commercial manufacture or sale of the --(B) the date of a
drug product until the court decides settlement order or consent
the issues of patent validity and decree signed and entered
infringement, and if the court later by the court stating that
decides that the patent is invalid, the patent that is the
unenforceable, or not infringed, subject of the
approval may be made effective on: certification is invalid or
--the date the court enters a final not infringed.
order or judgment that the patent is (iii) the district
invalid, unenforceable, or not court decides that the
infringed. patent has been infringed
and the judgment is
appealed, the 505(b)(2)
application or ANDA may be
approved on:
--(A) the date on which the
mandate is issued by the
court of appeals entering
judgment that the patent is
invalid or not infringed;
or
--(B) the date of a
settlement order or consent
decree signed and entered
by the court of appeals
stating that the patent is
invalid or not infringed.
(iv) the
district court decides
that the patent has been
infringed and the
judgment is not appealed
or is affirmed, the
505(b)(2) application or
ANDA may be approved no
earlier than the date
specified by the
district court in an
order under 35 U.S.C.
271(e)(4)(A).
(v) the district
court grants a
preliminary injunction
prohibiting the
applicant from engaging
in the commercial
manufacture or sale of
the drug product until
the court decides the
issues of patent
validity and
infringement:
-- if the court later
decides the patent is
invalid,
unenforceable, or not
infringed, the
505(b)(2) application
or ANDA may be
approved per Sec.
314.107(b)(3)(ii).
[[Page 6861]]
--if the court decides
that the patent has
been infringed, the
505(b)(2) application
or ANDA may be
approved per Sec.
314.107(b)(3)(iii) or
(b)(3)(iv), as
applicable.
(vi) the patent
owner or the exclusive
patent licensee (or
their representatives)
agrees in writing that
the 505(b)(2)
application or ANDA may
be approved any time on
or after the date of the
consent, approval may be
granted on or after that
date.
(vii) the court
enters an order
requiring the 30-month
or 7\1/2\-year period to
be terminated, the
505(b)(2) application or
ANDA may be approved in
accordance with the
court's order.
(viii) the court
enters an order of
dismissal, with or
without prejudice,
without a finding of
infringement, the
505(b)(2) application or
ANDA may be approved on
or after the date of the
order.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
II.M.1. General (Proposed Sec. 314.107(a))
We are not proposing any substantive revisions to Sec. 314.107(a).
As noted in section II.A.2.dd and II.I, we are proposing to amend
references to the ``effective date of approval'' and the date the
approval of a 505(b)(2) application or ANDA ``becomes effective'' to
simply refer to the date the 505(b)(2) application or ANDA ``is
approved.'' The current text incorrectly suggests that FDA might issue
an approval letter that would become effective at some date in the
future. The proposed revision clarifies that a 505(b)(2) application or
ANDA is not approved until the date the Agency issues its approval
letter.
II.M.2. Effect of Patent(s) on the Listed Drug (Proposed Sec.
314.107(b))
We are proposing to revise the introduction to proposed Sec.
314.107(b) to clarify that an analysis is required for each relevant
patent to determine the effect of one or more patents listed for the
listed drug(s) relied upon or the RLD on the date of approval of a
505(b)(2) application or ANDA, respectively. For each relevant patent,
the patent certification or statement submitted by the 505(b)(2) or
ANDA applicant is reviewed to determine the first possible date of
approval based upon each patent. The 505(b)(2) application or ANDA may
be approved on the last applicable date for all relevant patents. This
approach to the evaluation of multiple patent certifications is
described in current Sec. 314.107(b)(4), which is proposed for
deletion because the substance of that paragraph is in proposed Sec.
314.107(b).
II.M.2.a. Timing of approval based on patent certification or
statement (proposed Sec. 314.107(b)(1)). We are proposing to amend
Sec. 314.107(b)(1) to describe, in a more comprehensive manner, the
timing of approval of a 505(b)(2) application or ANDA based on the
patent certification(s) or statement(s) submitted by the 505(b)(2) or
ANDA applicant. As explained in proposed Sec. 314.107(b)(1), the
timing of approval based on an analysis of an applicant's patent
certification(s) or statement(s) is directed to a 505(b)(2) application
or ANDA that is otherwise eligible for approval. A 505(b)(2)
application or ANDA is otherwise eligible for approval if none of the
reasons in Sec. 314.125 or Sec. 314.127 for refusing to approve the
505(b)(2) application or ANDA applies, and if no delay is required by
the exclusivity provisions of Sec. 314.108, Sec. 316.31, or section
505A of the FD&C Act (see section II.I).
In proposed Sec. 314.107(b)(1)(i) and (b)(1)(ii), we describe the
types of patent certifications or statements that would result in an
immediate first possible date of approval of a 505(b)(2) application or
ANDA that is otherwise eligible for approval. Proposed Sec.
314.107(b)(1)(i) reflects a reorganization of the current regulation
and not a substantive revision. Current Sec. 314.107(b)(i) through
(b)(iv) are redesignated as proposed Sec. 314.107(b)(1)(i)(A) through
(b)(1)(i)(D). We have proposed to move the phrase ``except as provided
in paragraphs (b)(3) and (c)'' from the introduction to current Sec.
314.107(b)(1) to Sec. 314.107(b)(1)(i)(C) to more closely associate
this very important and common exception to an immediate date of
approval with the paragraph that describes a paragraph IV
certification. In addition, we are proposing to clarify that a
505(b)(2) application or ANDA containing a paragraph IV certification
may be approved immediately only if the 45-day period provided for in
section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act has expired.
We are proposing to revise Sec. 314.107(b)(1)(ii) (the current
text of which is proposed for incorporation into Sec.
314.107(b)(1)(i)) to clarify that an appropriate statement under Sec.
314.50(i)(1)(iii) or Sec. 314.94(a)(12)(iii) also could result in an
``immediate'' first possible date of approval. This proposed revision
addresses an omission in the current regulations. A 505(b)(2) or ANDA
applicant may submit a statement under Sec. 314.50(i)(1)(iii) or Sec.
314.94(a)(12)(iii), respectively, explaining that a method-of-use
patent does not claim an indication or other condition of use for which
the applicant is seeking approval (see section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act). If the patent only claims the method
of use for which the 505(b)(2) or ANDA applicant submitted a statement
under Sec. 314.50(i)(1)(iii) or Sec. 314.94(a)(12)(iii),
respectively, then a 505(b)(2) application or ANDA otherwise eligible
for approval may be approved immediately.
As described in section II.B.1.a, a listed patent may claim the
drug substance and/or drug product in addition to one or more methods
of use, and a 505(b)(2) or ANDA applicant could submit a statement
under Sec. 314.50(i)(1)(iii) or Sec. 314.94(a)(12)(iii) with respect
to one or more methods of use and a paragraph IV certification with
respect to the remaining drug substance and/or drug product claims and/
or any additional methods of use. In this scenario, the applicant's
paragraph IV certification and statement under Sec. 314.50(i)(1)(iii)
or Sec. 314.94(a)(12)(iii) to the patent would be analyzed in
accordance with proposed Sec. 314.107(b)(1)(i)(C) and (b)(1)(ii) to
determine whether the first possible date of approval for the 505(b)(2)
application or ANDA based on this patent is ``immediately'' or whether
[[Page 6862]]
the exceptions described in Sec. 314.107(b)(3) and (c) apply with
respect to the paragraph IV certification. Approval of a 505(b)(2)
application or ANDA that contains a statement under Sec.
314.50(i)(1)(iii) or Sec. 314.94(a)(12)(iii) with respect to one or
more methods of use and a paragraph IV certification with respect to
the remaining patent claims may be subject to a 30-month stay (or 7\1/
2\ years where applicable) if patent infringement litigation is
initiated within the statutory timeframe with respect to the patent
claims that were the subject of the paragraph IV certification (see
Sec. 314.107(b)(3)). It should be noted that if the paragraph IV
certification that gave rise to the 30-month stay (or 7\1/2\ years
where applicable) is subsequently amended to a statement under Sec.
314.50(i)(1)(iii) or Sec. 314.94(a)(12)(iii) with respect to one or
more methods of use, the 30-month stay (or 7\1/2\ years where
applicable) will not be terminated in the absence of a qualifying event
under Sec. 314.107(b)(3).
We are proposing to move Sec. 314.107(b)(2) regarding paragraph
III certifications, which delay approval until the date on which the
patent will expire, to proposed Sec. 314.107(b)(1)(iii) for
organizational convenience. An analysis of the effect of patents on the
timing of approval of a 505(b)(2) application or ANDA is made when the
505(b)(2) application or ANDA is otherwise eligible for approval.
II.M.2.b. Patent information filed after submission of 505(b)(2)
application or ANDA (proposed Sec. 314.107(b)(2)). We are proposing to
revise Sec. 314.107(b)(2) (redesignated as proposed Sec.
314.107(b)(1)(iii)) to clarify the effect of patent information filed
after submission of a 505(b)(2) application or ANDA on the date of
approval of a 505(b)(2) application or ANDA. If an NDA holder submits
patent information for a listed drug after the date on which a
505(b)(2) application or ANDA relying upon such drug was submitted to
FDA, the 505(b)(2) or ANDA applicant must comply with the requirements
of Sec. Sec. 314.50(i)(4) and (i)(6) and 314.94(a)(12)(vi) and
(a)(12)(viii) regarding amendment of its patent certification or
statement (see section II.E.4). Thus, if the patent information was
timely filed by the NDA holder under Sec. 314.53(d)(3), the 505(b)(2)
or ANDA applicant would be required to amend its patent certification
or statement for the listed drug relied upon or RLD, respectively, to
address the newly listed patent. (A 505(b)(2) or ANDA applicant whose
pending application did not contain an appropriate patent certification
at the time of submission would be required to submit a patent
certification or statement to the newly listed patent even if such
patent information was filed by the NDA holder more than 30 days after
patent issuance (i.e., untimely filed).)
If the 505(b)(2) or ANDA applicant submits an amendment containing
a paragraph IV certification to the newly listed patent, proposed Sec.
314.107(b)(2) clarifies that the 505(b)(2) application or ANDA may be
approved immediately upon the submission of an amendment containing
documentation that the NDA holder and each patent owner have received
notice of paragraph IV certification under Sec. 314.52(e) or Sec.
314.95(e). There is no need to delay approval until the expiration of
the 45-day period provided for in section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act. Even if the NDA holder or patent owner
initiated patent infringement litigation within the 45-day period after
receipt of notice of paragraph IV certification, a 30-month stay of
approval would not be available in connection with a paragraph IV
certification to a patent submitted after a 505(b)(2) application or
ANDA had been submitted to FDA (see section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act).
Although a 30-month stay of approval is not available in these
circumstances, a 505(b)(2) or ANDA applicant still must comply with the
requirements for provision of notice of paragraph IV certification
described in section 505(b)(3) and (j)(2)(B) of the FD&C Act and
Sec. Sec. 314.52 and 314.95. An NDA holder or patent owner may assert
a claim of patent infringement against the 505(b)(2) or ANDA applicant
in response to the notice of paragraph IV certification and may seek
injunctive relief during the pendency of the litigation despite the
absence of a 30-month stay. Notice of paragraph IV certification in
accordance with applicable regulations also is necessary for an ANDA
applicant to be eligible for 180-day exclusivity based upon a paragraph
IV certification to a newly listed patent (see section II.D.1).
II.M.2.c. Disposition of patent litigation (proposed Sec.
314.107(b)(3)).
II.M.2.c.i. Approval upon expiration of 30-month stay or 7\1/2\
years from date of reference product approval (proposed Sec.
314.107(b)(3)(i)). We are proposing to revise Sec. 314.107(b)(3)(i)(A)
to reflect one of the central elements of the MMA's amendments to the
FD&C Act: The limitation on multiple 30-month stays of approval of a
505(b)(2) application or an ANDA containing a paragraph IV
certification to certain patents submitted to FDA on or after August
18, 2003. Proposed Sec. 314.107(b)(3)(i)(A) states that a 30-month
stay of approval is available only when the patent owner or exclusive
patent licensee initiates a patent infringement action within the
statutory timeframe in response to a paragraph IV certification to a
patent submitted to FDA before the date on which the original 505(b)(2)
application or ANDA was submitted. As discussed in section II.E, the
MMA expressly provides that, for purposes of determining the
availability of a 30-month stay, the date of submission of a 505(b)(2)
application or ANDA does not include the date of submission of an
amendment or supplement to the 505(b)(2) application or ANDA (see
section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). In other
words, there will be no possibility of a 30-month stay with respect to
an action for infringement of a patent listed after the reference
product is approved if the patent was submitted to FDA on or after the
date the 505(b)(2) application or ANDA was first submitted. Due to this
limitation, most 505(b)(2) applications and ANDAs will be subject to no
more than one 30-month stay of approval.
Multiple 30-month stays, however, still may be possible in certain
cases. For example, an original 505(b)(2) application or ANDA may
contain a paragraph IV certification to a patent that results in a 30-
month stay of approval. If the same application also contains a
paragraph III certification to a different patent that was submitted to
FDA on or after August 18, 2003, and before the 505(b)(2) application
or ANDA was submitted, and the applicant subsequently amends the
paragraph III certification to a paragraph IV certification, a second
30-month stay would be possible. Two 30-month stays are possible in
this example because the challenged patents that gave rise to
sequential actions for patent infringement were both submitted to FDA
before submission of the original 505(b)(2) application or ANDA. It
should be noted that the relevant benchmark for determining whether a
patent was submitted by the NDA holder prior to submission of an
original 505(b)(2) application or prior to submission of an ANDA later
determined to be substantially complete is the date of submission of
the patent to FDA and not the date on which the patent information is
published in the Orange Book (see Sec. 314.53(d)(5)). We note,
however, that if the original submission of an ANDA is not determined
to be substantially complete (i.e., FDA refuses to receive the ANDA
under Sec. 314.101), then the relevant
[[Page 6863]]
benchmark is the date of the ANDA amendment that results in a
subsequent determination that the ANDA is substantially complete.
We also are proposing to revise Sec. 314.107(b)(3)(i) to clarify
that a 30-month stay of approval begins on the later of the date of
receipt of the notice of paragraph IV certification by any owner of the
listed patent or by the NDA holder who is an exclusive patent licensee
(or their representatives). This proposed revision codifies our current
practice and provides an administratively efficient means of ensuring
that each patent owner or NDA holder that is entitled to receive notice
of paragraph IV certification receives the full statutory 30-month stay
of approval should one of these parties initiate patent infringement
litigation within 45 days of its receipt of notice. Even if a patent
infringement action was initiated within 45 days of receipt of notice
of paragraph IV certification by the first of two intended recipients,
the 30-month stay of approval would begin on the later of the dates of
receipt of notice of paragraph IV certification by any owner of the
listed patent or by the NDA holder.
Finally, we are proposing to revise Sec. 314.107(b)(3) to
supplement the list that describes different scenarios related to the
timing of approval of a 505(b)(2) application or ANDA containing a
paragraph IV certification that was the subject of patent litigation.
Many of our proposed additions to the Sec. 314.107(b) list reflect
corresponding MMA amendments to section 505(c)(3)(C) and (j)(5)(B)(iii)
of the FD&C Act (see sections II.M.3.e to II.M.3.h). It should be noted
that we are not proposing revisions to Sec. 314.107(b)(3) to describe
the date on which a 505(b)(2) application or ANDA may be approved when
a 30-month stay relates to a patent to which pediatric exclusivity has
attached (see section 505A of the FD&C Act). However, a period of
pediatric exclusivity under section 505A of the FD&C Act may affect the
approval date of a 505(b)(2) application or ANDA in the circumstances
described in Sec. 314.107(b)(3).
II.M.2.c.ii. Federal district court decision of invalidity,
unenforceability, or non infringement (proposed Sec.
314.107(b)(3)(ii)). The MMA amended section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act for 505(b)(2) applications and ANDAs,
respectively, to clarify the type of court decision in patent
litigation that will terminate a 30-month stay (or 7\1/2\ years where
applicable) and lead to approval of a 505(b)(2) application or ANDA
that is otherwise eligible for approval. Prior to the MMA, FDA
interpreted the reference to a court decision in section
505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the FD&C Act to mean ``the
court that enters final judgment from which no appeal can be or has
been taken'' (see 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'' (March 2000),
available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072868.pdf)
(superseded Guidance on Court Decisions). The MMA amended the FD&C Act
to codify the types of Federal district court decisions and, as
discussed in section II.M.2.c.iii to II.M.2.c.iv, the types of Federal
appellate court decisions that will terminate a 30-month stay (or 7\1/
2\ years where applicable). Accordingly, FDA is not required to delay
approval of an otherwise approvable ANDA until there has been a court
decision from which no appeal can be or has been taken.
The MMA amended section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of
the FD&C Act to describe the Federal district court decisions in patent
litigation that will terminate a 30-month stay (or 7\1/2\ years where
applicable) and lead to approval of a 505(b)(2) application or ANDA
that is otherwise eligible for approval (see Sanofi-Aventis v. FDA, 643
F.Supp.2d 82, 86 (D.D.C.), inj. denied, 2009 U.S. Dist. LEXIS 74578
(D.D.C. 2009) (``The plain language of the entry of judgment provision
of the Hatch-Waxman Act is clear that the FDA's approval of a generic
application `shall be made effective on the . . . date on which the
court enters judgment' '' irrespective of whether the enforceability of
that judgment is stayed) (emphasis in original)). We are proposing to
revise Sec. 314.107(b)(3)(ii) to reflect these statutory revisions
that change the decisive event from court issuance of a final order
that the patent is invalid, unenforceable, or not infringed to a
district court's entry of judgment pursuant to Federal Rule of Civil
Procedure (Fed. R. Civ. P.) Rule 58 that the patent is invalid,
unenforceable, or not infringed. As with current Sec.
314.107(b)(3)(ii), we are proposing to implement section
505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the FD&C Act to include a
court decision that the applicable patent is unenforceable. Thus, a
Federal district court's entry of judgment that a patent has been
infringed by the 505(b)(2) or ANDA applicant but is unenforceable (for
example, due to inequitable conduct in patent prosecution) would
terminate a 30-month stay (or 7\1/2\ years where applicable).
Consistent with section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the
FD&C Act, proposed Sec. 314.107(b)(3)(ii) also includes cases in which
a Federal district court has made a substantive determination that
there is no cause of action for patent infringement or invalidity.
We are proposing to further revise Sec. 314.107(b)(3)(ii) to
incorporate the text of section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I)
of the FD&C Act, as amended by the MMA, regarding the timing of
approval of a 505(b)(2) application or ANDA in relation to the district
court decision. Proposed Sec. 314.107(b)(3)(ii) provides that in cases
in which a district court decides that the patent is invalid,
unenforceable, or not infringed, the 505(b)(2) application or ANDA may
be approved on the date on which the court enters judgment reflecting
the decision (paragraph (A)); or the date of a settlement order or
consent decree signed and entered by the court stating that the patent
that is the subject of the certification is invalid or not infringed
(paragraph (B)).
II.M.2.c.iii. Appeal of Federal district court judgment of
infringement (proposed Sec. 314.107(b)(3)(iii)). The MMA amended
section 505(c)(3)(C)(ii) and (j)(5)(B)(iii)(II) of the FD&C Act for
505(b)(2) applications and ANDAs, respectively, to describe the
earliest date on which a 30-month stay (or 7\1/2\ years where
applicable) can be terminated after a Federal district court has
decided that the patent has been infringed based on whether the
judgment is appealed. We are proposing to revise Sec.
314.107(b)(3)(iii) and, as discussed in section II.M.2.c.iv, Sec.
314.107(b)(3)(iv) to reflect these statutory revisions.
Proposed Sec. 314.107(b)(3)(iii) states that if the Federal
district court decides that the patent has been infringed and the
district court judgment is appealed, the 505(b)(2) application or ANDA
may be approved on the date on which the mandate is issued by the court
of appeals entering judgment that the patent is invalid or not
infringed (including any substantive determination that there is no
cause of action for patent infringement or invalidity) (paragraph (A));
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 (paragraph (B)). Proposed
Sec. 314.107(b)(3)(iii) restates the text of section 505(c)(3)(C)(ii)
and (j)(5)(B)(iii)(II) of the FD&C Act except that we are proposing to
further specify that the date of the court of appeals decision is the
date on which the
[[Page 6864]]
mandate is issued by the court of appeals (see Federal Rule of
Appellate Procedure Rule 41). This proposal reflects the Agency's
current practice in implementing section 505(c)(3)(C)(ii) and
(j)(5)(B)(iii)(II) of the FD&C Act, which recognizes that a party may
request rehearing by the appellate panel or rehearing en banc. In such
circumstances, it would be premature to terminate the 30-month stay and
possibly approve the 505(b)(2) application or ANDA while a decision
regarding patent noninfringement, invalidity, or unenforceability was
being reheard by the court of appeals. By interpreting the ``date on
which the court of appeals decides that the patent is invalid or not
infringed'' (see section 505(c)(3)(C)(ii) and (j)(5)(B)(iii)(II) of the
FD&C Act) to mean the date on which the mandate issues, we are ensuring
that the Agency's action reflects the judgment of the court of appeals.
We seek comment on this interpretation.
II.M.2.c.iv. Affirmation or non-appeal of Federal district court
judgment of infringement (proposed Sec. 314.107(b)(3)(iv)). The MMA
amended section 505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) of the
FD&C Act to describe the timing of approval of a 505(b)(2) application
or ANDA, respectively, that a Federal district court has decided
infringes a patent that was the subject of a paragraph IV certification
if the district court decision was not appealed or was affirmed on
appeal. In such a case, section 505(c)(3)(C)(ii)(II) and
(j)(5)(B)(iii)(II)(bb) of the FD&C Act provide that the 505(b)(2)
application or ANDA will be approved on the date specified by the
district court in an order under 35 U.S.C. 271(e)(4)(A). We are
proposing to revise Sec. 314.107(b)(3)(iv) to reflect these statutory
revisions with certain clarifications.
Proposed Sec. 314.107(b)(3)(iv) provides that if the district
court decides that the patent at issue is infringed and this judgment
is not appealed or is affirmed on appeal, the 505(b)(2) application or
ANDA may be approved no earlier than the date specified by the district
court in an order under 35 U.S.C. 271(e)(4)(A). Although the date
specified by the district court order would not be earlier than the
date of expiration of the infringed patent (see 35 U.S.C.
271(e)(4)(A)), the date specified by the order may not take into
account any other unexpired patents or unexpired exclusivity (or
deficiencies in the application) that would delay approval of the
505(b)(2) application or ANDA beyond the date of expiration of the
infringed patent. Therefore, proposed Sec. 314.107(b)(3)(iv) states
that the 505(b)(2) application or ANDA may be approved no earlier than
the date specified in a district court's order under 35 U.S.C.
271(e)(4)(A), rather than using the statutory phrasing that the
``approval shall be made effective on the date'' specified by such
order (see section 505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) of
the FD&C Act and section II.I regarding removal of references to the
effective date of approval).
II.M.2.c.v. Grant of preliminary injunction by Federal district
court (proposed Sec. 314.107(b)(3)(v)). The MMA amended section
505(c)(3)(C)(iii), (c)(3)(C)(iv), (j)(5)(B)(iii)(III), and
(j)(5)(B)(iii)(IV) of the FD&C Act to clarify that the timing of
approval of a 505(b)(2) application or ANDA, respectively, is subject
to provisions of section 505(c)(3)(C)(i), (c)(3)(C)(ii),
(j)(5)(B)(iii)(I), and (j)(5)(B)(iii)(II) even if preceded by a
preliminary injunction prohibiting the applicant from engaging in the
commercial manufacture or sale of the drug until the court decides the
issues of patent validity and infringement. We are proposing to revise
current Sec. 314.107(b)(3)(iv) (redesignated as proposed Sec.
314.107(b)(3)(v)) to reflect these statutory revisions. Proposed Sec.
314.107(b)(3)(v) cross-references the applicable paragraph of Sec.
314.107(b)(3) that would address the timing of approval of the
505(b)(2) application or ANDA based on the court's decision with
respect to patent validity and infringement. If a preliminary
injunction is entered before the expiration of the 30-month stay, FDA
interprets section 505(j)(5)(B)(iii) of the FD&C Act to require that
the stay of approval is extended until the court decides the issues of
patent infringement and validity. Once such a decision is made, the
references to section 505(j)(5)(B)(iii)(I) and (j)(5)(B)(iii)(II) of
the FD&C Act provide for the timing of approval (see section
505(j)(5)(B)(iii)(III) and (j)(5)(B)(iii)(IV) of the FD&C Act). We seek
comment on this approach.
In addition, proposed Sec. 314.107(b)(3)(v) makes clear that the
court that grants a preliminary injunction pending a decision on the
issues of patent validity and infringement refers to the Federal
district court hearing the patent infringement action.
II.M.2.c.vi. Written consent to approval by patent owner or
exclusive patent licensee (proposed Sec. 314.107(b)(3)(vi)). We are
proposing to add Sec. 314.107(b)(3)(vi) to clarify that if the patent
owner or exclusive patent licensee (or their representatives) agrees in
writing that the 505(b)(2) application or ANDA application may be
approved, the 30-month stay (or 7\1/2\ years where applicable) will be
terminated and the approval may be granted on or after the date of the
consent. Thus, proposed Sec. 314.107(b)(3)(vi) would permit
termination of the 30-month stay (or 7\1/2\ years where applicable)
without a court order. This scenario may arise, for example, if
settlement of the patent litigation results in a license to the
505(b)(2) or ANDA applicant.
II.M.2.c.vii. Court order terminating 30-month or 7\1/2\-year
period (proposed Sec. 314.107(b)(3)(vii)). We are proposing to add
Sec. 314.107(b)(3)(vii) to clarify that if a court enters an order
requiring the termination of the 30-month stay (or 7\1/2\ years where
applicable), the 505(b)(2) application or ANDA, if otherwise ready for
approval, may be approved in accordance with the court order.
II.M.2.c.viii. Court order of dismissal without a finding of
infringement (proposed Sec. 314.107(b)(3)(viii)). The MMA's amendments
to section 505(c)(3)(C)(i), (c)(3)(C)(ii), (j)(5)(B)(iii)(I), and
(j)(5)(B)(iii)(II) of the FD&C Act clarify the timing of approval of a
505(b)(2) application or ANDA, respectively, in relation to a
settlement order or consent decree stating that the patent that is the
subject of the paragraph IV certification is invalid or not infringed.
However, the statute does not address whether a 30-month stay may be
terminated and a 505(b)(2) application or ANDA approved if the court
enters an order of dismissal without a finding of patent infringement--
a scenario that FDA encounters frequently. We are proposing to add
Sec. 314.107(b)(3)(viii) to codify FDA's policy that court entry of an
order of dismissal, with or without prejudice, of patent infringement
litigation that was timely initiated in response to notice of a
paragraph IV certification will terminate the 30-month period (or 7\1/
2\ years where applicable) if such order does not state a finding of
patent infringement. It is appropriate that a 30-month stay terminates
under these circumstances because the statutory purpose of the stay is
to allow time for claims of patent infringement to be litigated prior
to approval of the potentially infringing drug product. If the patent
owner or exclusive patent licensee dismisses the patent infringement
action on terms that the court considers proper (see Fed. R. Civ. P.
Rule 41(a)(2)), then there should be no further delay of approval of a
505(b)(2) application or ANDA otherwise eligible for approval.
II.M.2.d. Tentative approval (proposed Sec. 314.107(b)(4)). We are
[[Page 6865]]
proposing to redesignate current Sec. 314.107(b)(3)(v) as proposed
Sec. 314.107(b)(4) for organizational convenience. Proposed Sec.
314.107(b)(4) describes tentative approval of a 505(b)(2) application
or ANDA as appropriate in accordance with Sec. 314.107(b)(3). In
addition, we are proposing to revise Sec. 314.107(b)(4) to state that
FDA will issue a tentative approval letter when tentative approval is
appropriate in accordance with a court order pursuant to 35 U.S.C.
271(e)(4)(A) that a 505(b)(2) application or ANDA may be approved no
earlier than the date specified, irrespective of whether the injunction
relates to a patent described in Sec. 314.107(b)(3) (see proposed
Sec. 314.107(e)(1)(vi)). This proposed revision is intended to
complement proposed Sec. 314.107(g), which clarifies that if a court
enters an order requiring that the date of approval be delayed for an
already approved 505(b)(2) application or ANDA, FDA will convert the
approval to a tentative approval, if appropriate. This scenario may
occur, for example, if a patent infringement action is initiated after
the 45-day period described in section 505(c)(3)(C) and (j)(5)(B)(iii)
of the FD&C Act and results in a judgment of patent infringement.
Proposed Sec. 314.107(b)(4) would expressly describe FDA's practice of
giving effect to the court order under 35 U.S.C. 271(e)(4)(A),
irrespective of whether the order relates to a patent associated with a
30-month stay of approval (see, e.g., Mylan Labs., Inc. v. Thompson,
389 F.3d 1272 (D.C. Cir. 2004)).
We also are proposing to amend references to ``receiv[ing] final
approval'' and making an approval ``effective'' to refer instead to
receipt of an approval letter (see sections II.A.2.dd and II.I).
II.M.3. Subsequent ANDA Submission (Proposed Sec. 314.107(c))
Section 1102 of the MMA amended section 505(j)(5) of the FD&C Act
to modify the conditions under which a 180-day period of exclusivity is
granted and to establish conditions under which a first applicant would
forfeit the 180-day exclusivity period. As noted in section I.D, we are
currently implementing the 180-day exclusivity provisions of the MMA
directly from the statute and will determine if additional rulemaking
is necessary in the future. At this time, we are proposing to revise
Sec. 314.107(c) to remove provisions that have been superseded by the
statute, as revised by the MMA, and to generally conform with the
statute.
Table 13 summarizes the proposed changes related to submission of
an ANDA containing a paragraph IV certification by a subsequent ANDA
applicant.
Table 13--Highlights of Proposed Changes Regarding Subsequent ANDA
Submission \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Subsequent ANDA submission (Sec. Subsequent ANDA submission
314.107(c)(1),(3)) (Sec. 314.107(c)(1))
If an ANDA contains a paragraph If an ANDA contains
IV certification and the ANDA is for a a paragraph IV
generic copy of the same listed drug for certification for a
which one or more substantially complete relevant patent and the
ANDAs were previously submitted ANDA is not that of a first
containing a paragraph IV certification applicant, the ANDA is
to the same patent, approval of the regarded as that of a
subsequent ANDA will be made effective no subsequent applicant.
sooner than 180 days from whichever of The ANDA of a
the following dates is earlier: subsequent applicant will
--(i) The date the applicant submitting not be approved during the
the first application first commences period when any first
commercial marketing of its drug product; applicant for the drug
or product is eligible for 180-
--(ii) The date of a decision of the court day exclusivity or during
holding the relevant patent invalid, the 180-day exclusivity
unenforceable, or not infringed. period of a first
applicant.
Any applicable 180-
day exclusivity period can
not extend beyond the
expiration of the patent
upon which the 180-day
exclusivity period was
based.
For purposes of Sec.
314.107(c)(1), if FDA concludes that the
applicant submitting the first ANDA is
not actively pursuing approval, FDA will
make the approval of subsequent ANDAs
immediately effective if they are
otherwise eligible for an immediately
effective approval.
Subsequent ANDA submission (Sec. Definitions (Sec.
314.107(c)(2)) 314.3(b))
For purposes of Sec. First applicant is
314.107(c)(1), the `applicant submitting an applicant that, on the
the first application' is the applicant first day on which a
that submits an ANDA that is both substantially complete ANDA
substantially complete and contains a containing a paragraph IV
certification that the patent was certification is submitted
invalid, unenforceable, or not infringed for approval of a drug,
prior to the submission of any other submits a substantially
application for the same listed drug that complete ANDA that
is both substantially complete and contains, and for which the
contains the same certification. applicant lawfully
A `substantially complete' maintains, a paragraph IV
application must contain the results of certification for the drug.
any required bioequivalence studies, or, Substantially
if applicable, a request for a waiver of complete application is an
such studies. ANDA that on its face is
sufficiently complete to
permit a substantive review
and contains all the
information required under
section 505(j)(2)(A) of the
FD&C Act and Sec. 314.94.
Subsequent ANDA submission (Sec. Subsequent ANDA submission
314.107(c)(4)) (Sec. 314.107(c)(2))
For purposes of Sec. For purposes of
314.107(c)(1)(i), the applicant Sec. 314.107(c)(1), a
submitting the first ANDA shall first applicant must submit
notify FDA of the date that it a supplement to its ANDA
commences commercial marketing of its notifying FDA within 30
drug product. days of the date of first
commercial marketing of its
drug product.
If an applicant does not If an applicant
promptly notify FDA of such date, the does not notify FDA, as
effective date of approval shall be required above, of this
deemed to be the date of the date, the date of first
commencement of first commercial commercial marketing will
marketing. be deemed to be the date of
the drug product's
approval.
Commercial marketing Definitions (Sec.
commences with the first date of 314.3(b))
introduction or delivery for Commercial
introduction into interstate commerce marketing is the
outside the control of the introduction or delivery
manufacturer of a drug product, for introduction into
except for investigational use under interstate commerce of a
part 312 of this chapter, but does drug product described in
not include transfer of the drug an approved ANDA, outside
product for reasons other than sale the control of the ANDA
within the control of the holder, except for
manufacturer or application holder. investigational use under
part 312 of this chapter,
but does not include
transfer of the drug
product for reasons other
than sale to parties
identified in the approved
ANDA.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
[[Page 6866]]
We are proposing to revise Sec. 314.107(c)(1) to incorporate the
term ``first applicant,'' as defined by section
505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and in proposed Sec. 314.3(b)
(see section II.A.2.q), and to distinguish a ``first applicant'' from a
``subsequent applicant.'' An ANDA has been submitted by a subsequent
applicant if the ANDA has not been submitted by a first applicant and
contains a paragraph IV certification to a relevant patent that has
been listed for the drug product for which a first applicant has
submitted an ANDA. A subsequent applicant's ANDA will not be approved
during the period when any first applicant for the drug product is
eligible for 180-day exclusivity or during the 180-day exclusivity
period of a first applicant (see section 505(j)(5)(B)(iv)(I) of the
FD&C Act). By including the period during which any first applicant is
eligible for 180-day exclusivity, proposed Sec. 314.107(c)(1)
clarifies that a subsequent ANDA for the drug product may not be
approved while a first applicant is eligible for 180-day exclusivity as
long as a forfeiture event has not occurred with respect to that first
applicant (see section 505(j)(2)(D)(ii) of the FD&C Act). These
proposed revisions replace the current text of Sec. 314.107(c)(1),
superseded by statute, which describe a patent-by-patent analysis to
determine eligibility for 180-day exclusivity and events that would
trigger the start of the 180-day period under the pre-MMA statutory
scheme.
We are proposing to delete the definition of the ``applicant
submitting the first application'' in current Sec. 314.107(c)(2)
because it has been superseded by the statutory definition added by the
MMA. We are proposing to incorporate the MMA's definition of the term
``first applicant,'' with minor editorial changes and additional
clarifying text, into Sec. 314.3(b) (see section
505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and section II.A.2.q). We also
are proposing to delete Sec. 314.107(c)(3), which described the
potential consequences of a first applicant's failure to actively
pursue approval of its ANDA because this regulation has been superseded
by the statutory provisions that specify events that will result in
forfeiture of the 180-day exclusivity period by a first applicant (see
section 505(j)(5)(D) of the FD&C Act).
The MMA amended the FD&C Act to modify the types of events that can
trigger the start of the 180-day exclusivity period for a first
applicant (see section 505(j)(5)(B)(iv)(I) of the FD&C Act; see also
section 1102(b)(3) of the MMA). Section 505(j)(5)(B)(iv)(I) of the FD&C
Act provides that the period of 180-day exclusivity will begin on the
``date of the first commercial marketing of the drug (including the
commercial marketing of the listed drug) by any first applicant.'' This
commercial marketing trigger differs from the version of section
505(j)(5)(B)(iv)(I) in effect prior to enactment of the MMA, which
provided that the 180-day exclusivity period will begin on the earlier
of two events, one of which was the date the Secretary receives notice
from the applicant of the first commercial marketing of the drug
eligible for 180-day exclusivity. We are proposing to revise Sec.
314.107(c)(4) to conform with these changes to the FD&C Act and
redesignate this provision as Sec. 314.107(c)(2) (``redesignated Sec.
314.107(c)(2)'').
In light of the change in the commercial marketing trigger from the
date on which FDA receives notice from the applicant of the first
commercial marketing to the date of the first commercial marketing of
the drug, we are proposing to revise redesignated Sec. 314.107(c)(2)
to require a first applicant to submit correspondence to its ANDA
notifying FDA within 30 days of the date of first commercial marketing
of the drug product (see current Sec. 314.107(c)(4)). This proposal to
require notification within 30 days of the date of first commercial
marketing is intended to facilitate the efficient enforcement of the
FD&C Act and provide adequate notice to subsequent applicants that have
received tentative approval and are awaiting expiration of the period
of 180-day exclusivity. If the first applicant does not notify FDA
within this timeframe, we are proposing to deem the date of first
commercial marketing to be the date of the drug product's approval.
This may have the effect of shortening the 180-day period of
exclusivity in a manner similar to current Sec. 314.107(c)(4).
We also are proposing to revise redesignated Sec. 314.107(c)(2) to
remove the description of ``commercial marketing.'' As explained in
section II.A.2.l, we are proposing to define ``commercial marketing''
in Sec. 314.3(b) with certain modifications, as compared to current
Sec. 314.107(c)(4), to the scope of the exclusion for transfer of the
drug product for reasons other than sale.
II.M.4. Delay of Approval Due to Exclusivity (Proposed Sec.
314.107(d))
We are proposing to revise Sec. 314.107(d) to clarify that
approval of a 505(b)(2) application or ANDA may be delayed by orphan
drug exclusivity and pediatric exclusivity in addition to the
exclusivities described in Sec. 314.108. Proposed Sec. 314.107(d)
explains that when approval of a 505(b)(2) application or ANDA is
delayed under Sec. 314.107 and Sec. 314.108, 21 CFR 316.31 (orphan
drug exclusivity), or section 505A of the FD&C Act (pediatric
exclusivity), the 505(b)(2) application or ANDA will be approved on the
latest of the dates specified under these provisions. We also have made
conforming revisions to proposed Sec. 314.107(d) that are described
elsewhere in section II.M.
II.M.5. Notification of Court Actions or Documented Agreement (Proposed
Sec. 314.107(e))
We are proposing to revise Sec. 314.107(e) to expand the scope of
documentation that an applicant must submit to FDA regarding court
actions and settlements related to patents. These changes are intended
to ensure that FDA is promptly advised of court actions and documented
agreements that may affect the timing of approval of a 505(b)(2)
application or ANDA for the efficient administration of the FD&C Act.
FDA does not have the resources to monitor the numerous court actions
that are pending at any given time which may affect the date of
approval of a 505(b)(2) application or ANDA that is otherwise eligible
for approval.
Table 14 summarizes the proposed changes related to notification of
court actions or documented agreements.
Table 14--Highlights of Proposed Changes Regarding Notification of Court
Actions or Documented Agreements\1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Notification of court actions (Sec. Notification of court actions
314.107(e)) or documented agreements (Sec.
314.107(e)(1) and (e)(2))
[[Page 6867]]
Applicant must submit a copy Applicant must submit
of the entry of the order or judgment the following information to
to the Office of Generic Drugs or to FDA, as applicable:
the appropriate division in the Office --a copy of any judgment by the
of New Drugs, as applicable, within 10 court (district court or
working days of a final judgment. mandate of the court of
appeals) or settlement order
or consent decree signed and
entered by the court (district
court or court of appeals)
finding a patent described in
Sec. 314.107(b)(3) invalid,
unenforceable, or not
infringed, or finding the
patent valid and infringed,
and written notification of
whether any such court action
has been appealed;
--A copy of any order
entered by the court
terminating the 30-month or
7\1/2\-year period
described in Sec.
314.107(b)(3)(i) and
(b)(3)(ii);
--A copy of any documented
agreement described in Sec.
314.107(b)(3)(vi);
--A copy of any preliminary
injunction described in
Sec. 314.107(b)(3)(v),
and a copy of any
subsequent court order
lifting the injunction; and
--A copy of any court order
pursuant to 35 U.S.C.
271(e)(4)(A) ordering that
a 505(b)(2) application or
ANDA may be approved no
earlier than the date
specified (irrespective of
whether the injunction
relates to a patent
described in Sec.
314.107(b)(3)).
All required
information must be sent to
the Office of Generic Drugs or
to the appropriate division in
the Office of New Drugs, as
applicable, within 14 days of:
--the date of entry by the
court,
--the date of appeal or
expiration of the time for
appeal, or
--the date of documented
agreement, as applicable.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
Proposed Sec. 314.107(e)(1)(i) would require a 505(b)(2) or ANDA
applicant to submit a copy of any judgment by the court (district court
or mandate of the court of appeals) finding a patent described in Sec.
314.107(b)(3) invalid, unenforceable, or not infringed, or finding the
patent valid and infringed. This proposed requirement imposes a duty on
505(b)(2) and ANDA applicants to notify FDA regarding any court
judgment regardless of whether or not the action for patent
infringement has resulted in a substantive determination by the court
regarding validity, enforceability, and/or infringement of the patent.
In addition, we are proposing to require 505(b)(2) and ANDA
applicants to submit to FDA a copy of certain documented agreements and
court actions other than judgments to facilitate FDA's administration
of the FD&C Act. Proposed Sec. 314.107(e)(1)(i) would require a
505(b)(2) or ANDA applicant to submit a copy of a settlement order or
consent decree signed and entered by the court (district court or court
of appeals) finding a patent described in proposed Sec. 314.107(b)(3)
invalid, unenforceable, or not infringed, or finding the patent valid
and infringed. It should be noted that this proposal would require
submission of written documentation that the parties have entered into
a settlement that has terminated the patent infringement litigation,
but does not require applicants to send copies of the actual settlement
agreement to FDA (compare section 1112 of the MMA (requiring that
generic drug applicants file certain agreements with the FTC)).
Proposed Sec. 314.107(e)(1)(ii) would require a 505(b)(2) or ANDA
applicant to submit written notification of whether or not any action
by the court described in Sec. 314.107(e)(1)(i) has been appealed
within the time permitted for an appeal. Proposed Sec.
314.107(e)(1)(iii) and (e)(1)(iv) would require a 505(b)(2) or ANDA
applicant to submit a copy of any order entered by the court
terminating the 30-month or 7\1/2\-year period described in proposed
Sec. 314.107(b)(3)(i) and (b)(3)(ii), and any documented agreement
described in proposed Sec. 314.107(b)(3)(vi). Proposed Sec.
314.107(e)(1)(v) would require a 505(b)(2) or ANDA applicant to submit
a copy of any preliminary injunction described in Sec.
314.107(b)(3)(v), and a copy of any subsequent court order lifting the
injunction. Proposed Sec. 314.107(e)(1)(vi) would require a 505(b)(2)
or ANDA applicant to submit a copy of any court order pursuant to 35
U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may
be approved no earlier than the date specified (irrespective of whether
the injunction relates to a patent described in Sec. 314.107(b)(3)).
This revision is intended to conform with proposed Sec. 314.107(b)(4)
(see section II.M.2.d). These court actions and documented agreements
also may affect the timing of approval of a 505(b)(2) application or
ANDA and frequently are unpublished. If an applicant is unsure whether
a particular court action or documented agreement requires notification
to FDA under proposed Sec. 314.107(e), we recommend submission.
We also are proposing to modify the timeframe for a 505(b)(2) or
ANDA applicant to submit the required information to the appropriate
division in OND or to OGD, as applicable, to ensure timely notification
to FDA. Proposed Sec. 314.107(e)(2) would require submission of all
required information within 14 calendar days of entry by the court, the
date of appeal or expiration of the time for appeal, or the date of
written agreement, as applicable. We are proposing to change the
timeframe for submission of required information from 10 working days
to 14 calendar days for clarity and consistency with other counting
conventions used in part 314.
II.M.6. Computation of the 45-Day Time Clock (Proposed Sec.
314.107(f))
We are proposing to revise Sec. 314.107(f) to clarify the
computation of the 45-day period after receipt of notice of paragraph
IV certification and to enhance the requirements for notifying FDA of
any legal action filed
[[Page 6868]]
within this timeframe. Table 15 summarizes the proposed changes related
to the 45-day period after receipt of notice of paragraph IV
certification. We seek comment on the proposed notification requirement
and alternative ways for FDA to monitor compliance with the FD&C Act.
Table 15--Highlights of Proposed Changes Regarding the 45-Day Period
After Receipt of Notice of Paragraph IV Certification \1\
------------------------------------------------------------------------
Proposed revisions to
Current regulations regulations
------------------------------------------------------------------------
Computation of 45-day time clock (Sec. Computation of 45-day time
314.107(f)(1)) clock (Sec.
314.107(f)(1))
The 45-day clock described in The 45-day clock
Sec. 314.107(b)(3) begins on the day described in Sec.
after the date of receipt of the 314.107(b)(3) as to each
applicant's notice of certification by recipient required to
the patent owner or its representative, receive notice of paragraph
and by the approved application holder. IV certification under Sec.
Sec. 314.52 or 314.95
begins on the day after the
date of receipt of the
applicant's notice of
certification by each
recipient.
Computation of 45-day time clock (Sec. Notification of filing of
314.107(f)(2)) legal action (Sec.
314.107(f)(2)(i) to
(f)(2)(ii))
The 505(b)(2) or ANDA applicant The 505(b)(2) or
must notify FDA immediately of the filing ANDA applicant must notify
of any legal action filed within 45 days FDA in writing within 14
of receipt of the notice of days of the filing of any
certification. legal action filed within
45 days of receipt of the
notice of certification by
any recipient.
The notification to FDA of the The notification to
legal action must include, among other FDA of the legal action
things: (iv) A certification that an must include, among other
action for patent infringement identified things: (iv) A statement
by number, has been filed in an that an action for patent
appropriate court on a specified date. infringement, identified by
A patent owner or its the court, case number and
representative may also notify FDA of the the patent number(s) of the
filing of any legal action for patent patent(s) at issue in the
infringement. action, has been filed in
an appropriate court on a
specified date.
A patent owner or
NDA holder (or their
representatives) may also
notify FDA of the filing of
any legal action for patent
infringement.
Computation of 45-day time clock (Sec. Notification of filing of
314.107(f)(2)) legal action (Sec.
314.107(f)(2)(iii))
If the 505(b)(2) or ANDA If the 505(b)(2) or
applicant or the patent owner or its ANDA applicant, the patent
representative does not notify FDA in owner(s), the NDA holder,
writing before the expiration of the 45- or their representatives do
day time period or the completion of the not notify FDA in writing
Agency's review of the application, before the expiration of
whichever occurs later, that a legal the 45-day time period or
action for patent infringement was filed the completion of the
within 45 days of receipt of the notice Agency's review of the
of certification, approval of the 505(b)(2) application or
505(b)(2) application or ANDA will be ANDA, whichever occurs
made effective immediately upon later, that a legal action
expiration of the 45 days or upon for patent infringement was
completion of FDA's review and approval filed within 45 days of
of the application, whichever is later. receipt of the notice of
paragraph IV certification,
the 505(b)(2) application
or ANDA may be approved
upon expiration of the 45-
day period (if the
505(b)(2) or ANDA applicant
confirms that a legal
action for patent
infringement has not been
filed) or upon completion
of FDA's review of the
505(b)(2) application or
ANDA, whichever is later.
Computation of 45-day time clock (Sec. Waiver (Sec.
314.107(f)(3)) 314.107(f)(3))
If the patent owner or approved If the patent owner
application holder who is an exclusive or NDA holder who is an
patent licensee waives its opportunity to exclusive patent licensee
file a legal action for patent (or their representatives)
infringement within 45 days of a receipt waives its opportunity to
of the notice of certification and the file a legal action for
patent owner or approved application patent infringement within
holder who is an exclusive patent 45 days of a receipt of the
licensee submits to FDA a valid waiver notice of certification and
before the 45 days elapse, approval of the patent owner or NDA
the ANDA or the 505(b)(2) application holder who is an exclusive
will be made effective upon completion of patent licensee (or their
FDA's review and approval of the representatives) submits to
application. FDA will only accept a FDA a valid waiver before
waiver in the form specified in Sec. the 45 days elapse, the
314.107(f)(3)). 505(b)(2) application or
ANDA may be approved upon
completion of the Agency's
review of the application.
FDA will only accept a
waiver in the form
specified in Sec.
314.107(f)(3), as proposed
for revision.
------------------------------------------------------------------------
\1\ These highlights describe important proposed revisions to our
regulations, but should not be relied upon in place of the proposed
regulation.
We are proposing to revise Sec. 314.107(f)(1) to clarify that the
45-day period after receipt of notice of paragraph IV certification is
calculated for each recipient required to be notified under Sec. Sec.
314.52(a) and 314.95(a). This proposed revision would codify FDA's
longstanding interpretation of section 505(b)(3) and (j)(2)(B) of the
FD&C Act, as amended by the MMA. This interpretation ensures that each
person required to receive notice under Sec. 314.52 or Sec. 314.95,
as applicable, also receives the full 45-day period in order to
evaluate whether to initiate an action for patent infringement and
obtain a 30-month (or 7\1/2\-year) stay of approval while litigation is
pending. Accordingly, a 505(b)(2) or ANDA applicant's notice of
paragraph IV certification may result in more than one ``45-day clock''
if the NDA holder and patent owners(s) are different entities and
receive notice of paragraph IV certification on different days.
Proposed Sec. 314.107(f)(2) would require that a 505(b)(2) or ANDA
applicant notify FDA in writing within 14 calendar days of the filing
of any legal action filed within 45 days of receipt of the notice of
certification. We are proposing to replace the current requirement for
``immediate'' notification to establish a date certain by which the
applicant must send written notification to FDA. This revision is
intended to enhance compliance and conform with proposed Sec.
314.107(e), which would require a 505(b)(2) or ANDA applicant to submit
notification of court actions and documented agreements (and a copy of
certain court actions) to FDA within 14 calendar days of entry by the
court, the date of appeal or expiration of the time for appeal, or the
date of documented agreement, as applicable (see section II.M.5).
We also are proposing to revise Sec. 314.107(f)(2)(iv)
(redesignated as Sec. 314.107(f)(2)(i)(D)) to eliminate the
requirement that the notification to the Agency include a
``certification'' that an action has been filed. This requirement has
resulted in confusion, and the Agency has concluded that a written
``statement'' containing the necessary information is adequate. We are
proposing to require that this statement contain the patent number(s)
of the listed patent(s) at issue in the patent infringement action, in
addition to the court and case number. The patent number(s) of the
listed patent(s) at issue in the litigation will assist FDA in its
administration of the approval
[[Page 6869]]
requirements for 505(b)(2) applications and ANDAs.
We are proposing to expressly state that an NDA holder or its
representative also may notify FDA of the filing of any legal action
for patent infringement, irrespective of whether the NDA holder is an
exclusive patent licensee and initiated the patent infringement action.
The notification must be sent to the appropriate office or division and
contain the information described in proposed Sec. 314.107(f)(2)(i).
Proposed Sec. 314.107(f)(2)(iii) clarifies that a 505(b)(2)
application or ANDA may be approved upon expiration of the 45-day
period (if the 505(b)(2) or ANDA applicant confirms that a legal action
for patent infringement has not been filed within the 45-day period) or
upon completion of FDA's review of the 505(b)(2) application or ANDA,
whichever is later. This provision would apply, for example, if an
applicant changed a paragraph III certification or a statement pursuant
to section 505(b)(2)(B) or 505(j)(2)(A)(viii), as applicable, to a
paragraph IV certification during review of the 505(b)(2) application
or ANDA and the 45-day period had not elapsed by the time the office or
division was ready to take an action on the application. It is unlikely
that this provision would be implicated in most cases, however, because
a 505(b)(2) or ANDA applicant is required by statute to provide notice
of paragraph IV certification not later than 20 days after the date of
the postmark on the acknowledgment letter or paragraph IV
acknowledgment letter, and review of an application would not be
expected to be completed before the 45-day period for each recipient
had ended. The proposed revisions to Sec. 314.107(f)(2)(iii) and
(f)(3) would replace the current references to the approval of a
505(b)(2) application or ANDA being made effective because this text
incorrectly suggests that FDA might issue an approval letter that would
become effective at some date in the future (see section II.A.2.dd and
II.I). In addition, proposed Sec. 314.107(f)(2)(iii) clarifies that
FDA would not approve a 505(b)(2) application or ANDA upon expiration
of the 45-day period unless the 505(b)(2) or ANDA applicant had
confirmed that a legal action for patent infringement had not been
filed.
Proposed Sec. 314.107(f)(3) would permit a representative of the
patent owner or NDA holder who is an exclusive patent licensee to waive
the opportunity to file a patent infringement action within the 45-day
period. This revision is intended to conform with other sections of
part 314, including Sec. Sec. 314.52 and 314.95 which permit notice of
paragraph IV certification to be sent to a representative designated by
the patent owner to receive notice and the NDA holder's attorney,
agent, or other authorized official.
Finally, we are proposing to revise the title to Sec. 314.107(f)
and add titles to paragraphs (f)(1), (f)(2), and (f)(3) of that section
for administrative convenience.
II.M.7. Conversion of Approval to Tentative Approval (Proposed Sec.
314.107(g))
We are proposing to add Sec. 314.107(g) to clarify that if FDA
issues an approval letter in error or a court enters an order requiring
that the date of approval be delayed for an already approved 505(b)(2)
application or ANDA, FDA will convert the approval to a tentative
approval if appropriate.
An approved application may be converted to tentatively approved
status if a court determines that a listed patent has been infringed by
a 505(b)(2) or ANDA applicant and issues an order pursuant to 35 U.S.C.
271(e)(4) requiring that the effective date of approval shall not be
earlier than the date on which the infringed patent will expire,
including any pediatric exclusivity that may attach to that patent
(see, e.g., Mylan Labs., Inc. v. Thompson, 389 F.3d 1272 (D.C. Cir.
2004)). In addition, FDA will convert an approval to tentatively
approved status if the approval letter was issued in error (for
example, if an ANDA applicant failed to notify FDA of an adverse
decision in patent infringement litigation).
II.N. Assessing Bioavailability and Bioequivalence for Drugs Not
Intended To Be Absorbed Into the Bloodstream (Proposed Sec. 320.23)
The MMA amends section 505(j)(8) of the FD&C Act to explicitly
authorize FDA to establish methods for assessing bioavailability and
bioequivalence for drugs that are not absorbed into the bloodstream
(see section 505(j)(8)(A)(ii) and (j)(8)(C) of the FD&C Act). These
amendments essentially codify our existing practice of establishing
such methods, as reflected in current Sec. Sec. 320.23(a)(1) and
320.24 and in our implementation of these regulations.
Our proposal would revise the text of Sec. 320.23 to more
precisely reflect the text of section 505(j)(8) of the FD&C Act.
However, these proposed revisions are not intended to change our
current interpretation of Sec. 320.23, as the amendments to section
505(j)(8) of the FD&C Act are intended to codify our existing
interpretation (see section 1103(b) of the MMA, which specifically
states that the amendments made to section 505(j)(8) of the FD&C Act
``do[] not alter the standards for approval of [ANDAs].'').
II.O. Miscellaneous
II.O.1. Clarifying Revisions and Editorial Changes
We are proposing several clarifying revisions and editorial changes
throughout the sections of parts 314 and 320 that are the subject of
this rulemaking. These changes are intended to promote consistency
throughout our regulations, incorporate ``plain language,'' employ
grammatically correct phrasing, and otherwise clarify the text of these
regulations. Examples of proposed revisions that are not otherwise
described in this document are provided below.
Change ``means'' to ``is'' after each term described in
the definitions section (see proposed Sec. 314.3(b));
change ``shall'' to ``must'' as appropriate (see generally
part 314);
change ``are required'' to ``must'' because an applicant
is always required to comply with applicable regulations (see proposed
Sec. 314.50(d)(5));
change ``prior to the submission of'' to ``before
submitting'' for clarity (see proposed Sec. 314.50(d)(5));
change ``claims no uses'' to ``does not claim a use'' to
correct grammar (see proposed Sec. Sec. 314.52(a) and 314.95(a)); and
change ``each amendment to Sec. 314.50(d)(1)'' to ``each
amendment to a section of the NDA described in Sec. 314.50(d)(1)'' for
clarity (see proposed Sec. 314.60(d)).
In the codified section of this proposed rule, we have indicated
proposed editorial changes as amendatory instructions to remove and add
text. In some instances, however, it was necessary to print an entire
paragraph to indicate proposed changes that are only editorial changes
and would not affect substantive portions of the proposed rule.
We also are proposing to correct statutory citations in part 314
that have changed due to a series of amendments to the FD&C Act (see,
e.g., proposed Sec. Sec. 314.52(c), 314.60(c), and 314.95(c) and (f)).
II.O.2. Effect of Other Rulemaking
In anticipation of the Agency's business process efforts to move
all submissions to FDA to electronic submission, we are proposing
certain revisions to provisions that clearly contemplate submission of
paper to facilitate the transition to electronic submissions and reduce
the volume of conforming revisions that may be needed in the future.
Examples of these proposed revisions are provided below:
[[Page 6870]]
Change ``in a form other than hard copy, for example, on
microfiche or computer tapes'' to ``in an alternate form'' to reflect
advances in technology and facilitate the transition to electronic
submissions (see proposed Sec. 314.50(f)(4));
delete references to ``mailing cover'' (see proposed
Sec. Sec. 314.53(d)(6) and 314.70(b)(4)); and
change ``cover letter'' to ``submission'' (see proposed
Sec. 314.70(a)(6)).
FDA is committed to adapting its business practices to evolving
technology, including using the significant advancements in Web-based,
electronic systems. We anticipate that Web-based filing of most
submissions eventually will be required. We anticipate that when such a
change to an electronic submission system is implemented, future
guidance will address any technical questions related to such
submissions. Until such time, the sponsor or applicant must submit them
in the manner described in the regulations and to the appropriate FDA
location identified in the regulations.
III. Legal Authority
The MMA and sections 505, 505A, 527, and 701 (21 U.S.C. 360cc and
371) of the FD&C Act provide the principal legal authority for this
proposed rule. Section 505(b) of the FD&C Act describes the contents of
an NDA and 505(b)(2) application, including patent listing and patent
certification requirements. Section 505(j) of the FD&C Act describes
the contents of an ANDA, including bioequivalence information, patent
certification requirements, and criteria for a petitioned ANDA. Section
505(b) and (j) of the FD&C Act restrict certain amendments and
supplements to a 505(b)(2) application or an ANDA. Section 505(b), (c),
and (j) of the FD&C Act describe the timing of approval for 505(b)(2)
applications and ANDAs that are subject to the patent and marketing
exclusivity protections accorded the listed drug(s) relied upon and the
RLD, respectively. Section 505(j) also describes the availability of
180-day exclusivity for a first ANDA applicant.
Section 505A of the FD&C Act describes the availability of
pediatric exclusivity and describes the effect of such exclusivity on
approval of 505(b)(2) applications and ANDAs. Section 527 of the FD&C
Act describes the effect of orphan exclusivity on approval of 505(b)(2)
applications and ANDAs.
Thus, sections 505, 505A, and 527 of the FD&C Act, in conjunction
with our general rulemaking authority in section 701(a) of the FD&C
Act, serve as our principal legal authority for this proposal.
IV. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity).
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. We do not believe this proposed rule would result in
a significant impact on a substantial number of small entities, but the
impacts are uncertain. Because we are uncertain whether the proposed
rule would have a significant economic impact on a substantial number
of small entities, this and other sections of the preamble and the full
preliminary regulatory impact analysis constitute the Agency's
regulatory flexibility analysis.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (20132) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.
This proposed rule would implement portions of the MMA in a manner
that preserves the balance struck in the 1984 Hatch-Waxman Amendments
between encouraging the availability of less expensive generic drugs
and bringing innovative new drugs to market. This rule would also
revise and clarify procedures related to the approval of 505(b)(2)
applications and ANDAs to reduce uncertainty among drug firms, reduce
costs to industry, and reduce demands on FDA resources responding to
industry inquiries.
FDA has been implementing the MMA directly from the statute for
several years and based on this experience has identified opportunities
to clarify MMA provisions through the adoption of codified language. To
the extent that clarified regulatory language improves certainty among
regulated entities, this proposal, if promulgated, would reduce
industry compliance costs and Agency enforcement costs. The full
discussion of economic impacts is available in docket FDA-2011-N-0830
and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 1).
IV.A. Summary of the Benefits and Costs of the Proposed Rule
Although many provisions of this proposed rule would codify current
practice, elements of this proposal would lead to changes that generate
additional benefits and costs. This proposed rule would affect
applicants and application holders for NDAs (including 505(b)(2)
applications) and ANDAs. Provisions of this rule would affect the
submission of patent information by NDA holders for listing in the
Orange Book and the submission by 505(b)(2) and ANDA applicants of a
patent certification or statement addressing the listed patent(s) for
the listed drug(s) relied upon or RLD, respectively. This proposed rule
would also affect, for those certifying that a listed patent is
invalid, unenforceable, or not infringed (paragraph IV certification),
the requirements for the provision of notice of the paragraph IV
certification to each patent owner and the NDA holder for the listed
drug. The proposed rule would also affect other requirements associated
with 505(b)(2) applications and ANDAs.
This proposed rule would revise certain aspects of the regulations
on listing of patent information, patent certification requirements,
and a 30-month stay of approval. It would also update regulations
pertaining to the type of bioavailability and bioequivalence data that
can be used to support 505(b)(2) applications and ANDAs. These proposed
revisions to the Agency's regulations in parts 314 and 320 would
implement portions of Title XI of the MMA and facilitate compliance
with and enforcement of the FD&C Act.
We present a summary of benefits and costs in Table 16. The
estimated annual monetized benefits of this proposed rule are $194,314,
and estimated annual monetized costs are $91,371. We have also
identified, but are unable to
[[Page 6871]]
quantify, impacts from proposed changes to submitted patent information
and the implementation of an administrative consequence for failing to
provide notice within the timeframe specified by the MMA.
Table 16--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
Primary Low High ---------------------------------------
Category estimate estimate estimate Year Discount Period Notes
dollars rate covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits
Annualized Monetized $millions/year............................ $0.19 $0.19 $0.19 ........... 7% Annual ...........
$0.19 $0.19 $0.19 ........... 3% Annual ...........
Annualized Quantified.......................................... ......... ......... ......... ........... 7% Annual ...........
...........
Qualitative.................................................... ......... ......... ......... ........... 3% Annual ...........
Costs
Annualized Monetized $millions/year............................ $0.09 $0.09 $0.09 2012 7% Annual ...........
$0.09 $0.09 $0.09 2012 3% Annual ...........
Annualized Quantified.......................................... ......... ......... ......... ........... 7% ........... ...........
Qualitative.................................................... ......... ......... ......... ........... 3% ...........
Transfers
Federal Annualized Monetized $millions/year.................... ......... ......... ......... ........... 7% ........... None.
......... ......... ......... ........... 3% ...........
From/To........................................................ From: To:
Other Annualized Monetized $millions/year...................... ......... ......... ......... ........... 7% ........... None.
From/To........................................................ From: To: 3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects
State, Local, or Tribal Government: Not applicable
Small Business: For firms with 25 to 49 employees, which is a more likely lower bound for firms submitting 505(b)(2) applications, the unit cost of this
provision would be less than 0.05 percent of average shipments.
Wages: No estimated effect
Growth: No estimated effect
--------------------------------------------------------------------------------------------------------------------------------------------------------
IV.B. Summary of Regulatory Flexibility Analysis
FDA conducted a regulatory flexibility analysis of the impact of
the proposed rule on small entities. Statistics on the classification
of firms by employment size from the U.S. Bureau of the Census show
that in 2005, at least 85 percent of pharmaceutical manufacturing
entities had fewer than 500 employees and would have been considered
small by the U.S. Small Business Administration (Ref. 2).
We have provided monetized estimates for $194,314 in benefits and
$91,371 in costs. These costs of this proposed rule are generally small
unit costs incurred across many entities. Our estimated unit costs for
all but one item are less than $190 per unit. In table 17, we express
the unit cost of an amendment to a patent certification in terms of
hundredths of a percent of average establishment shipments. Excluding
one item (505(b)(2) applicants providing a patent certification to a
pharmaceutically equivalent drug product), there are costs of $83,146
attributable to about 1,200 units. Some affected entities would face
multiple unit costs of some type in a year, but even this circumstance
would not approach a significant impact on a substantial number of
small entities. For a unit cost of $190 to amount to 1 percent of
average shipments among establishment with fewer than 5 employees, the
entity would have to incur that cost more than 40 times.
Table 17--Small Entity Characteristics and the Impact of Unit Costs
Attributable to This Proposed Rule
------------------------------------------------------------------------
------------------------------------------------------------------------
Pharmaceutical Preparation
Manufacturing
(NAICS 325412)
------------------------------------------------------------------------
No. of Employees.................... <5 20-49
Total Value of Shipments ($1,000)... 187,933 978,494
No. of Establishments............... 228 109
Average Value of Shipments ($)...... 824,268 8,977,009
Unit Costs of Identifying a 0.50% 0.046%
Pharmaceutically Equivalent Drug
Product as a Listed Drug Relied
Upon per Sec. 314.50(i)(1)(i)(C)
as a Percentage of the Average
Value of Shipments.................
------------------------------------------------------------------------
V. Paperwork Reduction Act of 1995
This proposed rule contains information collection requirements
that are subject to public comment and review by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). We describe these provisions below in this
section of the document with an estimate of the annual reporting
burden. Our estimate includes the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
[[Page 6872]]
We invite comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Title: Abbreviated New Drug Applications and 505(b)(2)
Applications; Proposed Revisions to Implement Portions of the Medicare
Prescription Drug, Improvement, and Modernization Act of 2003 and Other
Changes.
Description of Respondents: Respondents to this collection of
information are NDA applicants (including 505(b)(2) applicants) and
ANDA applicants, patent owners, and their representatives.
Burden Estimate: This proposed rule would implement portions of
Title XI of the MMA that pertain to a 505(b)(2) or ANDA applicant's
provision of notice of paragraph IV certification to each patent owner
and the NDA holder; the availability of 30-month stays of approval on
505(b)(2) applications and ANDAs that are otherwise ready to be
approved; submission of amendments and supplements to 505(b)(2)
applications and ANDAs; and the types of bioavailability and
bioequivalence data that can be used to support these applications.
This proposed rule also would amend certain regulations regarding
505(b)(2) applications and ANDAs to facilitate compliance with and
efficient enforcement of the FD&C Act.
FDA currently has OMB approval for the collection of information
entitled ``Application for Food and Drug Administration Approval to
Market a New Drug'' (OMB control number 0910-0001). This collection of
information includes, among other things:
The requirements in Sec. Sec. 314.50(i) and 314.94(a)(12)
for submission of an appropriate patent certification or statement in a
505(b)(2) application or ANDA;
the requirements in Sec. Sec. 314.52 and 314.95 for a
505(b)(2) or ANDA applicant to send notice of any paragraph IV
certification to each patent owner and the NDA holder and amend its
505(b)(2) application or ANDA to certify that notice has been provided
and to document receipt of the notice;
the content requirements in Sec. 314.54 for a 505(b)(2)
application;
the requirements in Sec. Sec. 314.60 and 314.96 for
applicants that amend an unapproved 505(b)(2) application or ANDA,
respectively;
the requirements in Sec. Sec. 314.70 and 314.97 for
supplements submitted to FDA for certain changes to an approved
505(b)(2) application or ANDA;
the requirements in Sec. Sec. 314.90 and 314.99 for
applicants that request waivers from FDA for compliance with Sec. Sec.
314.50 through 314.81 or Sec. Sec. 314.92 through 314.99,
respectively;
the procedures in Sec. 314.107(c) by which a first
applicant notifies FDA of the date of first commercial marketing;
the requirement in Sec. 314.107(e) for an applicant to
submit to FDA a copy of certain court decisions related to a patent
that is the subject of a paragraph IV certification;
the requirement in Sec. 314.107(f) for a 505(b)(2) or
ANDA applicant to notify FDA immediately of the filing of any legal
action within 45 days of receipt of the notice of paragraph IV
certification by each patent owner or the NDA holder; and
the requirement in Sec. 314.107(f) for a patent owner or
NDA holder who is an exclusive patent licensee that waives its
opportunity to file a legal action for patent infringement within the
45-day period to submit to FDA a waiver in the specified format.
FDA has OMB approval for the collection of information entitled
``General Administrative Procedures: Citizen Petitions; Petition for
Reconsideration or Stay of Action; Advisory Opinions'' (OMB control
number 0910-0183). This collection of information includes, among other
things, the requirements in Sec. 314.93 for submitting a suitability
petition in accordance with 21 CFR 10.20 and 10.30.
FDA also has received OMB approval for the collection of
information entitled ``Applications for Food and Drug Administration
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'' (OMB control number 0910-
0513). This collection of information includes the requirements in
Sec. 314.50(h) for submission of patent information in an NDA, an
amendment, or a supplement, as described in Sec. 314.53. Section
314.53 requires that an applicant submitting an NDA, an amendment, or a
supplement, except as provided in Sec. 314.53(d)(2), submit on Forms
FDA 3542a and 3542 the required patent information described in this
section.
We are not reestimating these approved burdens. Only the reporting
burdens associated with the MMA's amendments to the FD&C Act and the
proposed changes to parts 314 and 320 are estimated.
Under section 505(b), (c), and (j) of the FD&C Act and this
proposed rule, the following information would be submitted to FDA but
is not currently approved by OMB under the PRA:
Proposed Sec. 314.50(i)(1)(i)(C) would require a 505(b)(2)
applicant to submit an appropriate patent certification or statement
for each patent listed in the Orange Book for a drug product(s) that is
pharmaceutically equivalent to the proposed drug product for which the
505(b)(2) application is submitted. Proposed Sec. 314.54 would require
a 505(b)(2) applicant to identify a pharmaceutically equivalent product
as a listed drug relied upon and to comply with applicable regulatory
requirements. Generally, 505(b)(2) applications submitted for a
proposed drug product for which there is an approved pharmaceutical
equivalent already cite the pharmaceutically equivalent product as a
listed drug relied upon to support approval. Therefore, we are not
estimating a new burden for proposed Sec. 314.54 at this time. Based
on our experience reviewing 505(b)(2) applications, we estimate that
proposed Sec. 314.50(i)(1)(i)(C) may result in approximately two
instances per year in which an applicant is required to identify a
pharmaceutically equivalent drug product as a listed drug relied upon
and comply with applicable regulatory requirements (including
submission of an appropriate patent certification or statement for each
patent listed in the Orange Book for the pharmaceutically equivalent
listed drug relied upon). Based on an estimated average of 2.6 patents
by each NDA holder for listing in the Orange Book, we estimate that
there will be 5.2 responses per year, and the burden hours associated
with this requirement in proposed Sec. 314.50(i)(1)(i)(C) will be
approximately 2 hours per response. If the patent certification
submitted pursuant to proposed Sec. 314.50(i)(1)(i)(C) is a paragraph
IV certification, the applicant also must comply with the requirements
in Sec. 314.52 for notice of paragraph IV certification, which add
[[Page 6873]]
approximately 80 hours (15.33 hours per response) to the currently
approved burden hours. This estimate reflects other proposals described
in this section of the document that would reduce the currently
approved burden for Sec. 314.52 from 16 hours per response to 15 hours
per response, and the additional content requirement in proposed Sec.
314.52(c) that would increase the estimated burden by 0.33 hours per
response. As previously noted, we are not reestimating approved burdens
in this document. Accordingly, the estimate provided for Sec.
314.52(a), (b), (c), and (e) reflects the additional burden that may
arise from the requirement in proposed Sec. 314.50(i)(1)(i)(C) if the
505(b)(2) applicant submits a paragraph IV certification. We separately
describe and estimate the burden of the additional content requirement
in proposed Sec. 314.52(c) for the estimated average of seven
505(b)(2) applications filed per year that contain one or more
paragraph IV certification.
Proposed Sec. Sec. 314.50(i)(6) and 314.94(a)(12)(viii) would
require a 505(b)(2) or ANDA applicant to amend its patent certification
from a paragraph IV certification to a paragraph III certification
after the court enters a final decision from which no appeal has been
or can be taken, or signs a settlement order or consent decree with a
finding of infringement (unless the patent also is found invalid).
Proposed Sec. Sec. 314.50(i)(6) and 314.94(a)(12)(viii) also would
require a 505(b)(2) or ANDA applicant to submit an amended patent
certification in certain circumstances after the NDA holder has
requested to remove a patent or patent information from the list. Based
on our experience and review of selected court decisions, we estimate
that there are approximately 12 instances per year in which a party has
submitted a court decision or order with a finding of infringement. In
addition, there are approximately 24 instances per year in which the
NDA holder has requested to remove a patent or patent information from
the list and the patent or patent information has been removed. Based
on our experience, we estimate that this requirement may result in
approximately 36 and 108 instances per year in which an applicant
amends its 505(b)(2) application or ANDA, respectively, to submit a
revised patent certification, and the burden hours associated with this
requirement will be approximately 2 hours per response. Proposed
Sec. Sec. 314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(vi)(C)(1)(ii)
would expressly codify the current requirement for a 505(b)(2) or ANDA
applicant to submit a patent certification or statement if, after
submission of the application, a new patent is issued by the PTO that
in the opinion of the applicant and to the best of its knowledge,
claims the listed drug or an approved use for such listed drug and for
which information is required to be filed by the NDA holder. The burden
hours associated with compliance with current provisions of Sec. Sec.
314.50(i)(1) through (i)(6) and 314.94(a)(12)(i) through (a)(12)(viii)
are described in the burden hours estimate currently approved under OMB
control number 0910-0001.
Proposed Sec. Sec. 314.52(a) and 314.95(a) would expand the list
of acceptable delivery methods that may be used to send notice of
paragraph IV certification to the NDA holder and each patent owner, and
thereby reduce the burden on applicants to submit, under current
Sec. Sec. 314.52(a) and (e), a request to FDA to use common alternate
delivery methods. We receive approximately 205 written inquiries per
year from 505(b)(2) or ANDA applicants requesting permission to send
notice of paragraph IV certification by an overnight delivery service.
Proposed Sec. Sec. 314.52(a) and 314.95(a) would eliminate the
requirement to submit a request to use a designated delivery service,
as defined in proposed Sec. Sec. 314.52(f) and 314.95(f). We estimate
that approximately 95 percent of these written inquiries will no longer
be required because the alternate delivery method would fall within the
definition of a ``designated delivery service'' in proposed Sec. Sec.
314.52(g) and 314.95(g).
Proposed Sec. Sec. 314.52(c) and 314.95(c) would require that
notice of paragraph IV certification contain a statement that the
applicant has received the acknowledgment letter or the paragraph IV
acknowledgment letter, as applicable. In addition, proposed Sec.
314.52(c) would require that the notice of paragraph IV certification
contain a statement that a 505(b)(2) application that contains any
required bioavailability or bioequivalence data has been submitted by
the applicant and filed by FDA, as required by section 505(b)(3)(D)(i)
of the FD&C Act. We estimate that these additional content requirements
for the notice of paragraph IV certification would increase the burden
of providing notice of paragraph IV certification by approximately 20
minutes. Based on an estimated average of 7 505(b)(2) applications
filed per year that contain one or more paragraph IV certifications and
209 ANDAs received per year that contain one or more paragraph IV
certifications, we estimate that there will be 21 and 627 responses per
year, and the burden hours associated with this requirement will be
approximately 20 minutes per response.
Proposed Sec. Sec. 314.52(d)(1) and 314.95(d)(1) would require
notice of paragraph IV certification regardless of whether notice has
already been provided for another paragraph IV certification contained
in the 505(b)(2) application or ANDA or an amendment or supplement to
the 505(b)(2) application or ANDA, as required by section
505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act. Since enactment
of the MMA, FDA has regulated directly from the statute and required
notice of paragraph IV certification in these circumstances. Thus, the
burden associated with this statutory requirement is reflected in the
burden hours estimate for Sec. Sec. 314.52 and 314.95 currently
approved under OMB control number 0910-0001.
Proposed Sec. Sec. 314.52(e) and 314.95(e) would permit a
505(b)(2) or ANDA applicant to submit a single amendment containing
documentation of timely sending and receipt of notice of paragraph IV
certification. Currently, an applicant is required to amend its
505(b)(2) application or ANDA both at the time of sending notice of
paragraph IV certification and after the notice was received by each
patent owner and the NDA holder (see current Sec. Sec. 314.52(b) and
(e) and 314.95(b) and (e)). Proposed Sec. 314.95(e) also would require
an ANDA applicant to include in its amendment a dated printout of the
Orange Book entry for the RLD. FDA has OMB approval for the burden
hours estimate of 16 hours per response for the estimated 260 responses
submitted annually to comply with Sec. Sec. 314.52 and 314.95 (see OMB
control number 0910-0001). We estimate that 2 hours of the 16 hours per
response are attributable to compliance with current Sec. Sec.
314.52(b) and (e) and 314.95(b) and (e). We estimate that the burden
hours associated with the requirement in proposed Sec. Sec. 314.52(e)
and 314.95(e) (including submission of the dated printout of the Orange
Book entry) would be approximately 1 hour per response for each of the
estimated 7 and 209 responses per year by our updated estimate of 7
505(b)(2) applicants and 209 ANDA applicants whose applications were
filed or received, as applicable, by FDA and contained one or more
paragraph IV certifications. Therefore, the proposal would reduce the
currently approved burden for Sec. Sec. 314.52 and 314.95 by 1 hour.
Proposed Sec. 314.53(c)(2) would decrease the patent information
that NDA applicants are currently required to submit for listing in the
Orange Book.
[[Page 6874]]
Proposed Sec. 314.53(c)(2) would require an NDA applicant to submit
information on a previously submitted patent only if a patent is a
reissued patent of a patent previously submitted for listing for the
NDA or supplement. Proposed Sec. 314.53(c)(2) would require submission
of patent information on whether a drug substance patent claims a
polymorph only if such patent claims only a polymorph that is the same
active ingredient described in the NDA or supplement. Proposed Sec.
314.53(c)(2) also would provide that an applicant that submits
information for a patent that claims either the drug substance or drug
product and meets the requirements for patent listing on that basis is
not required to provide information on whether that patent also claims
the drug product or drug substance, respectively. The information
collection resulting from current Sec. 314.50(h) (citing Sec. 314.53)
and Form FDA 3542a has been approved by OMB under control number 0910-
0153 for FDA's estimate of 20 hours per response. We estimate the
proposed revisions to our regulations will reduce the time needed to
complete Form FDA 3542a by approximately 3 hours per response.
Proposed Sec. 314.53(d)(2) would enable FDA to reduce duplicative
submission of patent information and require such information only for
a supplement to change the dosage form or route of administration, to
change the strength, to change the drug product from prescription to
OTC use, or to correct previously submitted patent information that
differently or no longer claims the changed product.
Proposed Sec. 314.53(f)(2) would expressly require correction or
change of patent information if the NDA holder determines that a patent
or patent claim no longer meets the statutory requirements for listing,
if the NDA holder is required by court order to amend patent
information or withdraw a patent from the list, or if the term of a
listed patent is extended under 35 U.S.C. 156(e). We estimate that
these corrections and changes of patent information would result in
approximately 62 submissions of Form FDA 3542 or other written
submission, as provided in proposed Sec. 314.53(f)(2)(iv), by
approximately 39 NDA holders. We further estimate that the burden hours
associated with the requirement in proposed Sec. 314.53(f)(2) would be
approximately 1 hour per response.
Section 505(b)(4)(A) and (j)(2)(D)(i) of the FD&C Act generally
prohibit the submission of certain types of changes in an amendment or
a supplement to a 505(b)(2) application or an ANDA, respectively.
Proposed Sec. Sec. 314.60(e) and 314.70(h) would prohibit an applicant
from amending or supplementing a 505(b)(2) application to seek approval
of a drug that has been modified to have a different active ingredient,
different route of administration, different dosage form, or certain
differences in excipients that the drug proposed in the original
submission of the 505(b)(2) application. These changes must be
requested in a new 505(b)(2) application. This proposed requirement
conforms with FDA's current policy regarding the types of proposed
changes to a drug product that should be submitted as a separate
application (see Separate Marketing Application Guidance). Accordingly,
the burden associated with this statutory requirement is reflected in
the burden hours estimate for Sec. Sec. 314.50 and 314.94 currently
approved under OMB control number 0910-0001 for 505(b)(2) applications
and ANDAs, respectively.
Proposed Sec. Sec. 314.60(f), 314.70(i), 314.96(d), and 314.97(c)
would require an applicant to submit a patent certification if approval
is sought for either of the following types of amendments or
supplements to a 505(b)(2) application or ANDA: (1) To add a new
indication or other condition of use or (2) to add a new strength.
Proposed Sec. Sec. 314.60(f) and 314.96(d) also would require an
applicant to submit a patent certification if approval is sought for
either of the following types of amendments to a 505(b)(2) application
or ANDA: (1) To make other than minor changes in product formulation or
(2) to change the physical form or crystalline structure of the active
ingredient. Although currently the submission of a patent certification
is required if, at any time before approval, the applicant learns that
the previously submitted patent certification is no longer accurate
with respect to the pending application or supplement, as amended (thus
the burden hours are currently approved under OMB control number 0910-
0001), the patent certification requirements would be broadened under
this proposed rule. We estimate that this requirement may result in
approximately six and four instances per year in which an applicant is
required to submit a patent certification with an amendment or
supplement, respectively, to its 505(b)(2) application. We further
estimate that this requirement may result in approximately 95 and 16
instances per year in which an applicant is required to submit a patent
certification with an amendment or supplement, respectively, to its
ANDA. The burden hours associated with these requirements are estimated
to be approximately 2 hours per response.
Proposed Sec. Sec. 314.96(c) and 314.97(b) would prohibit an ANDA
applicant from amending or supplementing an ANDA to seek approval of a
drug referring to a listed drug that is different from the RLD
identified in the ANDA. An applicant must submit a change of the RLD in
a new ANDA. We estimate that approximately one ANDA applicant per year
will be required to submit a new ANDA instead of submitting an
amendment for a change of the RLD. We also estimate that approximately
one ANDA applicant per year will be required to submit a new ANDA
instead of submitting a supplement for a change of the RLD. We further
estimate that the burden of submitting an ANDA and complying with
applicable regulatory requirements, including any required study to
demonstrate bioequivalence to the new RLD, will be approximately 288
hours for each of the estimated two responses per year.
Proposed Sec. 314.107(e) would expand the scope of the court
actions and documented agreements related to a patent described in
Sec. 314.107(b)(3) that are required to be submitted to FDA. Proposed
Sec. 314.107(e) also would require submission of any court order
pursuant to 35 U.S.C. 271(e)(4)(A) ordering that a 505(b)(2)
application or ANDA may be approved no earlier than the date specified.
FDA has OMB approval for the burden hours estimate of 30 minutes per
response for the estimated 98 responses submitted annually by 25
505(b)(2) or ANDA applicants to comply with Sec. 314.107(e) (see OMB
control number 0910-0001). Based on our experience, we estimate that
140 505(b)(2) and ANDA applicants will be required to submit a copy of
a court action, documented agreement, or written notification of appeal
in approximately 310 instances per year. We continue to estimate that
the burden associated with submitting a copy of these documents to FDA
is approximately 30 minutes per response.
The estimated burden of the burden of this collection of
information is described in Table 18.
[[Page 6875]]
Table 18--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average burden
21 CFR section Number of responses per Total annual per response Total hours
respondents respondent responses (in hours)
----------------------------------------------------------------------------------------------------------------
314.50(i)(1).................. 2 2.6 5.2 2............... 10.4
314.50(i)(6).................. 36 1 36 2............... 72
314.52(a), (b), (c), and (e).. 2 2.6 5.2 15.33........... 79.7
314.52(c)..................... 7 3 21 0.33 (20 7
minutes)..
314.53(f)..................... 39 1.5 62 1............... 62
314.60(f)..................... 6 1 6 2............... 12
314.70(i)..................... 4 1 4 2............... 8
314.94(a)(12)................. 108 1 108 2............... 216
314.95(c)..................... 209 3 627 0.33 (20 209
minutes)..
314.96(c)..................... 1 1 1 288............. 288
314.96(d)..................... 95 1 95 2............... 190
314.97(b)..................... 1 1 1 288............. 288
314.97(c)..................... 16 1 16 2............... 32
314.107(e).................... 140 2.2 310 0.5 (30 155
minutes)..
Total Reporting Burden .............. .............. .............. ................ 1629.1
Hours.
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
We have submitted the information collection requirements of this
rule to OMB for review. Interested persons are requested to send
comments regarding information collection to the Office of Information
and Regulatory Affairs, OMB (see ADDRESSES).
VI. Environmental Impact
The Agency has determined under 21 CFR 25.30(h) and 25.31(a) and
(g) that this action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.
VII. Effective Date
FDA proposes that any final rule based on this proposal become
effective 60 days after publication in the Federal Register.
We intend to apply this rule, if finalized, to any new submission
received by FDA on or after the effective date. This proposed rule
provides sufficient notice to all interested parties, including NDA
holders, NDA applicants (including 505(b)(2) applicants), and ANDA
applicants to adjust their submissions and actions by the time we issue
any final rule. However, we invite comments on how a final rule should
be implemented.
VIII. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.
IX. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. Identify
comments with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday, and will
be posted to the docket at http://www.regulations.gov.
X. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES), and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site addresses, but we are not responsible
for any subsequent changes to the Web sites after this document
publishes in the Federal Register.)
1. Preliminary Regulatory Impact Analysis, Initial Regulatory
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for
Abbreviated New Drug Applications and 505(b)(2) Applications;
Proposed Rule, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
2. U.S. Department of Commerce, Bureau of the Census, Economic
Census, Manufacturing Industry Series, Pharmaceutical Preparation
Manufacturing, Table 4, EC02-311-325412 (RV), 2002.
List of Subjects
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 320
Drugs, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, FDA proposes
to amend 21 CFR parts 314 and 320 as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
0
1. The authority citation for 21 CFR part 314 is revised to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356,
356a, 356b, 356c, 360cc, 371, 374, 379e.
0
2. Section 314.3 is revised to read as follows:
Sec. 314.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the Federal Food, Drug, and Cosmetic Act apply to
[[Page 6876]]
those terms when used in this part and part 320 of this chapter.
(b) The following definitions of terms apply to this part and part
320 of this chapter:
180-day exclusivity period is the 180-day period beginning on the
date of the first commercial marketing of the drug (including the
commercial marketing of the reference listed drug) by any first
applicant. The 180-day period ends on the day before the date on which
an ANDA submitted by an applicant other than a first applicant could be
approved.
Abbreviated application, abbreviated new drug application, or ANDA
is the application described under Sec. 314.94, including all
amendments and supplements to the application.
Acknowledgment letter is a written, postmarked communication from
FDA to an applicant stating that the Agency has determined that a
505(b)(2) application or ANDA is sufficiently complete to permit a
substantive review. An acknowledgment letter indicates that the
505(b)(2) application is regarded as filed or the ANDA is regarded as
received.
Act is the Federal Food, Drug, and Cosmetic Act (section 201 et
seq. (21 U.S.C. 301 et seq.)).
Active ingredient is any component that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or to affect the
structure or any function of the body of man or other animals. The term
includes those components that may undergo chemical change in the
manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
Active moiety is the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt
(including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of
the molecule, responsible for the physiological or pharmacological
action of the drug substance.
ANDA holder is the applicant that owns an approved ANDA.
Applicant is any person who submits an NDA (including a 505(b)(2)
application) or ANDA or an amendment or supplement to an NDA or ANDA
under this part to obtain FDA approval of a new drug and any person who
owns an approved NDA (including a 505(b)(2) application) or ANDA.
Application, new drug application, or NDA is the application
described under Sec. 314.50, including all amendments and supplements
to the application. An NDA refers to ``stand-alone'' applications
submitted under section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act and to 505(b)(2) applications.
505(b)(2) application is an NDA submitted under section 505(b)(1)
of the Federal Food, Drug, and Cosmetic Act for a drug for which the
investigations described in section 505(b)(1)(A) of the Federal Food,
Drug, and Cosmetic Act and relied upon by the applicant for approval of
the NDA were not conducted by or for the applicant and for which the
applicant has not obtained a right of reference or use from the person
by or for whom the investigations were conducted.
Approval letter is a written communication to an applicant from FDA
approving an NDA or an ANDA.
Assess the effects of the change is to evaluate the effects of a
manufacturing change on the identity, strength, quality, purity, and
potency of a drug product as these factors may relate to the safety or
effectiveness of the drug product.
Authorized generic drug is a listed drug, as defined in this
section, that has been approved under section 505(c) of the Federal
Food, Drug, and Cosmetic Act and is marketed, sold, or distributed
directly or indirectly to the retail class of trade with labeling,
packaging (other than repackaging as the listed drug in blister packs,
unit doses, or similar packaging for use in institutions), product
code, labeler code, trade name, or trademark that differs from that of
the listed drug.
Bioavailability is the rate and extent to which the active
ingredient or active moiety is absorbed from a drug product and becomes
available at the site of drug action. For drug products that are not
intended to be absorbed into the bloodstream, bioavailability may be
assessed by scientifically valid measurements intended to reflect the
rate and extent to which the active ingredient or active moiety becomes
available at the site of drug action.
Bioequivalence is the absence of a significant difference in the
rate and extent to which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical alternatives becomes
available at the site of drug action when administered at the same
molar dose under similar conditions in an appropriately designed study.
Where there is an intentional difference in rate (e.g., in certain
extended release dosage forms), certain pharmaceutical equivalents or
alternatives may be considered bioequivalent if there is no significant
difference in the extent to which the active ingredient or moiety from
each product becomes available at the site of drug action. This applies
only if the difference in the rate at which the active ingredient or
moiety becomes available at the site of drug action is intentional and
is reflected in the proposed labeling, is not essential to the
attainment of effective body drug concentrations on chronic use, and is
considered medically insignificant for the drug. For drug products that
are not intended to be absorbed into the bloodstream, bioequivalence
may be assessed by scientifically valid measurements intended to
reflect the rate and extent to which the active ingredient or active
moiety becomes available at the site of drug action.
Bioequivalence requirement is a requirement imposed by FDA for in
vitro and/or in vivo testing of specified drug products that must be
satisfied as a condition of marketing.
Class 1 resubmission is the resubmission of an NDA or efficacy
supplement, following receipt of a complete response letter, that
contains one or more of the following: Final printed labeling, draft
labeling, certain safety updates, stability updates to support
provisional or final dating periods, commitments to perform
postmarketing studies (including proposals for such studies), assay
validation data, final release testing on the last lots used to support
approval, minor reanalyses of previously submitted data, and other
comparatively minor information.
Class 2 resubmission is the resubmission of an NDA or efficacy
supplement, following receipt of a complete response letter, that
includes any item not specified in the definition of ``Class 1
resubmission,'' including any item that would require presentation to
an advisory committee.
Commercial marketing is the introduction or delivery for
introduction into interstate commerce of a drug product described in an
approved ANDA, outside the control of the ANDA holder, except for
investigational use under part 312 of this chapter, but does not
include transfer of the drug product for reasons other than sale to
parties identified in the approved ANDA.
Complete response letter is a written communication to an applicant
from FDA usually describing all of the deficiencies that the Agency has
identified in an NDA or ANDA that must be satisfactorily addressed
before it can be approved.
Component is any ingredient intended for use in the manufacture of
a drug product, including those that may not appear in such drug
product.
[[Page 6877]]
Date of approval is the date on the approval letter from FDA
stating that the NDA or ANDA is approved. ``Date of approval'' refers
only to a final approval and not to a tentative approval.
Dosage form is the physical manifestation containing the active and
inactive ingredients that delivers a dose of the drug product. This
includes such factors as:
(1) The physical appearance of the drug product,
(2) The physical form of the drug product prior to dispensing to
the patient,
(3) The way the product is administered, and
(4) The design features that affect frequency of dosing.
Drug product is a finished dosage form, e.g., tablet, capsule, or
solution that contains a drug substance, generally, but not
necessarily, in association with one or more other ingredients.
Drug substance is an active ingredient that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease or to affect the
structure or any function of the human body, but does not include
intermediates used in the synthesis of such ingredient.
Efficacy supplement is a supplement to an approved NDA proposing to
make one or more related changes from among the following changes to
product labeling:
(1) Add or modify an indication or claim;
(2) Revise the dose or dose regimen;
(3) Provide for a new route of administration;
(4) Make a comparative efficacy claim naming another drug product;
(5) Significantly alter the intended patient population;
(6) Change the marketing status from prescription to over-the-
counter use;
(7) Provide for, or provide evidence of effectiveness necessary
for, the traditional approval of a product originally approved under
subpart H of part 314; or
(8) Incorporate other information based on at least one adequate
and well-controlled clinical study.
FDA is the Food and Drug Administration.
First applicant is an applicant that, on the first day on which a
substantially complete ANDA containing a paragraph IV certification is
submitted for approval of a drug, submits a substantially complete ANDA
that contains, and for which the applicant lawfully maintains, a
paragraph IV certification for the drug.
Inactive ingredient is any component other than an active
ingredient.
Listed drug is a new drug product that has been approved under
section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety
and effectiveness or under section 505(j) of the Federal Food, Drug,
and Cosmetic Act, which has not been withdrawn or suspended under
section 505(e)(1) through (e)(5) or section 505(j)(6) of the Federal
Food, Drug, and Cosmetic Act, 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 in the current edition of FDA's ``Approved Drug Products
With Therapeutic Equivalence Evaluations'' (the list) as an approved
drug. A drug product is deemed to be a listed drug on the date of the
approval letter for the NDA or ANDA for that drug product.
NDA holder is the applicant that owns an approved NDA.
Newly acquired information is data, analyses, or other information
not previously submitted to the Agency, which may include (but is not
limited to) data derived from new clinical studies, reports of adverse
events, or new analyses of previously submitted data (e.g., meta-
analyses) if the studies, events, or analyses reveal risks of a
different type or greater severity or frequency than previously
included in submissions to FDA.
Original application, original NDA is a pending NDA for which FDA
has never issued a complete response letter or approval letter, or an
NDA that was submitted again after FDA had refused to file it or after
it was withdrawn without being approved.
Paragraph IV acknowledgment letter is a written, postmarked
communication from FDA to an applicant stating that the Agency has
determined that a 505(b)(2) application or ANDA containing a paragraph
IV certification is sufficiently complete to permit a substantive
review. A paragraph IV acknowledgment letter indicates that the
505(b)(2) application is regarded as filed or the ANDA is regarded as
received.
Paragraph IV certification is a patent certification of invalidity,
unenforceability, or noninfringement described in Sec.
314.50(i)(1)(i)(A)(4) or Sec. 314.94(a)(12)(i)(A)(4).
Patent owner is the owner of the patent for which information is
submitted for an NDA.
Pharmaceutical alternatives are drug products that contain the
identical therapeutic moiety, or its precursor, but not necessarily in
the same amount or dosage form or as the same salt or ester. Each such
drug product individually meets either the identical or its own
respective compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where applicable,
content uniformity, disintegration times, and/or dissolution rates.
Pharmaceutical equivalents are drug products in identical dosage
forms and route(s) of administration that contain identical amounts of
the identical active drug ingredient, i.e., the same salt or ester of
the same therapeutic moiety, or, in the case of modified release dosage
forms that require a reservoir or overage or such forms as prefilled
syringes where residual volume may vary, that deliver identical amounts
of the active drug ingredient over the identical dosing period; do not
necessarily contain the same inactive ingredients; and meet the
identical compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where applicable,
content uniformity, disintegration times, and/or dissolution rates.
Postmark is an independently verifiable evidentiary record of the
date on which a document is transmitted, in an unmodifiable format, to
another party. For postmarks made by the U.S. Postal Service or a
designated delivery service, the date of transmission is the date on
which the document is received by the domestic mail service of the U.S.
Postal Service or by a designated delivery service. For postmarks
documenting an electronic event, the date of transmission is the date
(in a particular time zone) that FDA sends the electronic transmission
on its host system as evidenced by a verifiable record. If the sender
and the intended recipient are located in different time zones, it is
the sender's time zone that provides the controlling date of electronic
transmission.
Reference listed drug is the listed drug identified by FDA as the
drug product upon which an applicant relies in seeking approval of its
ANDA.
Reference standard is the drug product selected by FDA that an
applicant seeking approval of an ANDA must use in conducting an in vivo
bioequivalence study required for approval.
Resubmission is submission by the applicant of all materials needed
to fully address all deficiencies identified in the complete response
letter. An NDA or ANDA for which FDA issued a complete response letter,
but which was withdrawn before approval and later submitted again, is
not a resubmission.
Right of reference or use is the authority to rely upon, and
otherwise
[[Page 6878]]
use, an investigation for the purpose of obtaining approval of an NDA,
including the ability to make available the underlying raw data from
the investigation for FDA audit, if necessary.
Same drug product formulation is the formulation of the drug
product submitted for approval and any formulations that have minor
differences in composition or method of manufacture from the
formulation submitted for approval, but are similar enough to be
relevant to the Agency's determination of bioequivalence.
Specification is the quality standard (i.e., tests, analytical
procedures, and acceptance criteria) provided in an approved NDA or
ANDA to confirm the quality of drug substances, drug products,
intermediates, raw materials, reagents, components, in-process
materials, container closure systems, and other materials used in the
production of a drug substance or drug product. For the purpose of this
definition, acceptance criteria means numerical limits, ranges, or
other criteria for the tests described.
Strength is the amount of drug substance contained in, delivered,
or deliverable from a drug product, which includes:
(1)(i) The total quantity of drug substance in mass or units of
activity in a dosage unit or container closure (e.g., weight/unit dose,
weight/volume or weight/weight in a container closure, or units/volume
or units/weight in a container closure); and/or, as applicable.
(ii) The concentration of the drug substance in mass or units of
activity per unit volume or mass (e.g., weight/weight, weight/volume,
or units/volume); or
(2) Such other criteria the Agency establishes for determining the
amount of drug substance contained in, delivered, or deliverable from a
drug product if the weights and measures described in paragraph (i) of
this definition do not apply (e.g., certain drug-device combination
products for which the amount of drug substance is emitted per use or
unit time).
Substantially complete application is an ANDA that on its face is
sufficiently complete to permit a substantive review and contains all
the information required under section 505(j)(2)(A) of the Federal
Food, Drug, and Cosmetic Act and Sec. 314.94.
Tentative approval is notification that an NDA or ANDA otherwise
meets the requirements for approval under the Federal Food, Drug, and
Cosmetic Act, but cannot be approved because there is a 7-year period
of orphan exclusivity for a listed drug under section 527 of the
Federal Food, Drug, and Cosmetic Act and Sec. 316.31 of this chapter,
or that a 505(b)(2) application or ANDA otherwise meets the
requirements for approval under the Federal Food, Drug, and Cosmetic
Act, but cannot be approved until the conditions in Sec.
314.107(b)(1)(iii), (b)(3), or (c) are met; because there is a period
of exclusivity for the listed drug under Sec. 314.108; because there
is a period of pediatric exclusivity for the listed drug under section
505A of the Federal Food, Drug, and Cosmetic Act, or because a court
order pursuant to 35 U.S.C. 271(e)(4)(A) orders that the application
may be approved no earlier than the date specified. A drug product that
is granted tentative approval is not an approved drug and will not be
approved until FDA issues an approval letter after any necessary
additional review of the NDA or ANDA.
The list is the list of approved drug products published in FDA's
current ``Approved Drug Products With Therapeutic Equivalence
Evaluations,'' available electronically on FDA's Web site at http://www.fda.gov/cder.
Therapeutic equivalents are approved drug products that are
pharmaceutical equivalents and for which bioequivalence has been
demonstrated. Therapeutic equivalents can be expected to have the same
clinical effect and safety profile when administered to patients under
the conditions specified in the labeling.
0
3. Section 314.50 is amended by:
0
a. Removing from paragraph (a) introductory text, paragraphs (a)(5),
(d)(1)(v), (d)(5)(v), and (d)(5)(vi)(a), paragraph (e)(2) introductory
text, and paragraphs (f)(3), (g)(2), and (k) the word ``shall'' each
time it appears and adding in its place the word ``must'';
0
b. Removing from paragraphs (a)(5), (b), (c)(1), (c)(2)(i), and
(c)(2)(iv) through (c)(2)(viii), paragraph (d) introductory text,
paragraphs (d)(1)(i), (d)(1)(ii)(a), (d)(1)(iii) through (d)(1)(v),
(d)(3)(ii), and (d)(5)(iv), paragraph (e)(1)(i) introductory text,
paragraph (e)(2), paragraph (f) introductory text, paragraphs (f)(1)
through (f)(3), (g)(2), (j)(4)(i), (j)(4)(ii), and (k), paragraph (l)
heading, paragraph (l)(1) introductory text, and paragraphs (l)(2) and
(l)(4) the word ``application'' each time it appears and adding in its
place ``NDA'';
0
c. Removing from paragraph (j) introductory text the word ``shall'' and
adding in its place the word ``must'' and removing the phrase ``new
drug application'' and adding in its place ``NDA''; and
0
d. Revising the section heading and section introductory text,
paragraphs (a)(1) and (d)(5)(vi)(b), paragraph (e)(1) introductory
text, paragraphs (f)(4), (g)(3), and (i), paragraph (j)(4) introductory
text, the first two sentences of paragraph (j)(4)(iii), and paragraph
(l)(3).
The revisions read as follows:
Sec. 314.50 Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted
in the form and contain the information, as appropriate for the
particular submission, required under this section. Three copies of the
NDA are required: An archival copy, a review copy, and a field copy. An
NDA for a new chemical entity will generally contain an application
form, an index, a summary, five or six technical sections, case report
tabulations of patient data, case report forms, drug samples, and
labeling, including, if applicable, any Medication Guide required under
part 208 of this chapter. Other NDAs will generally contain only some
of those items, and information will be limited to that needed to
support the particular submission. These include an NDA of the type
described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic
Act, an amendment, and a supplement. The NDA is required to contain
reports of all investigations of the drug product sponsored by the
applicant, and all other information about the drug pertinent to an
evaluation of the NDA that is received or otherwise obtained by the
applicant from any source. FDA will maintain guidance documents on the
format and content of NDAs to assist applicants in their preparation.
(a) * * *
(1) The name and address of the applicant; the date of the NDA; the
NDA number if previously issued (for example, if the NDA is a
resubmission or an amendment or supplement); the name of the drug
product, including its established, proprietary, code, and chemical
names; the dosage form and strength; the route of administration; the
identification numbers of all INDs (as defined in Sec. 312.3(b) of
this chapter) that are referenced in the NDA; the identification
numbers of all drug master files and other applications under this part
that are referenced in the NDA; and the drug product's proposed
indications for use.
* * * * *
(d) * * *
(5) * * *
(vi) * * *
(b) The applicant must, under section 505(i) of the Federal Food,
Drug, and Cosmetic Act, update periodically its pending NDA with new
safety information learned about the drug that
[[Page 6879]]
may reasonably affect the statement of contraindications, warnings,
precautions, and adverse reactions in the draft labeling and, if
applicable, any Medication Guide required under part 208 of this
chapter. These ``safety update reports'' must include the same kinds of
information (from clinical studies, animal studies, and other sources)
and must be submitted in the same format as the integrated summary in
paragraph (d)(5)(vi)(a) of this section. In addition, the reports must
include the case report forms for each patient who died during a
clinical study or who did not complete the study because of an adverse
event (unless this requirement is waived). The applicant must submit
these reports:
(1) 4 months after the initial submission;
(2) In a resubmission following receipt of a complete response
letter; and
(3) At other times as requested by FDA. Before submitting the first
such report, applicants are encouraged to consult with FDA regarding
further details on its form and content.
* * * * *
(e) * * * (1) Upon request from FDA, the applicant must submit the
samples described below to the places identified in the Agency's
request. FDA generally will ask applicants to submit samples directly
to two or more Agency laboratories that will perform all necessary
tests on the samples and validate the applicant's analytical
procedures.
* * * * *
(f) * * *
(4) Applicants are invited to meet with FDA before submitting an
NDA to discuss the presentation and format of supporting information.
If the applicant and FDA agree, the applicant may submit tabulations of
patient data and case report forms in an alternate form.
(g) * * *
(3) If an applicant who submits an NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act obtains a ``right of reference or
use,'' as defined under Sec. 314.3(b), to an investigation described
in clause (A) of section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act, the applicant must include in its NDA a written statement
signed by the owner of the data from each such investigation that the
applicant may rely on in support of the approval of its NDA, and
provide FDA access to, the underlying raw data that provide the basis
for the report of the investigation submitted in its NDA.
* * * * *
(i) Patent certification--(1) Contents. A 505(b)(2) application is
required to contain the following:
(i) Patents claiming drug substance, drug product, or method of
use. (A) A certification with respect to each patent issued by the U.S.
Patent and Trademark Office that, in the opinion of the applicant and
to the best of its knowledge, claims the drug substance or drug product
on which investigations that are relied upon by the applicant for
approval of its 505(b)(2) application were conducted or that claims an
approved use for such drug and for which information is required to be
filed under section 505(b) and (c) of the Federal Food, Drug, and
Cosmetic Act and Sec. 314.53. For each such patent, the applicant must
provide the patent number and certify, in its opinion and to the best
of its knowledge, one of the following circumstances:
(1) That the patent information has not been submitted to FDA. The
applicant must entitle such a certification ``Paragraph I
Certification'';
(2) That the patent has expired. The applicant must entitle such a
certification ``Paragraph II Certification'';
(3) The date on which the patent will expire. The applicant must
entitle such a certification ``Paragraph III Certification''; or
(4) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for
which the 505(b)(2) application is submitted. The applicant must
entitle such a certification ``Paragraph IV Certification''. This
certification must be submitted in the following form:
I, (name of applicant), certify that Patent No. ______ (is
invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of) (name of proposed drug product) for which this
505(b)(2) application is submitted.
The certification must be accompanied by a statement that the
applicant will comply with the requirements under Sec. 314.52(a) with
respect to providing a notice to each owner of the patent or its
representative and to the holder of the approved NDA for the drug
product which is claimed by the patent or a use of which is claimed by
the patent and with the requirements under Sec. 314.52(b) with respect
to sending the notice and under Sec. 314.52(c) with respect to the
content of the notice.
(B) If the drug on which investigations that are relied upon by the
applicant were conducted is itself a licensed generic drug of a
patented drug first approved under section 505(b) of the Federal Food,
Drug, and Cosmetic Act, the appropriate patent certification under this
section with respect to each patent that claims the first-approved
patented drug or that claims an approved use for such a drug.
(C) If, before the date of submission of the 505(b)(2) application,
there is an approved drug product that is pharmaceutically equivalent
to the drug product for which the 505(b)(2) application is submitted,
an appropriate patent certification under this section with respect to
each patent that claims the drug substance or drug product or that
claims an approved use for such drug.
(ii) No relevant patents. If, in the opinion of the applicant and
to the best of its knowledge, there are no patents described in
paragraph (i)(1)(i) of this section, a certification in the following
form:
In the opinion and to the best knowledge of (name of applicant),
there are no patents that claim the drug or drugs on which
investigations that are relied upon in this 505(b)(2) application
were conducted or that claim a use of such drug or drugs.
(iii) Method-of-use patent. (A) If information that is submitted
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act
and Sec. 314.53 is for a method-of-use patent, and the labeling for
the drug product for which the applicant is seeking approval does not
include any indications or other conditions of use that are covered by
the use patent, a statement explaining that the method-of-use patent
does not claim any of the proposed indications or other conditions of
use.
(B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication or other condition of use that,
according to the patent information submitted under section 505(b) or
(c) of the Federal Food, Drug, and Cosmetic Act and Sec. 314.53 or in
the opinion of the applicant, is claimed by a use patent, the applicant
must submit an applicable certification under paragraph (i)(1)(i) of
this section.
(2) [Reserved]
(3) Licensing agreements. If a 505(b)(2) application is for a drug
or method of using a drug claimed by a patent and the applicant has a
licensing agreement with the patent owner, the applicant must submit a
certification under paragraph (i)(1)(i)(A)(4) of this section
(``Paragraph IV Certification'') as to that patent and a statement that
it has been granted a patent license. If the patent owner consents to
approval of the 505(b)(2) application (if otherwise justified) as of a
specific date, the 505(b)(2) application must contain a written
statement from the patent owner that it has a licensing agreement with
[[Page 6880]]
the applicant and that it consents to approval of the 505(b)(2)
application as of a specific date.
(4) Untimely filing of patent information. If a patent described in
paragraph (i)(1)(i) of this section is issued and the holder of the
approved NDA for the patented drug does not file with FDA the required
information on the patent within 30 days of issuance of the patent, an
applicant who submitted a 505(b)(2) application that, before the
submission of the patent information, contained an appropriate patent
certification is not required to submit an amended certification to
address the patent that is late-listed with respect to the pending
505(b)(2) application. Except as provided in Sec. 314.53(f)(1), an NDA
holder's amendment to the description of the approved method(s) of use
claimed by the patent will be considered untimely filing of patent
information if:
(i) The amendment is submitted more than 30 days after patent
issuance and it is not related to a corresponding change in approved
product labeling; or
(ii) The amendment is submitted more than 30 days after a
corresponding change in approved product labeling. An applicant whose
505(b)(2) application is filed after the NDA holder's untimely filing
of patent information or whose 505(b)(2) application was previously
filed but did not contain an appropriate patent certification at the
time of the patent submission must submit a certification under
paragraph (i)(1)(i) of this section or a statement under paragraph
(i)(1)(iii) of this section as to that patent.
(5) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec. 314.53(f).
Unless the patent information is withdrawn or changed, the applicant
must submit an appropriate certification for each relevant patent.
(6) Amended certifications. A certification submitted under
paragraphs (i)(1)(i) through (i)(1)(iii) of this section may be amended
at any time before the approval of the 505(b)(2) application. An
applicant must submit an amended certification as an amendment to a
pending 505(b)(2) application. If an applicant with a pending 505(b)(2)
application voluntarily makes a patent certification for an untimely
filed patent, the applicant may withdraw the patent certification for
the untimely filed patent. Once an amendment for the change in
certification has been submitted, the 505(b)(2) application will no
longer be considered to be one containing the prior certification.
(i) After finding of infringement. An applicant who has submitted a
paragraph IV certification and is sued for patent infringement must
submit an amendment to change its certification if a court enters a
final decision from which no appeal has been or can be taken, or signs
a settlement order or consent decree in the action that includes a
finding that the patent is infringed, unless the final decision,
settlement order, or consent decree also finds the patent to be
invalid. In its amendment, the applicant must certify under paragraph
(i)(1)(i)(A)(3) of this section that the patent will expire on a
specific date or, with respect to a patent claiming a method of use,
the applicant may instead provide a statement under paragraph
(i)(1)(iii) of this section if the applicant amends its 505(b)(2)
application such that the applicant is no longer seeking approval for a
method of use claimed by the patent.
(ii) After request to remove a patent or patent information from
the list. If the list reflects that an NDA holder has requested that a
patent be removed from the list and no ANDA applicant is eligible for
180-day exclusivity based on a paragraph IV certification to that
patent, the patent will be removed and any applicant with a pending
505(b)(2) application (including a tentatively approved 505(b)(2)
application) who has made a certification with respect to such patent
must submit an amendment to withdraw its certification. In the
amendment, the applicant must state the reason for withdrawing the
certification (that the patent has been removed from the list). If the
list reflects that an NDA holder has requested that a patent be removed
from the list and one or more first applicants are eligible for 180-day
exclusivity based on a paragraph IV certification to that patent, the
patent shall remain listed until any 180-day exclusivity is
extinguished. A 505(b)(2) applicant is not required to provide or
maintain a certification to a patent that remains listed only for
purposes of a first applicant's 180-day exclusivity for its ANDA. Once
an amendment to withdraw the certification has been submitted, the
505(b)(2) application will no longer be considered to be one containing
a paragraph IV certification to the patent. If removal of a patent from
the list results in there being no patents listed for the listed
drug(s) identified in the 505(b)(2) application, the applicant must
submit an amended certification reflecting that there are no listed
patents.
(iii) Other amendments. (A) Except as provided in paragraphs (i)(4)
and (i)(6)(iii)(B) of this section:
(1) An applicant must amend a submitted certification if, at any
time before the approval of the 505(b)(2) application, the applicant
learns that the submitted certification is no longer accurate; and
(2) An applicant must submit a certification or statement under
paragraph (i)(1) of this section if, after submission of the 505(b)(2)
application, a new patent is issued by the U.S. Patent and Trademark
Office that, in the opinion of the applicant and to the best of its
knowledge, claims a listed drug relied upon or that claims an approved
use for such listed drug for which information is required to be filed
under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic
Act and Sec. 314.53.
(B) An applicant is not required to submit a supplement to change a
submitted certification when information on an otherwise applicable
patent is submitted after the approval of the 505(b)(2) application,
except as provided in Sec. 314.70(i).
(j) * * *
(4) If the applicant claims exclusivity under Sec. 314.108(b)(4)
or (b)(5), the following information to show that the NDA contains
``new clinical investigations'' that are ``essential to approval of the
application or supplement'' and ``were conducted or sponsored by the
applicant'':
* * * * *
(iii) * * * If the applicant was the sponsor named in the Form FDA
1571 for an IND under which the new clinical investigation(s) that is
essential to the approval of its NDA was conducted, identification of
the IND by number. If the applicant was not the sponsor of the IND
under which the clinical investigation(s) was conducted, a
certification that the applicant or its predecessor in interest
provided substantial support for the clinical investigation(s) that is
essential to the approval of its NDA, and information supporting the
certification. * * *
* * * * *
(l) * * *
(3) Field copy. The applicant must submit a field copy of the NDA
that contains the technical section described in paragraph (d)(1) of
this section, a copy of the application form required under paragraph
(a) of this section, a copy of the summary required under paragraph (c)
of this section, and a certification that the field copy is a true copy
of the technical section described in paragraph (d)(1) of this section
[[Page 6881]]
contained in the archival and review copies of the NDA.
* * * * *
0
4. Section 314.52 is revised to read as follows:
Sec. 314.52 Notice of certification of invalidity or noninfringement
of a patent.
(a) Notice of certification. For each patent that claims the listed
drug or drugs relied upon or that claims a use for such listed drug or
drugs and for which the applicant submits a paragraph IV certification,
the applicant must send notice of such certification by registered or
certified mail, return receipt requested, or by a designated delivery
service, as defined in paragraph (g) of this section to each of the
following persons:
(1) Each owner of the patent that is the subject of the
certification or the representative designated by the owner to receive
the notice. The name and address of the patent owner or its
representative may be obtained from the U.S. Patent and Trademark
Office; and
(2) The holder of the approved NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act for each drug product which is
claimed by the patent or a use of which is claimed by the patent and
for which the applicant is seeking approval, or, if the NDA holder does
not reside or maintain a place of business within the U.S., the NDA
holder's attorney, agent, or other authorized official. The name and
address of the NDA holder or its attorney, agent, or authorized
official may be obtained from the Orange Book Staff, Office of Generic
Drugs, 7620 Standish Pl., Rockville, MD 20855.
(3) This paragraph does not apply to a use patent that does not
claim a use for which the applicant is seeking approval.
(4) An applicant may send notice by an alternative method only if
FDA has agreed in advance that the method will produce an acceptable
form of documentation.
(b) Sending the notice. (1) Except as provided under paragraph (d)
of this section, the applicant must send the notice required by
paragraph (a) of this section on or after the date it receives a
paragraph IV acknowledgment letter from FDA, but not later than 20 days
after the date of the postmark on the paragraph IV acknowledgment
letter. The 20-day clock described in this paragraph begins on the day
after the date of the postmark on the paragraph IV acknowledgment
letter. When the 20th day falls on Saturday, Sunday, or a Federal
holiday, the 20th day will be the next day that is not a Saturday,
Sunday, or Federal holiday.
(2) Any notice required by paragraph (a) of this section is invalid
if it is sent before the applicant's receipt of a paragraph IV
acknowledgment letter. The applicant will not have complied with this
paragraph until it sends valid notice.
(3) At the same time it sends the notice required by paragraph (a)
of this section, the applicant must submit to FDA an amendment to its
505(b)(2) application that includes a statement certifying that the
notice has been provided to each person identified under paragraph (a)
of this section and that the notice met the content requirement under
paragraph (c) of this section. A copy of the notice itself need not be
submitted to the Agency.
(c) Content of a notice. In the notice, the applicant must cite
section 505(b)(3)(D) of the Federal Food, Drug, and Cosmetic Act and
must include, but is not limited to, the following information:
(1) A statement that a 505(b)(2) application that contains any
required bioavailability or bioequivalence studies has been submitted
by the applicant and filed by FDA.
(2) The NDA number.
(3) A statement that the applicant has received the paragraph IV
acknowledgment letter for the 505(b)(2) application.
(4) The established name, if any, as defined in section 502(e)(3)
of the Federal Food, Drug, and Cosmetic Act, of the proposed drug
product.
(5) The active ingredient, strength, and dosage form of the
proposed drug product.
(6) The patent number and expiration date of each patent on the
list alleged to be invalid, unenforceable, or not infringed.
(7) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or
will not be infringed. The applicant must include in the detailed
statement:
(i) For each claim of a patent alleged not to be infringed, a full
and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or
unenforceable, a full and detailed explanation of the grounds
supporting the allegation.
(8) If the applicant alleges that the patent will not be infringed
and the applicant may later decide to file a civil action for
declaratory judgment in accordance with section 505(c)(3)(D) of the
Federal Food, Drug, and Cosmetic Act, then the notice must be
accompanied by an offer of confidential access to the 505(b)(2)
application for the sole and limited purpose of evaluating possible
infringement of the patent that is the subject of the paragraph IV
certification.
(9) If the applicant does not reside or have a place of business in
the United States, the name and address of an agent in the United
States authorized to accept service of process for the applicant.
(d) Amendment or supplement to a 505(b)(2) application. (1) If,
after receipt of an acknowledgment letter or paragraph IV
acknowledgment letter, an applicant submits an amendment or supplement
to its 505(b)(2) application that includes a paragraph IV
certification, the applicant must send the notice required by paragraph
(a) of this section at the same time that the amendment or supplement
to the 505(b)(2) application is submitted to FDA, regardless of whether
the applicant has already given notice with respect to another such
certification contained in the 505(b)(2) application or in an amendment
or supplement to the 505(b)(2) application.
(2) If, before receipt of a paragraph IV acknowledgment letter, an
applicant submits a paragraph IV certification in an amendment, the
applicant must send the notice required by paragraph (a) of this
section in accordance with the procedures in paragraph (b) of this
section.
(3) An applicant that submits an amendment or supplement to seek
approval of a different strength must provide notice of any paragraph
IV certification in accordance with paragraphs (d)(1) or (d)(2) of this
section, as applicable.
(e) Documentation of timely sending and receipt of notice. The
applicant must amend its 505(b)(2) application to provide documentation
of the date of receipt of the notice required under paragraph (a) of
this section by each person provided the notice. The amendment must be
submitted to FDA within 30 days after the last date on which notice was
received by a person described in paragraph (a) of this section. The
applicant's amendment also must include documentation that its notice
was sent on a date that complies with the timeframe required by
paragraph (b) or paragraph (d) of this section, as applicable. FDA will
accept, as adequate documentation of the date the notice was sent, a
copy of the registered mail receipt, certified mail receipt, or receipt
from a designated delivery service, as defined in paragraph (g) of this
section. FDA will accept as adequate documentation of the date of
receipt a return receipt, a signature proof of delivery by a designated
[[Page 6882]]
delivery service, or a letter acknowledging receipt by the person
provided the notice. An applicant may rely on another form of
documentation only if FDA has agreed to such documentation in advance.
A copy of the notice itself need not be submitted to the Agency.
(f) Approval. If the requirements of this section are met, the
Agency will presume the notice to be complete and sufficient and will
count the day following the date of receipt of the notice by the patent
owner or its representative and by the approved NDA holder as the first
day of the 45-day period provided for in section 505(c)(3)(C) of the
Federal Food, Drug, and Cosmetic Act. FDA may, if the applicant amends
its 505(b)(2) application with a written statement that a later date
should be used, count from such later date.
(g) Designated delivery services. (1) For purposes of this section,
the term ``designated delivery service'' is any delivery service
provided by a trade or business that the Agency determines:
(i) Is available to the general public throughout the United
States;
(ii) Records electronically to its database, kept in the regular
course of its business, or marks on the cover in which any item
referred to in this section is to be delivered, the date on which such
item was given to such trade or business for delivery; and
(iii) Provides overnight or 2-day delivery service throughout the
United States.
(2) FDA will periodically issue guidance regarding designated
delivery services that meet these criteria.
0
5. Section 314.53 is revised to read as follows:
Sec. 314.53 Submission of patent information.
(a) Who must submit patent information. This section applies to any
applicant who submits to FDA an NDA or an amendment to it under section
505(b) of the Federal Food, Drug, and Cosmetic Act and Sec. 314.50 or
a supplement to an approved NDA under Sec. 314.70, except as provided
in paragraph (d)(2) of this section.
(b) Patents for which information must be submitted and patents for
which information must not be submitted--(1) General requirements. An
applicant described in paragraph (a) of this section must submit the
required information, on the required FDA declaration form, set forth
in paragraph (c) of this section for each patent that claims the drug
or a method of using the drug that is the subject of the NDA or
amendment or supplement to it and with respect to which a claim of
patent infringement could reasonably be asserted if a person not
licensed by the owner of the patent engaged in the manufacture, use, or
sale of the drug product. For purposes of this part, such patents
consist of drug substance (active ingredient) patents, drug product
(formulation and composition) patents, and method-of-use patents. For
patents that claim the drug substance, the applicant must submit
information only on those patents that claim the drug substance that is
the subject of the pending or approved NDA or that claim a drug
substance that is the same as the active ingredient that is the subject
of the approved or pending NDA. For patents that claim only a polymorph
that is the same as the active ingredient described in the approved or
pending NDA, the applicant must certify in the required FDA declaration
form that the applicant has test data, as set forth in paragraph (b)(2)
of this section, demonstrating that a drug product containing the
polymorph will perform the same as the drug product described in the
NDA. For patents that claim a drug product, the applicant must submit
information only on those patents that claim a drug product, as is
defined in Sec. 314.3, that is described in the pending or approved
application. For patents that claim a method of use, the applicant must
submit information only on those patents that claim indications or
other conditions of use for which approval is sought or has been
granted in the NDA. The applicant must separately identify each pending
or approved method of use and related patent claim(s). For approved
NDAs, the applicant submitting the method-of-use patent must identify
with specificity the section of the approved labeling that corresponds
to the method of use claimed by the patent submitted. If the scope of
the method-of-use claim(s) of the patent does not cover every use of
the drug, the applicant must only identify the specific portion(s) of
the indication or other condition of use claimed by the patent. Process
patents, patents claiming packaging, patents claiming metabolites, and
patents claiming intermediates are not covered by this section, and
information on these patents must not be submitted to FDA.
(2) Test data for submission of patent information for patents that
claim only a polymorph. The test data, referenced in paragraph (b)(1)
of this section, must include the following:
(i) A full description of the polymorphic form of the drug
substance, including its physical and chemical characteristics and
stability; the method of synthesis (or isolation) and purification of
the drug substance; the process controls used during manufacture and
packaging; and such specifications and analytical methods as are
necessary to assure the identity, strength, quality, and purity of the
polymorphic form of the drug substance;
(ii) The executed batch record for a drug product containing the
polymorphic form of the drug substance and documentation that the batch
was manufactured under current good manufacturing practice
requirements;
(iii) Demonstration of bioequivalence between the executed batch of
the drug product that contains the polymorphic form of the drug
substance and the drug product as described in the NDA;
(iv) A list of all components used in the manufacture of the drug
product containing the polymorphic form and a statement of the
composition of the drug product; a statement of the specifications and
analytical methods for each component; a description of the
manufacturing and packaging procedures and in-process controls for the
drug product; such specifications and analytical methods as are
necessary to assure the identity, strength, quality, purity, and
bioavailability of the drug product, including release and stability
data complying with the approved product specifications to demonstrate
pharmaceutical equivalence and comparable product stability; and
(v) Comparative in vitro dissolution testing on 12 dosage units
each of the executed test batch and the NDA product.
(c) Reporting requirements--(1) General requirements. An applicant
described in paragraph (a) of this section must submit the required
patent information described in paragraph (c)(2) of this section for
each patent that meets the requirements described in paragraph (b) of
this section. We will not accept the patent information unless it is
submitted on the appropriate form, Form FDA 3542 or 3542a, and contains
the information required in paragraph (c)(2) of this section. These
forms may be obtained on the Internet at http://www.fda.gov by
searching for ``forms''.
(2) Drug substance (active ingredient), drug product (formulation
or composition), and method-of-use patents--(i) Original declaration.
For each patent that claims a drug substance (active ingredient), drug
product (formulation and composition), or method of use, the applicant
must submit Form FDA 3542a. The following information and verification
is required, subject to the exceptions listed in paragraph (c)(2)(i)(S)
of this section:
(A) NDA number;
[[Page 6883]]
(B) Name of NDA sponsor;
(C) Trade name (or proposed trade name) of new drug;
(D) Active ingredient(s) of new drug;
(E) Strength(s) of new drug;
(F) Dosage form of new drug;
(G) U.S. patent number, issue date, and expiration date of patent
submitted;
(H) The patent owner's name, full address, phone number and, if
available, fax number and email address;
(I) The name, full address, phone number and, if available, fax
number and email address of an agent or representative who resides or
maintains a place of business within the United States authorized to
receive notice of patent certification under section 505(b)(3) and
(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and Sec. Sec.
314.52 and 314.95 (if patent owner or NDA applicant or holder does not
reside or have a place of business within the United States);
(J) Information on whether the patent is a reissued patent of a
patent submitted previously for listing for the NDA or supplement;
(K) Information on whether the expiration date is a new expiration
date if the patent had been submitted previously for listing;
(L) Information on whether the patent is a product-by-process
patent in which the product claimed is novel;
(M) Information on the drug substance (active ingredient) patent,
including the following:
(1) Whether the patent claims the drug substance that is the active
ingredient in the drug product described in the NDA or supplement;
(2) Whether the patent claims only a polymorph that is the same
active ingredient that is described in the pending NDA or supplement;
(3) Whether the applicant has test data, described in paragraph
(b)(2) of this section, demonstrating that a drug product containing
only the polymorph will perform the same as the drug product described
in the NDA or supplement, and a description of the polymorphic form(s)
claimed by the patent for which such test data exist;
(4) Whether the patent claims only a metabolite of the active
ingredient; and
(5) Whether the patent claims only an intermediate;
(N) Information on the drug product (composition/formulation)
patent, including the following:
(1) Whether the patent claims the drug product for which approval
is being sought, as defined in Sec. 314.3; and
(2) Whether the patent claims only an intermediate;
(O) Information on each method-of-use patent, including the
following:
(1) Whether the patent claims one or more methods of using the drug
product for which use approval is being sought and a description of
each pending method of use or related indication and related patent
claim of the patent being submitted;
(2) Identification of the specific section(s) of the proposed
labeling for the drug product that corresponds to the method of use
claimed by the patent submitted (if the scope of the method-of-use
claim(s) of the patent does not cover every use of the drug, the
applicant must only identify the specific portion(s) of the indication
or other condition of use claimed by the patent); and
(3) An applicant that submits information for a patent that claims
one or more methods of using the drug product must also submit
information described in either paragraph (c)(2)(i)(M) or (c)(2)(i)(N)
of this section, regarding whether that patent also claims either the
drug substance (active ingredient) or the drug product (composition/
formulation).
(P) Whether there are no relevant patents that claim the drug
substance (active ingredient), drug product (formulation or
composition), or method(s) of use, for which the applicant is seeking
approval and with respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner of the
patent engaged in the manufacture, use, or sale of the drug product;
(Q) A signed verification that states:
The undersigned declares that this is an accurate and complete
submission of patent information for the NDA, amendment, or
supplement pending under section 505 of the Federal Food, Drug, and
Cosmetic Act. This time-sensitive patent information is submitted
pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR
314.53 and this submission complies with the requirements of the
regulation. I verify under penalty of perjury that the foregoing is
true and correct.;
and
(R) Information on whether the applicant, patent owner or attorney,
agent, representative, or other authorized official signed the form;
the name of the person; and the full address, phone number and, if
available, the fax number and email address.
(S) Exceptions to required submission of patent information:
(1) If an applicant submits the information described in paragraph
(c)(2)(i)(M) of this section for a patent that claims the drug
substance (active ingredient) and meets the requirements for listing on
that basis, then the applicant is not required to provide the
information described in paragraph (c)(2)(i)(N) of this section on
whether that patent also claims the drug product (composition/
formulation).
(2) If an applicant submits the information described in paragraph
(c)(2)(i)(N) of this section for a patent that claims the drug product
(composition/formulation) and meets the requirements for listing on
that basis, then the applicant is not required to provide the
information described in paragraph (c)(2)(i)(M) of this section on
whether that patent also claims the drug substance (active ingredient).
(ii) Submission of patent information upon and after approval.
Within 30 days after the date of approval of its NDA or supplement, the
applicant must submit Form FDA 3542 for each patent that claims the
drug substance (active ingredient), drug product (formulation and
composition), or approved method of use. FDA will rely only on the
information submitted on this form and will not list or publish patent
information if the patent declaration is incomplete or indicates the
patent is not eligible for listing. Patent information must also be
submitted for patents issued after the date of approval of the NDA as
required in paragraph (c)(2)(ii) of this section. As described in
paragraph (d)(3) of this section, to be timely filed, patent
information for patents issued after the date of approval of the NDA
must be submitted to FDA within 30 days of the date of issuance of the
patent. If the applicant submits the required patent information within
the 30 days, but we notify an applicant that a declaration form is
incomplete or shows that the patent is not eligible for listing, the
applicant must submit an acceptable declaration form within 15 days of
FDA notification to be considered timely filed. The following
information and verification statement is required, subject to the
exceptions listed in paragraph (c)(2)(ii)(T) of this section:
(A) NDA number;
(B) Name of NDA sponsor;
(C) Trade name of new drug;
(D) Active ingredient(s) of new drug;
(E) Strength(s) of new drug;
(F) Dosage form of new drug;
(G) Approval date of NDA or supplement;
(H) U.S. patent number, issue date, and expiration date of patent
submitted;
(I) The patent owner's name, full address, phone number and, if
available, fax number and email address;
(J) The name, full address, phone number and, if available, fax
number and email address of an agent or representative who resides or
maintains
[[Page 6884]]
a place of business within the United States authorized to receive
notice of patent certification under section 505(b)(3) and (j)(2)(B) of
the Federal Food, Drug, and Cosmetic Act and Sec. Sec. 314.52 and
314.95 (if patent owner or NDA applicant or holder does not reside or
have a place of business within the United States);
(K) Information on whether the patent is a reissued patent of a
patent submitted previously for listing for the NDA or supplement;
(L) Information on whether the expiration date is a new expiration
date if the patent had been submitted previously for listing;
(M) Information on whether the patent is a product-by-process
patent in which the product claimed is novel;
(N) Information on the drug substance (active ingredient) patent,
including the following:
(1) Whether the patent claims the drug substance that is the active
ingredient in the drug product described in the approved NDA;
(2) Whether the patent claims only a polymorph that is the same as
the active ingredient that is described in the approved NDA;
(3) Whether the applicant has test data, described in paragraph
(b)(2) of this section, demonstrating that a drug product containing
only the polymorph will perform the same as the drug product described
in the approved NDA and a description of the polymorphic form(s)
claimed by the patent for which such test data exist;
(4) Whether the patent claims only a metabolite of the active
ingredient; and
(5) Whether the patent claims only an intermediate;
(O) Information on the drug product (composition/formulation)
patent, including the following:
(1) Whether the patent claims the approved drug product as defined
in Sec. 314.3; and
(2) Whether the patent claims only an intermediate;
(P) Information on each method-of-use patent, including the
following:
(1) Whether the patent claims one or more approved methods of using
the approved drug product and a description of each approved method of
use or indication and related patent claim of the patent being
submitted;
(2) Identification of the specific section(s) of the approved
labeling for the drug product that corresponds to the method of use
claimed by the patent submitted (if the scope of the method-of-use
claim(s) of the patent does not cover every use of the drug, the
applicant must only identify the specific portion(s) of the indication
or other condition of use claimed by the patent);
(3) The description of the patented method of use as required for
publication (which must contain adequate information to assist
505(b)(2) and ANDA applicants in determining whether a listed method-
of-use patent claims a use for which the 505(b)(2) or ANDA applicant is
not seeking approval; for example, if the scope of the method-of-use
claim(s) of the patent does not cover every approved use of the drug,
then the description of the patented method of use must contain only
the specific portion(s) of the indication or other method of use
claimed by the patent); and
(4) An applicant that submits information for a patent that claims
one or more methods of using the drug product must also submit
information described in either paragraph (c)(2)(ii)(N) or
(c)(2)(ii)(O) of this section, regarding whether that patent also
claims either the drug substance (active ingredient) or the drug
product (composition/formulation).
(Q) Whether there are no relevant patents that claim the approved
drug substance (active ingredient), the approved drug product
(formulation or composition), or approved method(s) of use and with
respect to which a claim of patent infringement could reasonably be
asserted if a person not licensed by the owner of the patent engaged in
the manufacture, use, or sale of the drug product;
(R) A signed verification that states:
The undersigned declares that this is an accurate and complete
submission of patent information for the NDA, amendment, or
supplement approved under section 505 of the Federal Food, Drug, and
Cosmetic Act. This time-sensitive patent information is submitted
pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR
314.53 and this submission complies with the requirements of the
regulation. I verify under penalty of perjury that the foregoing is
true and correct.;
and
(S) Information on whether the applicant, patent owner or attorney,
agent, representative, or other authorized official signed the form;
the name of the person; and the full address, phone number and, if
available, the fax number and email address.
(T) Exceptions to required submission of patent information:
(1) If an applicant submits the information described in paragraph
(c)(2)(ii)(N) of this section for a patent that claims the drug
substance (active ingredient) and meets the requirements for listing on
that basis, then the applicant is not required to provide the
information described in paragraph (c)(2)(ii)(O) of this section on
whether that patent also claims the drug product (composition/
formulation).
(2) If an applicant submits the information described in paragraph
(c)(2)(ii)(O) of this section for a patent that claims the drug product
(composition/formulation) and meets the requirements for listing on
that basis, then the applicant is not required to provide the
information described in paragraph (c)(2)(ii)(N) of this section on
whether that patent also claims the drug substance (active ingredient).
(3) No relevant patents. If the applicant believes that there are
no relevant patents that claim the drug substance (active ingredient),
drug product (formulation or composition), or the method(s) of use for
which the applicant has received approval, and with respect to which a
claim of patent infringement could reasonably be asserted if a person
not licensed by the owner of the patent engaged in the manufacture,
use, or sale of the drug product, the applicant will verify this
information in the appropriate forms, Form FDA 3542 or 3542a.
(4) Authorized signature. The declarations required by this section
must be signed by the applicant or patent owner, or the applicant's or
patent owner's attorney, agent (representative), or other authorized
official.
(d) When and where to submit patent information--(1) Original NDA.
An applicant must submit with its original NDA submitted under this
part, including a 505(b)(2) application, the information described in
paragraph (c) of this section on each drug substance (ingredient), drug
product (formulation and composition), and method-of-use patent issued
before the NDA is filed with FDA and for which patent information is
required to be submitted under this section. If a patent is issued
after the NDA is filed with FDA but before the NDA is approved, the
applicant shall, within 30 days of the date of issuance of the patent,
submit the required patent information in an amendment to the NDA under
Sec. 314.60.
(2) Supplements. (i) An applicant must submit patent information
required under paragraph (c) of this section for a patent that claims
the drug substance, drug product, or method of use for which approval
is sought in any of the following supplements:
(A) To change the dosage form or route of administration;
(B) To change the strength; or
(C) To change the drug product from prescription use to over-the-
counter use.
[[Page 6885]]
(ii) If the applicant submits a supplement for a change other than
one of the changes listed under paragraph (d)(2)(i) of this section
(for example, to change the formulation, to add a new indication or
other condition of use, or to make any other patented change regarding
the drug substance, drug product, or any method of use), the following
patent information submission requirements apply:
(A) If existing patents for which information has already been
submitted to FDA for the product approved in the original NDA claim the
changed product, the applicant is not required to resubmit this patent
information unless the description of the patented method of use would
change upon approval of the supplement, and FDA will continue to list
this patent information for the product;
(B) If one or more existing patents for which information has
already been submitted to FDA no longer claim the changed product, the
applicant must submit a request to remove that patent information from
the list at the time of approval of the supplement;
(C) If one or more existing drug substance (active ingredient),
drug product (formulation and composition), or method-of-use patents
claim the changed product for which approval is sought in the
supplement and such patent information has not been submitted to FDA,
the applicant must submit the patent information required under
paragraph (c) of this section.
(3) Newly issued patents. If a patent is issued for a drug
substance, drug product, or method of use after an NDA is approved, the
applicant must submit to FDA, as described in paragraph (d)(4) of this
section, the required patent information within 30 days of the date of
issuance of the patent. If the required patent information is not
submitted within 30 days of the issuance of the patent, FDA will list
the patent, but patent certifications will be governed by the
provisions regarding untimely filed patents at Sec. Sec. 314.50(i)(4)
and (i)(6) and 314.94(a)(12)(vi) and (a)(12)(viii).
(4) Submission of Forms FDA 3542a and 3542.
(i) Patent information submitted with the filing of an NDA,
amendment, or supplement. The applicant must submit patent information
required by paragraphs (c)(1) and (c)(2)(i) of this section and Sec.
314.50(h) or Sec. 314.70(f) on Form FDA 3542a to the Central Document
Room, Center for Drug Evaluation and Research, Food and Drug
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. Form
FDA 3542a should not be submitted to the Orange Book Staff in the
Office of Generic Drugs.
(ii) Patent information submitted upon and after approval of an NDA
or supplement. The applicant must submit patent information required by
paragraphs (c)(1) and (c)(2)(ii) of this section on Form FDA 3542 to
the Office of Generic Drugs, OGD Document Room, Attention: Orange Book
Staff, 7620 Standish Pl., Rockville, MD 20855.
(5) Submission date. Patent information will be considered to be
submitted to FDA for purposes of paragraph (d)(3) of this section as of
the earlier of the date the information submitted on Form FDA 3542 is
date-stamped by the Office of Generic Drugs, Document Room, or
officially received electronically by FDA through the Electronic
Submissions Gateway.
(6) Identification. Each submission of patent information, except
information submitted with an original NDA, must bear prominent
identification as to its contents, i.e., ``Patent Information,'' or, if
submitted after approval of an NDA, ``Time-Sensitive Patent
Information.''
(e) Public disclosure of patent information. FDA will publish in
the list the patent number and expiration date of each patent that is
required to be, and is, submitted to FDA by an applicant, and for each
use patent, the approved indications or other conditions of use covered
by a patent. FDA will publish such patent information upon approval of
the NDA, or, if the patent information is submitted by the applicant
after approval of an NDA as provided under paragraph (d)(2) of this
section, as soon as possible after the submission to the Agency of the
patent information. A request for copies of the submitted patent
information must be sent in writing to the Division of Freedom of
Information (ELEM-1029), Food and Drug Administration, 12420 Parklawn
Dr., Element Bldg., Rockville, MD 20857. This information, and requests
for delisting patents, will be subject to public disclosure.
(f) Correction or change of patent information--(1) Requests by
persons other than the NDA holder. If any person disputes the accuracy
or relevance of patent information submitted to the Agency under this
section and published by FDA in the list, or believes that an NDA
holder has failed to submit required patent information, that person
must first notify the Agency in a written or electronic communication
titled ``314.53(f) Patent Listing Dispute'' that states the grounds for
disagreement. Such notification should be directed to the Office of
Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620
Standish Pl., Rockville, MD 20855. The Agency will then request of the
applicable NDA holder that the correctness of the patent information or
omission of patent information be confirmed within 30 days. For listed
patents that claim an approved method of using the drug product, FDA
will request that the NDA holder confirm the correctness of its
description of the approved indication or method of use that has been
included as the ``Use Code'' in the Orange Book, and provide
information on the specific approved use claimed by the patent that
enables the Agency to make a determination in accordance with section
505(b)(2)(B) or 505(j)(2)(C)(viii) of the Federal Food, Drug, and
Cosmetic Act. Unless the NDA holder withdraws or amends its patent
information in response to FDA's request, the Agency will not change
the patent information in the list. If the NDA holder does not change
the patent information submitted to FDA, a 505(b)(2) application or an
ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act
submitted for a drug that is claimed by a patent for which information
has been submitted must, despite any disagreement as to the correctness
of the patent information, contain an appropriate certification for
each listed patent. However, if there is insufficient information to
make a determination in accordance with section 505(b)(2)(B) or
505(j)(2)(C)(viii) of the Federal Food, Drug, and Cosmetic Act, and the
NDA holder has confirmed the correctness of its description of the
specific approved use claimed by the patent, the Agency will review the
proposed labeling for the 505(b)(2) application or ANDA with deference
to the 505(b)(2) or ANDA applicant's interpretation of the scope of the
patent.
(2) Requests by the NDA holder.--(i) Patents or patent claims that
no longer meet the statutory requirements for listing. If the NDA
holder determines that a patent or patent claim no longer meets the
requirements for listing in section 505(b)(1) or 505(c)(2) of the
Federal Food, Drug, and Cosmetic Act (including if there has been a
judicial finding of invalidity for a listed patent, from which no
appeal has been or can be taken), the NDA holder is required to
promptly notify FDA to withdraw the patent or patent information and
request that the patent or patent information be removed from the list.
If the NDA holder is required by court order to amend patent
information or withdraw a patent from the list, it must submit a copy
of the order, within 14 days of the date the order was entered, to the
Office of
[[Page 6886]]
Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620
Standish Pl., Rockville, MD 20855. FDA will remove a patent from the
list if there is no first applicant eligible for 180-day exclusivity or
upon the expiration of the 180-day exclusivity period of a first
applicant.
(ii) Patent term restoration. If the term of a listed patent is
extended under 35 U.S.C. 156(e), the NDA holder must submit on Form FDA
3542 a correction to the expiration date of the patent. This correction
must be submitted within 30 days of receipt of a certificate of
extension as described in 35 U.S.C. 156(e)(1) or documentation of an
extension of the term of the patent as described in 35 U.S.C.
156(e)(2).
(iii) Submission of corrections or changes to patent information.
Corrections or changes to previously submitted patent information,
other than withdrawal of a patent and requests to remove a patent from
the list, must be submitted on Form FDA 3542 or 3542a, as appropriate.
We will not accept the corrections or changes unless they are submitted
on the appropriate forms.
(iv) Submission of patent withdrawals and requests to remove a
patent from the list. Withdrawal of a patent and requests to remove a
patent from the list must be submitted to the same addresses described
in paragraph (d)(4) of this section, except that the withdrawal or
request to remove a patent from the list is not required to be
submitted on Form FDA 3542 and may be submitted by letter. Withdrawal
of a patent and a request to delist a patent must contain the following
information:
(A) The NDA number to which the request applies;
(B) Each product(s) approved in the NDA to which the request
applies; and
(C) The patent number.
6. Section 314.54 is amended by removing the word ``shall'' and
adding in its place the word ``must'' in paragraph (a)(1) introductory
text and paragraph (a)(1)(i) and by revising the section heading,
paragraph (a) introductory text, and paragraphs (a)(1)(iii),
(a)(1)(vi), (a)(4), and (b) to read as follows:
Sec. 314.54 Procedure for submission of a 505(b)(2) application
requiring investigations for approval of a new indication for, or other
change from, a listed drug.
(a) The Federal Food, Drug, and Cosmetic Act does not permit
approval of an ANDA for a new indication, nor does it permit approval
of other changes in a listed drug if investigations, other than
bioavailability or bioequivalence studies, are essential to the
approval of the change. Any person seeking approval of a drug product
that represents a modification of a listed drug (e.g., a new indication
or new dosage form) and for which investigations, other than
bioavailability or bioequivalence studies, are essential to the
approval of the changes may, except as provided in paragraph (b) of
this section, submit a 505(b)(2) application. This 505(b)(2)
application need contain only that information needed to support the
modification(s) of the listed drug.
(1) * * *
(iii) Identification of each listed drug for which FDA has made a
finding of safety and effectiveness and on which finding the applicant
relies in seeking approval of its proposed drug product by established
name, if any, proprietary name, dosage form, strength, route of
administration, name of listed drug's application holder, and listed
drug's approved NDA number. The listed drug or drugs identified as
relied upon must include any approved drug product that:
(A) Is pharmaceutically equivalent to the drug product for which
the 505(b)(2) application is submitted; and
(B) Was approved before the 505(b)(2) application was submitted.
* * * * *
(vi) Any patent certification or statement required under section
505(b)(2) of the Federal Food, Drug, and Cosmetic Act with respect to
any relevant patents that claim the listed drug or drugs on which
investigations relied on by the applicant for approval of the
application were conducted, or that claim a use for the listed drug or
drug(s).
* * * * *
(4) The applicant must submit a field copy of the 505(b)(2)
application that contains the technical section described in Sec.
314.50(d)(1), a copy of the information required under Sec. 314.50(a)
and (c), and certification that the field copy is a true copy of the
technical section described in Sec. 314.50(d)(1) contained in the
archival and review copies of the 505(b)(2) application.
(b) A 505(b)(2) application may not be submitted under this section
for a drug product whose only difference from a listed drug is that:
(1) The extent to which its active ingredient(s) is absorbed or
otherwise made available to the site of action is less than that of the
listed drug; or
(2) The rate at which its active ingredient(s) is absorbed or
otherwise made available to the site of action is unintentionally less
than that of the listed drug.
0
7. Section 314.60 is amended by:
0
a. Removing the word ``application'' each time it appears and adding in
its place ``NDA'';
0
b. Removing ``(505)(c)(3)(D)(ii)'' in paragraphs (c)(1)(i) and (c)(2)
and adding in its place ``(505)(c)(3)(E)(ii)'';
0
c. Adding paragraph headings in paragraphs (a), (b), and (c);
0
d. Revising the section heading and paragraph (d); and
0
e. Adding new paragraphs (e) and (f).
The revisions read as follows:
Sec. 314.60 Amendments to an unapproved NDA, supplement, or
resubmission.
(a) Submission of NDA. * * *
(b) Submission of major amendment. * * *
(c) Limitation on certain amendments. * * *
(d) Field copy. The applicant must submit a field copy of each
amendment to a section of the NDA described in Sec. 314.50(d)(1). The
applicant must include in its submission of each such amendment to FDA
a statement certifying that a field copy of the amendment has been sent
to the applicant's home FDA district office.
(e) Different drug. An applicant may not amend a 505(b)(2)
application to seek approval of a drug that is a different drug from
the drug in the original submission of the 505(b)(2) application. For
purposes of this section, a drug is a different drug if it has been
modified to have a different active ingredient, different route of
administration, different dosage form, or difference in excipients that
requires either a separate clinical study to establish safety or
effectiveness or, for topical products, that requires a separate in
vivo demonstration of bioequivalence. However, notwithstanding the
limitation described in this paragraph, an applicant may amend the
505(b)(2) application to seek approval of a different strength.
(f) Patent certification requirements. An amendment to a 505(b)(2)
application is required to contain patent certifications described in
Sec. 314.50(i) if approval is sought for any of the following types of
amendments:
(1) To add a new indication or other condition of use;
(2) To add a new strength;
(3) To make other than minor changes in product formulation; or
(4) To change the physical form or crystalline structure of the
active ingredient.
0
8. Section 314.70 is amended by:
0
a. Removing the word ``application'' each time it appears and adding in
its place ``NDA'';
[[Page 6887]]
0
b. Removing the words ``cover letter'' in paragraph (a)(6), and adding
in their place the word ``submission'';
0
c. Removing the words ``and its mailing cover'' in paragraph (b)(4);
0
d. Revising the section heading and paragraph (f); and
0
e. Adding paragraphs (h) and (i).
The revisions read as follows:
Sec. 314.70 Supplements and other changes to an approved NDA.
* * * * *
(f) Patent information. The applicant must comply with the patent
information requirements under section 505(c)(2) of the Federal Food,
Drug, and Cosmetic Act and Sec. 314.53.
* * * * *
(h) Different drug. An applicant may not supplement a 505(b)(2)
application to seek approval of a drug that is a different drug from
the drug in the approved 505(b)(2) application. For purposes of this
section, a drug is a different drug if it has been modified to have a
different active ingredient, different route of administration,
different dosage form, or difference in excipients that requires either
a separate clinical study to establish safety or effectiveness or, for
topical products, that requires a separate in vivo demonstration of
bioequivalence. However, notwithstanding the limitation described in
this paragraph, an applicant may supplement the 505(b)(2) application
to seek approval of a different strength.
(i) Patent certification requirements. (1) Except as provided in
paragraph (i)(2) of this section, a supplement to a 505(b)(2)
application is required to contain patent certifications described in
Sec. 314.50(i) if approval is sought for either of the following types
of supplements:
(i) To add a new indication or other condition of use; or
(ii) To add a new strength.
(2) A supplement to a 505(b)(2) application that only seeks
approval to add a new indication or other condition of use is required
to contain patent certifications described in Sec. 314.50(i) only for
patents that are identified as claiming an approved use. If a method-
of-use patent is identified as also claiming the drug substance or drug
product, the patent certification also must address the drug substance
and/or drug product claims.
0
9. Section 314.90 is amended by removing the word ``application'' each
time it appears and adding in its place ``NDA'' and by adding paragraph
(c) to read as follows:
Sec. 314.90 Waivers.
* * * * *
(c) If FDA grants the applicant's waiver request with respect to a
requirement under Sec. Sec. 314.50 through 314.81, the waived
requirement will not constitute a basis for refusal to approve an NDA
under Sec. 314.125.
0
10. Section 314.93 is amended by:
0
a. Removing the words ``abbreviated new drug applications'' in
paragraph (a) and adding in their place ``ANDAs'';
0
b. Removing the words ``abbreviated new drug application'' in
paragraphs (b), (c), and (e)(3) and adding in their place ``ANDA'';
0
c. Removing the word ``or'' from the end of paragraph (e)(1)(iv) ;
0
d. Removing ``reasons.'' in paragraph (e)(1)(v) and adding in its place
``reasons; or'';
0
e. Adding paragraph (e)(1)(vi);
0
f. Redesignating paragraph (f) as paragraph (f)(1); and
0
g. Adding paragraph (f)(2).
The revisions read as follows:
Sec. 314.93 Petition to request a change from a listed drug.
* * * * *
(e) * * *
(1) * * *
(vi) A drug product is approved in an NDA for the change described
in the petition.
* * * * *
(f) * * *
(2) If, after approval of a petition and before approval of an ANDA
submitted pursuant to the approved petition, a drug product is approved
in an NDA for the change described in the petition, the petition and
the listed drug identified in the petition can no longer be the basis
for ANDA submission, irrespective of whether FDA has withdrawn approval
of the petition. A person seeking approval for such drug product must
submit a new ANDA that identifies the pharmaceutically equivalent
reference listed drug as the basis for ANDA submission and comply with
applicable regulatory requirements.
0
11. Section 314.94 is amended by:
0
a. Removing the words ``abbreviated application'' in paragraphs
(a)(5)(ii)(A), (a)(6)(ii), (d)(1)(i), and (d)(4) each time they appear
and adding in their place ``ANDA'';
0
b. Removing the word ``shall'' in paragraphs (a)(9)(i) through
(a)(9)(iv), (a)(12)(i)(A)(1) through (a)(12)(i)(A)(3), and (a)(12)(vii)
each time it appears and adding in its place the word ``must'';
0
c. Removing and reserving paragraph (a)(12)(iv); and
0
d. Revising the section heading and the introductory text, paragraph
(a) heading and introductory text, paragraphs (a)(1) and (a)(2),
paragraph (a)(3) heading and introductory text, paragraphs (a)(3)(i),
(a)(3)(iii), the first sentence of paragraph (a)(7)(ii), paragraphs
(a)(7)(iii), (a)(8)(i),(a)(9)(v), paragraph (a)(12)(i)(A) introductory
text, paragraphs (a)(12)(i)(A)(4), (a)(12)(i)(B), (a)(12)(iii)(A),
(a)(12)(iii)(B), (a)(12)(v), (a)(12)(vi), (a)(12)(viii), (a)(13), (b),
paragraph (d) heading, paragraph (d)(1) introductory text, and
paragraphs (d)(2) and (d)(5).
The revisions read as follows:
Sec. 314.94 Content and format of an ANDA.
ANDAs are required to be submitted in the form and contain the
information required under this section. Three copies of the
application are required, an archival copy, a review copy, and a field
copy. FDA will maintain guidance documents on the format and content of
applications to assist applicants in their preparation.
(a) ANDAs. Except as provided in paragraph (b) of this section, the
applicant must submit a complete archival copy of the ANDA that
includes the following:
(1) Application form. The applicant must submit a completed and
signed application form that contains the information described under
Sec. 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant must
state whether the submission is an ANDA under this section or a
supplement to an ANDA under Sec. 314.97.
(2) Table of contents. The archival copy of the ANDA is required to
contain a table of contents that shows the volume number and page
number of the contents of the submission.
(3) Basis for ANDA submission. An ANDA must refer to a listed drug.
Ordinarily, that listed drug will be the drug product selected by the
Agency as the reference standard for conducting bioequivalence testing.
The application must contain:
(i) The name of the reference listed drug, including its dosage
form and strength. For an ANDA based on an approved petition under
Sec. 10.30 of this chapter or Sec. 314.93, the reference listed drug
must be the same as the listed drug approved in the petition.
* * * * *
(iii) For an ANDA based on an approved petition under Sec. 10.30
of this chapter or Sec. 314.93, a reference to the FDA-assigned docket
number for the petition and a copy of FDA's correspondence approving
the petition.
* * * * *
(7) * * *
(ii) If the ANDA is submitted pursuant to a petition approved under
Sec. 314.93,
[[Page 6888]]
the results of any bioavailability or bioequivalence testing required
by the Agency, or any other information required by the Agency to show
that the active ingredients of the proposed drug product are of the
same pharmacological or therapeutic class as those in the reference
listed drug and that the proposed drug product can be expected to have
the same therapeutic effect as the reference listed drug. * * *
* * * * *
(iii) For each in vivo or in vitro bioequivalence study contained
in the ANDA:
(A) A description of the analytical and statistical methods used in
each study; and
(B) With respect to each study involving human subjects, a
statement that it either was conducted in compliance with the
institutional review board regulations in part 56 of this chapter, or
was not subject to the regulations under Sec. 56.104 or Sec. 56.105
of this chapter, and that it was conducted in compliance with the
informed consent regulations in part 50 of this chapter.
(8) Labeling--(i) Listed drug labeling. A copy of the currently
approved labeling (including, if applicable, any Medication Guide
required under part 208 of this chapter) for the listed drug referred
to in the ANDA, if the ANDA relies on a reference listed drug.
* * * * *
(9) * * *
(v) Inactive ingredient changes permitted in drug products intended
for topical use. Generally, a drug product intended for topical use,
solutions for aerosolization or nebulization, and nasal solutions must
contain the same inactive ingredients as the reference listed drug
identified by the applicant under paragraph (a)(3) of this section.
However, an ANDA may include different inactive ingredients provided
that the applicant identifies and characterizes the differences and
provides information demonstrating that the differences do not affect
the safety or efficacy of the proposed drug product.
* * * * *
(12) Patent certification--(i) Patents claiming drug, drug product,
or method of use. (A) A certification with respect to each patent
issued by the U.S. Patent and Trademark Office that, in the opinion of
the applicant and to the best of its knowledge, claims the reference
listed drug or that claims a use of such listed drug for which the
applicant is seeking approval under section 505(j) of the Federal Food,
Drug, and Cosmetic Act and for which information is required to be
filed under section 505(b) and (c) of the Federal Food, Drug, and
Cosmetic Act and Sec. 314.53. For each such patent, the applicant must
provide the patent number and certify, in its opinion and to the best
of its knowledge, one of the following circumstances:
* * * * *
(4) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for
which the ANDA is submitted. The applicant shall entitle such a
certification ``Paragraph IV Certification''. This certification must
be submitted in the following form:
I, (name of applicant), certify that Patent No. ____________(is
invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of) (name of proposed drug product) for which this
application is submitted.
The certification must be accompanied by a statement that the applicant
will comply with the requirements under Sec. 314.95(a) with respect to
providing a notice to each owner of the patent or their representatives
and to the holder of the approved application for the listed drug, with
the requirements under Sec. 314.95(b) with respect to sending the
notice, and with the requirements under Sec. 314.95(c) with respect to
the content of the notice.
(B) If the ANDA refers to a listed drug that is itself a licensed
generic product of a patented drug first approved under section 505(b)
of the Federal Food, Drug, and Cosmetic Act, the appropriate patent
certification under paragraph (a)(12)(i) of this section with respect
to each patent that claims the first-approved patented drug or that
claims a use for such drug.
* * * * *
(iii) Method-of-use patent. (A) If patent information is submitted
under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act
and Sec. 314.53 for a patent claiming a method of using the listed
drug, and the labeling for the drug product for which the applicant is
seeking approval does not include any indications or other conditions
of use that are covered by the use patent, a statement explaining that
the method-of-use patent does not claim any of the proposed indications
or other conditions of use.
(B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication or other condition of use that,
according to the patent information submitted under section 505(b) or
(c) of the Federal Food, Drug, and Cosmetic Act and Sec. 314.53 or in
the opinion of the applicant, is claimed by a use patent, an applicable
certification under paragraph (a)(12)(i) of this section.
(iv) [Reserved]
(v) Licensing agreements. If the ANDA is for a drug or method of
using a drug claimed by a patent and the applicant has a licensing
agreement with the patent owner, a paragraph IV certification as to
that patent and a statement that it has been granted a patent license.
(vi) Untimely filing of patent information. If a patent on the
listed drug is issued and the holder of the approved NDA for the listed
drug does not file with FDA the required information on the patent
within 30 days of issuance of the patent, an applicant who submitted an
ANDA for that drug that contained an appropriate patent certification
before the submission of the patent information is not required to
submit an amended certification to address the patent that is late-
listed with respect to the pending ANDA. Except as provided in Sec.
314.53(f)(1), an NDA holder's amendment to the description of the
approved method(s) of use claimed by the patent will be considered
untimely filing of patent information if:
(A) The amendment is submitted more than 30 days after patent
issuance and it is not related to a corresponding change in approved
product labeling; or
(B) The amendment is submitted more than 30 days after a
corresponding change in approved product labeling. An applicant whose
ANDA is submitted after the NDA holder's untimely filing of patent
information, or whose pending ANDA was previously submitted but did not
contain an appropriate patent certification at the time of the patent
submission, must submit a certification under paragraph (a)(12)(i) of
this section or a statement under paragraph (a)(12)(iii) of this
section as to that patent.
* * * * *
(viii) Amended certifications. A certification submitted under
paragraphs (a)(12)(i) through (a)(12)(iii) of this section may be
amended at any time before the date of approval of the ANDA. If an
applicant with a pending ANDA voluntarily makes a patent certification
for an untimely filed patent, the applicant may withdraw the patent
certification for the untimely filed patent. An applicant must submit
an amended certification as an amendment to a pending ANDA. Once an
amendment is submitted to change a certification, the ANDA will no
longer be considered to contain the prior certification.
[[Page 6889]]
(A) After finding of infringement. An applicant who has submitted a
paragraph IV certification and is sued for patent infringement must
submit an amendment to change its certification if a court enters a
final decision from which no appeal has been or can be taken, or signs
a settlement order or consent decree in the action that includes a
finding that the patent is infringed, unless the final decision,
settlement order, or consent decree also finds the patent to be
invalid. In its amendment, the applicant must certify under paragraph
(a)(12)(i)(A)(3) of this section that the patent will expire on a
specific date. Once an amendment for the change has been submitted, the
ANDA will no longer be considered to be one containing a paragraph IV
certification to the patent. If a final judgment finds the patent to be
invalid and infringed, an amended certification is not required.
(B) After request to remove a patent or patent information from the
list. If the list reflects that an NDA holder has requested that a
patent be removed from the list and no ANDA applicant is eligible for
180-day exclusivity based on a paragraph IV certification to that
patent, the patent will be removed and any applicant with a pending
ANDA (including a tentatively approved application) who has made a
certification with respect to such patent must submit an amendment to
withdraw its certification. In the amendment, the applicant must state
the reason for withdrawing the certification (that the patent is or has
been removed from the list). If the list reflects that an NDA holder
has requested that a patent be removed from the list and one or more
first applicants are eligible for 180-day exclusivity based on a
paragraph IV certification to that patent, the patent shall remain
listed until any 180-day exclusivity is extinguished. If one or more
first applicants are eligible for 180-day exclusivity based on a
paragraph IV certification to a patent that has been reissued, then the
first applicant must submit a paragraph IV certification to the
reissued patent within 30 days of listing to have lawfully maintained
its paragraph IV certification for purposes of eligibility for 180-day
exclusivity. After any applicable 180-day exclusivity has been
extinguished, the patent will be removed and any applicant with a
pending ANDA (including a tentatively approved application) who has
made a certification with respect to such patent must submit an
amendment to withdraw its certification. Once an amendment to withdraw
the certification has been submitted, the ANDA will no longer be
considered to be one containing a paragraph IV certification to the
patent. If removal of a patent from the list results in there being no
patents listed for the listed drug identified in the ANDA, the
applicant must submit an amended certification reflecting that there
are no listed patents.
(C) Other amendments. (1) Except as provided in paragraphs
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section:
(i) An applicant must amend a submitted certification if, at any
time before the date of approval of the ANDA, the applicant learns that
the submitted certification is no longer accurate; and
(ii) An applicant must submit a certification or statement under
paragraph (a)(12)(i) of this section if, after submission of the ANDA,
a new patent is issued by the U.S. Patent and Trademark Office that, in
the opinion of the applicant and to the best of its knowledge, claims
the reference listed drug or that claims an approved use for such
reference listed drug and for which information is required to be filed
under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic
Act and Sec. 314.53. For a paragraph IV certification, the
certification must not be submitted earlier than the first working day
after the day the patent is published in the list.
(2) An applicant is not required to submit a supplement to change a
submitted certification when information on a patent on the listed drug
is submitted after the approval of the ANDA, except as provided in
Sec. 314.97(c).
(13) Financial certification or disclosure statement. An ANDA must
contain a financial certification or disclosure statement as required
by part 54 of this chapter.
(b) Drug products subject to the Drug Efficacy Study Implementation
(DESI) review. If the ANDA is for a duplicate of a drug product that is
subject to FDA's DESI review (a review of drug products approved as
safe between 1938 and 1962) or other DESI-like review and the drug
product evaluated in the review is a listed drug, the applicant must
comply with the provisions of paragraph (a) of this section.
(c) [Reserved]
(d) Format of an ANDA. (1) The applicant must submit a complete
archival copy of the ANDA as required under paragraphs (a) and (c) of
this section. FDA will maintain the archival copy during the review of
the ANDA to permit individual reviewers to refer to information that is
not contained in their particular technical sections of the ANDA, to
give other Agency personnel access to the ANDA for official business,
and to maintain in one place a complete copy of the ANDA.
* * * * *
(2) For ANDAs, the applicant must submit a review copy of the ANDA
that contains two separate sections. One section must contain the
information described under paragraphs (a)(2) through (a)(6), (a)(8),
and (a)(9) of this section, and section 505(j)(2)(A)(vii) of the
Federal Food, Drug, and Cosmetic Act and a copy of the analytical
procedures and descriptive information needed by FDA's laboratories to
perform tests on samples of the proposed drug product and to validate
the applicant's analytical procedures. The other section must contain
the information described under paragraphs (a)(3), (a)(7), and (a)(8)
of this section. Each of the sections in the review copy is required to
contain a copy of the application form described under Sec. 314.50(a).
* * * * *
(5) The applicant must submit a field copy of the ANDA that
contains the technical section described in paragraph (a)(9) of this
section, a copy of the application form required under paragraph (a)(1)
of this section, and a certification that the field copy is a true copy
of the technical section described in paragraph (a)(9) of this section
contained in the archival and review copies of the ANDA.
0
12. Section 314.95 is revised to read as follows:
Sec. 314.95 Notice of certification of invalidity or noninfringement
of a patent.
(a) Notice of certification. For each patent that claims the listed
drug or that claims a use for such listed drug for which the applicant
is seeking approval and for which the applicant submits a paragraph IV
certification, the applicant must send notice of such certification by
registered or certified mail, return receipt requested, or by a
designated delivery service, as defined in paragraph (g) of this
section to each of the following persons:
(1) Each owner of the patent which is the subject of the
certification or the representative designated by the owner to receive
the notice. The name and address of the patent owner or its
representative may be obtained from the U.S. Patent and Trademark
Office; and
(2) The holder of the approved NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act for the listed drug that is
claimed by the patent and for which the applicant is seeking approval
or, if the NDA holder does not reside or maintain a place of business
[[Page 6890]]
within the United States, the NDA holder's attorney, agent, or other
authorized official. The name and address of the NDA holder or its
attorney, agent, or authorized official may be obtained from the Orange
Book Staff, Office of Generic Drugs, 7620 Standish Pl., Rockville, MD
20855.
(3) This paragraph does not apply to a use patent that does not
claim a use for which the applicant is seeking approval.
(4) An applicant may send notice by an alternative method only if
FDA has agreed in advance that the method will produce an acceptable
form of documentation.
(b) Sending the notice. (1) Except as provided under paragraph (d)
of this section, the applicant must send the notice required by
paragraph (a) of this section on or after the date it receives an
acknowledgment letter or a paragraph IV acknowledgment letter from FDA,
but not later than 20 days after the date of the postmark on the
acknowledgment letter. The 20-day clock described in this paragraph
begins on the day after the date of the postmark on the paragraph IV
acknowledgment letter. When the 20th day falls on Saturday, Sunday, or
a Federal holiday, the 20th day will be the next day that is not a
Saturday, Sunday, or Federal holiday.
(2) Any notice required by paragraph (a) of this section is invalid
if it is sent before the applicant's receipt of an acknowledgment
letter or a paragraph IV acknowledgment letter, or before the first
working day after the day the patent is published in the list. The
applicant will not have complied with this paragraph until it sends
valid notice.
(3) At the same time it sends the notice required by paragraph (a)
of this section, the applicant must submit to FDA an amendment to its
ANDA that includes a statement certifying that the notice has been
provided to each person identified under paragraph (a) of this section
and that the notice met the content requirements under paragraph (c) of
this section. A copy of the notice itself need not be submitted to the
Agency.
(c) Contents of a notice. In the notice, the applicant must cite
section 505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act
and must include, but is not limited to, the following information:
(1) A statement that FDA has received an ANDA submitted by the
applicant containing any required bioavailability or bioequivalence
data or information.
(2) The ANDA number.
(3) A statement that the applicant has received the acknowledgment
letter or paragraph IV acknowledgment letter for the ANDA.
(4) The established name, if any, as defined in section 502(e)(3)
of the Federal Food, Drug, and Cosmetic Act, of the proposed drug
product.
(5) The active ingredient, strength, and dosage form of the
proposed drug product.
(6) The patent number and expiration date of each listed patent for
the reference listed drug alleged to be invalid, unenforceable, or not
infringed.
(7) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or
will not be infringed. The applicant must include in the detailed
statement:
(i) For each claim of a patent alleged not to be infringed, a full
and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or
unenforceable, a full and detailed explanation of the grounds
supporting the allegation.
(8) If the applicant alleges that the patent will not be infringed
and the applicant may later decide to file a civil action for
declaratory judgment in accordance with section 505(j)(5)(C) of the
Federal Food, Drug, and Cosmetic Act, then the notice must be
accompanied by an offer of confidential access to the ANDA for the sole
and limited purpose of evaluating possible infringement of the patent
that is the subject of the paragraph IV certification.
(9) If the applicant does not reside or have a place of business in
the United States, the name and address of an agent in the United
States authorized to accept service of process for the applicant.
(d) Amendment or supplement to an ANDA. (1) If, after receipt of a
paragraph IV acknowledgment letter, an applicant submits an amendment
or supplement to its ANDA that includes a paragraph IV certification,
the applicant must send the notice required by paragraph (a) of this
section at the same time that the amendment or supplement to the ANDA
is submitted to FDA, regardless of whether the applicant has already
given notice with respect to another such certification contained in
the application or in an amendment or supplement to the application.
(2) If, before receipt of an acknowledgment letter or a paragraph
IV acknowledgment letter, an applicant submits an amendment to its ANDA
that includes a paragraph IV certification, the applicant must send the
notice required by paragraph (a) of this section in accordance with the
procedures in paragraph (b) of this section. If an ANDA applicant's
notice of its paragraph IV certification is timely provided in
accordance with paragraph (b) of this section, FDA will base its
determination of whether the applicant is a first applicant on the date
of submission of the amendment containing the paragraph IV
certification.
(3) An applicant that submits an amendment or supplement to seek
approval of a different strength must provide notice of any paragraph
IV certification in accordance with paragraph (d)(1) or (d)(2) of this
section, as applicable.
(e) Documentation of timely sending and receipt of notice. The
applicant must amend its ANDA to provide documentation of the date of
receipt of the notice required under paragraph (a) of this section by
each person provided the notice. The amendment must be submitted to FDA
within 30 days after the last date on which notice was received by a
person described in paragraph (a) of this section. The applicant's
amendment also must include documentation that its notice was sent on a
date that complies with the timeframe required by paragraph (b) or
paragraph (d) of this section, as applicable, and a dated printout of
the entry for the reference listed drug in FDA's ``Approved Drug
Products With Therapeutic Equivalence Evaluations'' (the list) that
includes the patent that is the subject of the paragraph IV
certification. FDA will accept, as adequate documentation of the date
the notice was sent, a copy of the registered mail receipt, certified
mail receipt, or receipt from a designated delivery service, as defined
in paragraph (g) of this section. FDA will accept as adequate
documentation of the date of receipt a return receipt, signature proof
of delivery by a designated delivery service, or a letter acknowledging
receipt by the person who provided the notice. An applicant may rely on
another form of documentation only if FDA has agreed to such
documentation in advance. A copy of the notice itself need not be
submitted to the Agency.
(f) Approval. If the requirements of this section are met, FDA will
presume the notice to be complete and sufficient, and it will count the
day following the date of receipt of the notice by the patent owner or
its representative and by the approved application holder as the first
day of the 45-day period provided for in section 505(j)(5)(B)(iii) of
the Federal Food, Drug, and Cosmetic Act. FDA may, if the applicant
provides a written statement to FDA that a later date should be used,
count from such later date.
[[Page 6891]]
(g) Designated delivery services. (1) For purposes of this section,
the term ``designated delivery service'' means any delivery service
provided by a trade or business that the Agency determines:
(i) Is available to the general public throughout the United
States;
(ii) Records electronically to its database, kept in the regular
course of its business, or marks on the cover in which any item
referred to in this section is to be delivered, the date on which such
item was given to such trade or business for delivery; and
(iii) Provides overnight or 2-day delivery service throughout the
United States.
(2) FDA will periodically issue guidance regarding designated
delivery services that meet these criteria.
0
13. Section 314.96 is amended by:
0
a. Revising the section heading;
0
b. Removing from the heading of paragraph (a) and from paragraph (a)(1)
the words ``abbreviated new drug application'' and adding in their
place ``ANDA'';
0
c. Removing from paragraph (a)(1) ``320.1(g)'' and adding in its place
``314.3'';
0
d. Removing from paragraph (b) the word ``shall'' each time it appears
and adding in its place the word ``must'';
0
e. Adding a heading to paragraph (b); and
0
f. Adding paragraphs (c) and (d).
The revisions read as follows:
Sec. 314.96 Amendments to an unapproved ANDA.
* * * * *
(b) Field copy. * * *
(c) Different listed drug. An applicant may not amend an ANDA to
seek approval of a drug referring to a listed drug that is different
from the reference listed drug identified in the ANDA. This paragraph
applies if, at any time before the approval of the ANDA, a different
listed drug is approved that is the pharmaceutical equivalent to the
product in the ANDA and is designated as a reference listed drug. This
paragraph also applies if changes are proposed in an amendment to the
ANDA such that the proposed product is a pharmaceutical equivalent to a
different listed drug than the reference listed drug identified in the
ANDA. A change of the reference listed drug must be submitted in a new
ANDA. However, notwithstanding the limitation described in this
paragraph, an applicant may amend the ANDA to seek approval of a
different strength.
(d) Patent certification requirements. An amendment to an ANDA is
required to contain patent certifications described in Sec.
314.94(a)(12) if approval is sought for any of the following types of
amendments:
(1) To add a new indication or other condition of use;
(2) To add a new strength;
(3) To make other than minor changes in product formulation; or
(4) To change the physical form or crystalline structure of the
active ingredient.
0
14. Section 314.97 is revised to read as follows:
Sec. 314.97 Supplements and other changes to an approved ANDA.
(a) General requirements. The applicant must comply with the
requirements of Sec. Sec. 314.70 and 314.71 regarding the submission
of supplemental applications and other changes to an approved ANDA.
(b) Different listed drug. An applicant may not supplement an ANDA
to seek approval of a drug referring to a listed drug that is different
from the current reference listed drug identified in the ANDA. This
paragraph applies if changes are proposed in a supplement to the ANDA
such that the proposed product is a pharmaceutical equivalent to a
different listed drug than the reference listed drug identified in the
ANDA. A change of reference listed drug must be submitted in a new
ANDA. However, notwithstanding the limitation described in this
paragraph, an applicant may supplement the ANDA to seek approval of a
different strength.
(c) Patent certification requirements. A supplement to an ANDA is
required to contain patent certifications described in Sec.
314.94(a)(12) if approval is sought for either of the following types
of supplements:
(1) To add a new indication or other condition of use; or
(2) To add a new strength.
0
15. Section 314.99 is revised to read as follows:
Sec. 314.99 Other responsibilities of an applicant of an ANDA.
(a) An applicant must comply with the requirements of Sec. 314.65
regarding withdrawal by the applicant of an unapproved ANDA and Sec.
314.72 regarding a change in ownership of an ANDA.
(b) An applicant may ask FDA to waive under this section any
requirement that applies to the applicant under Sec. Sec. 314.92
through 314.99. The applicant must comply with the requirements for a
waiver under Sec. 314.90. If FDA grants the applicant's waiver request
with respect to a requirement under Sec. Sec. 314.92 through 314.99,
the waived requirement will not constitute a basis for refusal to
approve an ANDA under Sec. 314.127.
0
16. Section 314.101 is revised to read as follows:
Sec. 314.101 Filing an NDA and receiving an ANDA.
(a) Filing an NDA. (1) Within 60 days after FDA receives an NDA,
the Agency will determine whether the NDA may be filed. The filing of
an NDA means that FDA has made a threshold determination that the NDA
is sufficiently complete to permit a substantive review.
(2) If FDA finds that none of the reasons in paragraphs (d) and (e)
of this section for refusing to file the NDA applies, the Agency will
file the NDA and notify the applicant in writing. In the case of a
505(b)(2) application that contains a paragraph IV certification, the
applicant will be notified via a paragraph IV acknowledgment letter.
The date of filing will be the date 60 days after the date FDA received
the NDA. The date of filing begins the 180-day period described in
section 505(c) of the Federal Food, Drug, and Cosmetic Act. This 180-
day period is called the ``filing clock.''
(3) If FDA refuses to file the NDA, the Agency will notify the
applicant in writing and state the reason under paragraph (d) or (e) of
this section for the refusal. If FDA refuses to file the NDA under
paragraph (d) of this section, the applicant may request in writing
within 30 days of the date of the Agency's notification an informal
conference with the Agency about whether the Agency should file the
NDA. If, following the informal conference, the applicant requests that
FDA file the NDA (with or without amendments to correct the
deficiencies), the Agency will file the NDA over protest under
paragraph (a)(2) of this section, notify the applicant in writing, and
review it as filed. If the NDA is filed over protest, the date of
filing will be the date 60 days after the date the applicant requested
the informal conference. The applicant need not resubmit a copy of an
NDA that is filed over protest. If FDA refuses to file the NDA under
paragraph (e) of this section, the applicant may amend the NDA and
resubmit it, and the Agency will make a determination under this
section whether it may be filed.
(b) Receiving an ANDA. (1) An ANDA will be reviewed after it is
submitted to determine whether the ANDA may be received. Receipt of an
ANDA means that FDA has made a threshold determination that the ANDA is
substantially complete.
[[Page 6892]]
(2) If FDA finds that none of the reasons in paragraphs (d) and (e)
of this section for considering the ANDA not to have been received
applies, the ANDA is substantially complete and the Agency will receive
the ANDA and notify the applicant in writing. If an ANDA is determined
to be substantially complete, the date of submission is considered to
be the date of receipt. In the case of an ANDA that contains a
paragraph IV certification, the applicant will be notified via a
paragraph IV acknowledgment letter.
(3) If FDA considers the ANDA not to have been received under
paragraph (d) or (e) of this section, FDA will notify the applicant.
The applicant may then:
(i) Withdraw the ANDA under Sec. 314.99; or
(ii) Amend the ANDA to correct the deficiencies; or
(iii) Take no action, in which case FDA will refuse to receive the
ANDA.
(4) If, after an ANDA has been received under paragraph (b)(2) of
this section, FDA determines that the applicant did not send notice of
a paragraph IV certification as required under Sec. 314.95 within the
timeframe specified in paragraph (b) or (d) of that section, the date
that the ANDA was submitted will be deemed to be delayed by the number
of days by which the timeframe required by Sec. 314.95(b) or (d) was
exceeded. When the date as delayed falls on Saturday, Sunday, or a
Federal holiday, the filing date will be the next day that is not a
Saturday, Sunday, or a Federal holiday.
(c) [Reserved]
(d) Application deficiencies. FDA may refuse to file an NDA or may
not consider an ANDA to be received if any of the following applies:
(1) The NDA or ANDA does not contain a completed application form.
(2) The NDA or ANDA is not submitted in the form required under
Sec. 314.50 or Sec. 314.94.
(3) The NDA or ANDA is incomplete because it does not on its face
contain information required under section 505(b) or section 505(j) of
the Federal Food, Drug, and Cosmetic Act and Sec. 314.50 or Sec.
314.94.
(4) The applicant fails to submit a complete environmental
assessment that addresses each of the items specified in the applicable
format under Sec. 25.40 of this chapter or fails to provide sufficient
information to establish that the requested action is subject to
categorical exclusion under Sec. 25.30 or Sec. 25.31 of this chapter.
(5) The NDA or ANDA does not contain an accurate and complete
English translation of each part of the application that is not in
English.
(6) The NDA or ANDA does not contain a statement for each
nonclinical laboratory study that it was conducted in compliance with
the requirements set forth in part 58 of this chapter or, for each
study not conducted in compliance with part 58 of this chapter, a brief
statement of the reason for the noncompliance.
(7) The NDA or ANDA does not contain a statement for each clinical
study that it was conducted in compliance with the institutional review
board regulations in part 56 of this chapter or was not subject to
those regulations, and that it was conducted in compliance with the
informed consent regulations in part 50 of this chapter or, if the
study was subject to but was not conducted in compliance with those
regulations, the NDA or ANDA does not contain a brief statement of the
reason for the noncompliance.
(8) The drug product that is the subject of the submission is
already covered by an approved NDA or ANDA and the applicant of the
submission:
(i) Has an approved NDA or ANDA for the same drug product; or
(ii) Is merely a distributor and/or repackager of the already
approved drug product.
(9) The NDA is submitted as a 505(b)(2) application for a drug that
is a duplicate of a listed drug and is eligible for approval under
section 505(j) of the Federal Food, Drug, and Cosmetic Act.
(e) Regulatory deficiencies. The Agency will refuse to file an NDA
or will consider an ANDA not to have been received if any of the
following applies:
(1) The drug product is subject to licensing by FDA under the
Public Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of
this chapter.
(2) Submission of a 505(b)(2) application or an ANDA for the active
moiety is not permitted under Sec. 314.108(b)(2).
(f) Outcome of FDA review. (1) Within 180 days after the date of
filing, plus the period of time the review period was extended (if
any), FDA will either:
(i) Approve the NDA; or
(ii) Issue a notice of opportunity for a hearing if the applicant
asked FDA to provide it an opportunity for a hearing on an NDA in
response to a complete response letter.
(2) Within 180 days after the date of receipt, plus the period of
time the review clock was extended (if any), FDA will either approve or
disapprove the ANDA. If FDA disapproves the ANDA, FDA will issue a
notice of opportunity for hearing if the applicant asked FDA to provide
it an opportunity for a hearing on an ANDA in response to a complete
response letter.
(3) This paragraph does not apply to NDAs or ANDAs that have been
withdrawn from FDA review by the applicant.
0
17. Section 314.105 is revised to read as follows:
Sec. 314.105 Approval of an NDA and an ANDA.
(a) FDA will approve an NDA and send the applicant an approval
letter if none of the reasons in Sec. 314.125 for refusing to approve
the NDA applies. An NDA is approved on the date of the issuance of the
approval letter. FDA will issue a tentative approval letter if an NDA
otherwise meets the requirements for approval under the Federal Food,
Drug, and Cosmetic Act, but cannot be approved because there is a 7-
year period of orphan exclusivity for the listed drug under section 527
of the Federal Food, Drug, and Cosmetic Act and Sec. 316.31, or if a
505(b)(2) application otherwise meets the requirements for approval
under the Federal Food, Drug, and Cosmetic Act, but cannot be approved
until the conditions in Sec. 314.107(b)(3) or (c) are met; because
there is a period of exclusivity for the listed drug under Sec.
314.108; or because there is a period of pediatric exclusivity for the
listed drug under section 505A of the Federal Food, Drug, and Cosmetic
Act. A drug product that is granted tentative approval is not an
approved drug and will not be approved until FDA issues an approval
after any necessary additional review of the NDA. FDA's tentative
approval of a drug product is based on information available to FDA at
the time of the tentative approval letter (i.e., information in the
505(b)(2) application and the status of current good manufacturing
practices of the facilities used in the manufacturing and testing of
the drug product) and is therefore subject to change on the basis of
new information that may come to FDA's attention. A new drug product
may not be marketed until the date of the approval letter.
(b) FDA will approve an NDA and issue the applicant an approval
letter on the basis of draft labeling if the only deficiencies in the
NDA concern editorial or similar minor deficiencies in the draft
labeling. Such approval will be conditioned upon the applicant
incorporating the specified labeling changes exactly as directed, and
upon the applicant submitting to FDA a copy of the final printed
labeling prior to marketing.
(c) FDA will approve an NDA after it determines that the drug meets
the
[[Page 6893]]
statutory standards for safety and effectiveness, manufacturing and
controls, and labeling, and an ANDA after it determines that the drug
meets the statutory standards for manufacturing and controls, labeling,
and, where applicable, bioequivalence. While the statutory standards
apply to all drugs, the many kinds of drugs that are subject to the
statutory standards and the wide range of uses for those drugs demand
flexibility in applying the standards. Thus FDA is required to exercise
its scientific judgment to determine the kind and quantity of data and
information an applicant is required to provide for a particular drug
to meet the statutory standards. FDA makes its views on drug products
and classes of drugs available through guidance documents,
recommendations, and other statements of policy.
(d) FDA will approve an ANDA and send the applicant an approval
letter if none of the reasons in Sec. 314.127 for refusing to approve
the ANDA applies. The date of approval is the date of the issuance of
the Agency's approval letter. FDA will issue a tentative approval
letter if an ANDA otherwise meets the requirements for approval under
the Federal Food, Drug, and Cosmetic Act, but cannot be approved
because there is a 7-year period of orphan exclusivity for the listed
drug under section 527 of the Federal Food, Drug, and Cosmetic Act and
Sec. 316.31, or cannot be approved until the conditions in Sec.
314.107(b)(3) or (c) are met; because there is a period of exclusivity
for the listed drug under Sec. 314.108; or because there is a period
of pediatric exclusivity for the listed drug under section 505A of the
Federal Food, Drug, and Cosmetic Act. A drug product that is granted
tentative approval is not an approved drug and will not be approved
until FDA issues an approval after any necessary additional review of
the ANDA. FDA's tentative approval of a drug product is based on
information available to FDA at the time of the tentative approval
letter (i.e., information in the ANDA and the status of current good
manufacturing practices of the facilities used in the manufacturing and
testing of the drug product) and is therefore subject to change on the
basis of new information that may come to FDA's attention. A new drug
product may not be marketed until the date of the approval letter.
0
18. Section 314.107 is revised to read as follows:
Sec. 314.107 Date of approval of a 505(b)(2) application or ANDA.
(a) General. A drug product may be introduced or delivered for
introduction into interstate commerce when the 505(b)(2) application or
ANDA for the drug product is approved. A 505(b)(2) application or ANDA
for a drug product is approved on the date FDA issues an approval
letter under Sec. 314.105 for the 505(b)(2) application or ANDA.
(b) Effect of patent(s) on the listed drug. As described in
paragraphs (b)(1) and (b)(2) of this section, the status of patents
listed for the listed drug(s) relied upon or reference listed drug, as
applicable, must be considered in determining the first possible date
of approval of a 505(b)(2) application or ANDA. The criteria in
paragraphs (b)(1) and (b)(2) of this section will be used to determine,
for each relevant patent, the date that patent will no longer prevent
approval. The first possible date of approval will be calculated for
each patent, and the 505(b)(2) application or ANDA may be approved on
the last applicable date.
(1) Timing of approval based on patent certification or statement.
If none of the reasons in Sec. 314.125 or Sec. 314.127 for refusing
to approve the application applies, and none of the reasons in
paragraph (d) of this section for delaying approval applies, the
505(b)(2) application or ANDA may be approved as follows:
(i) Immediately, if the applicant certifies under Sec. 314.50(i)
or Sec. 314.94(a)(12) that:
(A) The applicant is aware of a relevant patent but the patent
information required under section 505(b) or (c) of the Federal Food,
Drug, and Cosmetic Act has not been submitted to FDA; or
(B) The relevant patent has expired; or
(C) The relevant patent is invalid, unenforceable, or will not be
infringed, except as provided in paragraphs (b)(3) and (c) of this
section, and the 45-day period provided for in section 505(c)(3)(C) and
(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act has expired;
or
(D) There are no relevant patents.
(ii) Immediately, if the applicant submits an appropriate statement
under Sec. 314.50(i) or Sec. 314.94(a)(12) explaining that a method-
of-use patent does not claim an indication or other condition of use
for which the applicant is seeking approval.
(iii) On the date specified, if the applicant certifies under Sec.
314.50(i) or Sec. 314.94(a)(12) that the relevant patent will expire
on a specified date.
(2) Patent information filed after submission of 505(b)(2)
application or ANDA. If the holder of the approved NDA for the listed
drug submits patent information required under Sec. 314.53 after the
date on which the 505(b)(2) application or ANDA was submitted to FDA,
the 505(b)(2) applicant or ANDA applicant must comply with the
requirements of Sec. 314.50(i)(4) and (i)(6) and Sec.
314.94(a)(12)(vi) and (a)(12)(viii) regarding amendment of its patent
certification or statement. If the applicant submits an amendment
certifying under Sec. 314.50(i)(1)(i)(A)(4) or Sec.
314.94(a)(12)(i)(A)(4) that the relevant patent is invalid,
unenforceable, or will not be infringed, and complies with the
requirements of Sec. 314.52 or Sec. 314.95, the 505(b)(2) application
or ANDA may be approved immediately upon submission of documentation of
receipt of notice of paragraph IV certification under Sec. 314.52(e)
or Sec. 314.95(e). The 45-day period provided for in section
505(c)(3)(C) and (j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic
Act does not apply in these circumstances.
(3) Disposition of patent litigation--(i) Approval upon expiration
of 30-month period or 7\1/2\ years from date of reference product
approval. (A) Except as provided in paragraphs (b)(3)(ii) through
(b)(3)(viii) of this section, if, with respect to patents for which
required information was submitted under Sec. 314.53 before the date
on which the 505(b)(2) application or ANDA was submitted to FDA
(excluding an amendment or supplement to the 505(b)(2) application or
ANDA), the applicant certifies under Sec. 314.50(i) or Sec.
314.94(a)(12) that the relevant patent is invalid, unenforceable, or
will not be infringed, and the patent owner or its representative or
the exclusive patent licensee brings suit for patent infringement
within 45 days of receipt of the notice of certification from the
applicant under Sec. 314.52 or Sec. 314.95, the 505(b)(2) application
or ANDA may be approved 30 months after the later of the date of the
receipt of the notice of certification by any owner of the listed
patent or by the NDA holder who is an exclusive patent licensee (or
their representatives) unless the court has extended or reduced the
period because of a failure of either the plaintiff or defendant to
cooperate reasonably in expediting the action; or
(B) If the patented drug product qualifies for 5 years of exclusive
marketing under Sec. 314.108(b)(2) and the patent owner or its
representative or the exclusive patent licensee brings suit for patent
infringement during the 1-year period beginning 4 years after the date
the patented drug was approved and within 45 days of receipt of the
notice of certification from the applicant under Sec. 314.52 or Sec.
314.95, the 505(b)(2) application or ANDA may be approved at the
expiration of 7\1/2\ years from the date of approval of the NDA for the
patented drug product.
[[Page 6894]]
(ii) Federal district court decision of invalidity,
unenforceability, or non-infringement. If before the expiration of the
30-month period, or 7\1/2\ years where applicable, the district court
decides that the patent is invalid, unenforceable, or not infringed
(including any substantive determination that there is no cause of
action for patent infringement or invalidity), the 505(b)(2)
application or ANDA may be approved on:
(A) The date on which the court enters judgment reflecting the
decision; or
(B) The date of a settlement order or consent decree signed and
entered by the court stating that the patent that is the subject of the
certification is invalid or not infringed.
(iii) Appeal of Federal district court judgment of infringement. If
before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the district court decides that the patent has been
infringed, and if the judgment of the district court is appealed, the
505(b)(2) application or ANDA may be approved on:
(A) The date on which the mandate is issued by the court of appeals
entering judgment 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
(B) 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.
(iv) Affirmation or non-appeal of Federal district court judgment
of infringement. If before the expiration of the 30-month period, or
7\1/2\ years where applicable, the district court decides that the
patent has been infringed, and if the judgment of the district court is
not appealed or is affirmed, the 505(b)(2) application or ANDA may be
approved no earlier than the date specified by the district court in an
order under 35 U.S.C. 271(e)(4)(A).
(v) Grant of preliminary injunction by Federal district court. If
before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the district court grants a preliminary injunction
prohibiting the applicant from engaging in the commercial manufacture
or sale of the drug product until the court decides the issues of
patent validity and infringement, and if the court later decides that
the patent is invalid, unenforceable, or not infringed, the 505(b)(2)
application or ANDA may be approved as provided in paragraph (b)(3)(ii)
of this section. If the court decides that the patent has been
infringed, the 505(b)(2) application or ANDA may be approved as
provided in paragraph (b)(3)(iii) or (b)(3)(iv) of this section,
whichever is applicable.
(vi) Written consent to approval by patent owner or exclusive
patent licensee. If before the expiration of the 30-month period, or
7\1/2\ years where applicable, the patent owner or the exclusive patent
licensee (or their representatives) agrees in writing that the
505(b)(2) application or ANDA may be approved any time on or after the
date of the consent, approval may be granted on or after that date.
(vii) Court order terminating 30-month or 7\1/2\ year period. If
before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the court enters an order requiring the 30-month or 7\1/2\-
year period to be terminated, the 505(b)(2) application or ANDA may be
approved in accordance with the court's order.
(viii) Court order of dismissal without a finding of infringement.
If before the expiration of the 30-month period, or 7\1/2\ years where
applicable, the court enters an order of dismissal, with or without
prejudice, without a finding of infringement, the 505(b)(2) application
or ANDA may be approved on or after the date of the order.
(4) Tentative approval. FDA will issue a tentative approval letter
when tentative approval is appropriate in accordance with paragraphs
(b)(3) or (e)(1)(vi) of this section. In order for a 505(b)(2)
application or ANDA to be approved under paragraph (b)(3) of this
section, the applicant must receive an approval letter from the Agency.
Tentative approval of an application does not constitute ``approval''
of an application and cannot, absent an approval letter from the
Agency, result in an approval under paragraph (b)(3) of this section.
(c) Subsequent ANDA submission. (1) If an ANDA contains a paragraph
IV certification for a relevant patent and the ANDA is not that of a
first applicant, the ANDA is regarded as the ANDA of a subsequent
applicant. The ANDA of a subsequent applicant will not be approved
during the period when any first applicant is eligible for 180-day
exclusivity or during the 180-day exclusivity period of a first
applicant. Any applicable 180-day exclusivity period cannot extend
beyond the expiration of the patent upon which the 180-day exclusivity
period was based.
(2) For purposes of paragraph (c)(1) of this section, a first
applicant must submit correspondence to its ANDA notifying FDA within
30 days of the date of first commercial marketing of its drug product.
If an applicant does not notify FDA, as required in this paragraph, of
this date, the date of first commercial marketing will be deemed to be
the date of the drug product's approval.
(d) Delay due to exclusivity. The Agency will also delay the
approval of a 505(b)(2) application or an ANDA if delay is required by
the exclusivity provisions in Sec. 314.108, Sec. 316.31, or section
505A of the Federal Food, Drug, and Cosmetic Act. When the approval of
a 505(b)(2) application or ANDA is delayed under this section and Sec.
314.108, Sec. 316.31, or section 505A of the Federal Food, Drug, and
Cosmetic Act, the 505(b)(2) application or ANDA will be approved on the
latest of the days specified under this section and Sec. 314.108,
Sec. 316.31, or section 505A of the Federal Food, Drug, and Cosmetic
Act, as applicable.
(e) Notification of court actions or documented agreement. (1) The
applicant must submit the following information to FDA, as applicable:
(i) A copy of any judgment by the court (district court or mandate
of the court of appeals) or settlement order or consent decree signed
and entered by the court (district court or court of appeals) finding a
patent described in paragraph (b)(3) of this section invalid,
unenforceable, or not infringed, or finding the patent valid and
infringed;
(ii) Written notification of whether or not any action by the court
described in paragraph (e)(1)(i) of this section has been appealed
within the time permitted for an appeal;
(iii) A copy of any order entered by the court terminating the 30-
month or 7\1/2\-year period described in paragraphs (b)(3)(i) and
(b)(3)(ii) of this section;
(iv) A copy of any documented agreement described in paragraph
(b)(3)(vi) of this section;
(v) A copy of any preliminary injunction described in paragraph
(b)(3)(v) of this section, and a copy of any subsequent court order
lifting the injunction; and
(vi) A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A)
ordering that a 505(b)(2) application or ANDA may be approved no
earlier than the date specified (irrespective of whether the injunction
relates to a patent described in paragraph (b)(3) of this section).
(2) All information required by paragraph (e)(1) of this section
must be sent to the Office of Generic Drugs (HFD-600) or to the
appropriate division in the Office of New Drugs within 14 days of the
date of entry by the court, the date of appeal or expiration of the
time for appeal, or the
[[Page 6895]]
date of documented agreement, as applicable.
(f) Forty-five day period after receipt of notice of paragraph IV
certification--(1) Computation of 45-day time clock. The 45-day clock
described in paragraph (b)(3) of this section as to each recipient
required to receive notice of paragraph IV certification under Sec.
314.52 or Sec. 314.95 begins on the day after the date of receipt of
the applicant's notice of paragraph IV certification by the recipient.
When the 45th day falls on Saturday, Sunday, or a Federal holiday, the
45th day will be the next day that is not a Saturday, Sunday, or a
Federal holiday.
(2) Notification of filing of legal action. (i) The 505(b)(2) or
ANDA applicant must notify FDA in writing within 14 days of the filing
of any legal action filed within 45 days of receipt of the notice of
paragraph IV certification by any recipient. A 505(b)(2) applicant must
send the notification to the appropriate division in the Office of New
Drugs reviewing the 505(b)(2) application. An ANDA applicant must send
the notification to FDA's Office of Generic Drugs (HFD-600). The
notification to FDA of the legal action must include:
(A) The 505(b)(2) application or ANDA number.
(B) The name of the 505(b)(2) or ANDA applicant.
(C) The established name of the drug product or, if no established
name exists, the name(s) of the active ingredient(s), the drug
product's strength, and dosage form.
(D) A statement that an action for patent infringement, identified
by the court, case number, and the patent number(s) of the patent(s) at
issue in the action, has been filed in an appropriate court on a
specified date.
(ii) A patent owner or NDA holder (or their representatives) may
also notify FDA of the filing of any legal action for patent
infringement. The notice should contain the information and be sent to
the offices or divisions described in paragraph (f)(2)(i) of this
section.
(iii) If the 505(b)(2) or ANDA applicant, the patent owner(s), the
NDA holder, or their representatives do not notify FDA in writing
before the expiration of the 45-day time period or the completion of
the Agency's review of the 505(b)(2) application or ANDA, whichever
occurs later, that a legal action for patent infringement was filed
within 45 days of receipt of the notice of paragraph IV certification,
the 505(b)(2) application or ANDA may be approved upon expiration of
the 45-day period (if the 505(b)(2) or ANDA applicant confirms that a
legal action for patent infringement has not been filed) or upon
completion of the Agency's review of the 505(b)(2) application or ANDA,
whichever is later.
(3) Waiver. If the patent owner or NDA holder who is an exclusive
patent licensee (or their representatives) waives its opportunity to
file a legal action for patent infringement within 45 days of a receipt
of the notice of certification and the patent owner or NDA holder who
is an exclusive patent licensee (or their representatives) submits to
FDA a valid waiver before the 45 days elapse, the 505(b)(2) application
or ANDA may be approved upon completion of the Agency's review of the
application. FDA will only accept a waiver in the following form:
(Name of patent owner or NDA holder who is an exclusive patent
licensee or their representatives) has received notice from (name of
applicant) under (section 505(b)(3) or 505(j)(2)(B) of the Federal
Food, Drug, and Cosmetic Act) and does not intend to file an action
for patent infringement against (name of applicant) concerning the
drug (name of drug) before (date on which 45 days elapses). (Name of
patent owner or NDA holder who is an exclusive patent licensee)
waives the opportunity provided by (section 505(c)(3)(C) or
505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act) and
does not object to FDA's approval of (name of applicant)'s
(505(b)(2) application or ANDA) for (name of drug) with an approval
date on or after the date of this submission.
(g) Conversion of approval to tentative approval. If FDA issues an
approval letter in error or a court enters an order requiring, in the
case of an already approved 505(b)(2) application or ANDA, that the
date of approval be delayed, FDA will convert the approval to a
tentative approval if appropriate.
0
19. Section 314.108 is amended by:
0
a. Revising paragraph (a) introductory text and the definitions of
``Approved under section 505(b)'', ``Essential to approval'', and ``New
chemical entity'';
0
b. Removing from paragraph (a) the definitions of ``Active moiety'',
``Date of approval'', and ``FDA'';
0
c. Adding alphabetically to paragraph (a) the definition of
``Bioavailability study''; and
0
d. Revising paragraph (b).
The revisions read as follows:
Sec. 314.108 New drug product exclusivity.
(a) Definitions. The definitions at Sec. 314.3 and the following
definitions of terms apply to this section:
Approved under section 505(b) means an NDA submitted under section
505(b) and approved on or after October 10, 1962, or an application
that was ``deemed approved'' under section 107(c)(2) of Public Law 87-
781.
Bioavailability study means a study to determine the
bioavailability or the pharmacokinetics of a drug.
* * * * *
Essential to approval means, with regard to an investigation, that
there are no other data available that could support approval of the
NDA.
New chemical entity means a drug that contains no active moiety
that has been approved by FDA in any other NDA submitted under section
505(b) of the Federal Food, Drug, and Cosmetic Act.
* * * * *
(b) Submission of and date of approval of a 505(b)(2) application
or ANDA.
(1) [Reserved]
(2) If a drug product that contains a new chemical entity was
approved after September 24, 1984, in an NDA submitted under section
505(b) of the Federal Food, Drug, and Cosmetic Act, no person may
submit a 505(b)(2) application or ANDA under section 505(j) of the
Federal Food, Drug, and Cosmetic Act for a drug product that contains
the same active moiety as in the new chemical entity for a period of 5
years from the date of approval of the first approved NDA, except that
the 505(b)(2) application or ANDA may be submitted after 4 years if it
contains a certification of patent invalidity or noninfringement
described in Sec. 314.50(i)(1)(i)(A)(4) or Sec.
314.94(a)(12)(i)(A)(4).
(3) The approval of a 505(b)(2) application or ANDA described in
paragraph (b)(2) of this section will occur as provided in Sec.
314.107(b)(1) or (b)(2), unless the owner of a patent that claims the
drug, the patent owner's representative, or exclusive licensee brings
suit for patent infringement against the applicant during the 1-year
period beginning 48 months after the date of approval of the NDA for
the new chemical entity and within 45 days after receipt of the notice
described at Sec. 314.52 or Sec. 314.95, in which case, approval of
the 505(b)(2) application or ANDA will occur as provided in Sec.
314.107(b)(3).
(4) If an NDA:
(i) Was submitted under section 505(b) of the Federal Food, Drug,
and Cosmetic Act;
(ii) Was approved after September 24, 1984;
(iii) Was for a drug product that contains an active moiety that
has been previously approved in another NDA under section 505(b) of the
Federal Food, Drug, and Cosmetic Act; and
(iv) Contained reports of new clinical investigations (other than
bioavailability
[[Page 6896]]
studies) conducted or sponsored by the applicant that were essential to
approval of the application, for a period of 3 years after the date of
approval of the application, the Agency will not approve a 505(b)(2)
application or an ANDA for the conditions of approval of the original
NDA, or an ANDA submitted pursuant to an approved petition under
section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act that
relies on the information supporting the conditions of approval of an
original NDA.
(5) If a supplemental NDA:
(i) Was approved after September 24, 1984; and
(ii) Contained reports of new clinical investigations (other than
bioavailability studies) that were conducted or sponsored by the
applicant that were essential to approval of the supplemental NDA, for
a period of 3 years after the date of approval of the supplemental
application, the Agency will not approve a 505(b)(2) application or an
ANDA for a change, or an ANDA submitted pursuant to an approved
petition under section 505(j)(2)(C) of the Federal Food, Drug, and
Cosmetic Act that relies on the information supporting a change
approved in the supplemental NDA.
0
20. Section 314.125 is amended by:
0
a. Removing the word ``application'' wherever it appears in the section
heading, paragraph (a) introductory text, and paragraphs (a)(2),
(b)(7), (b)(9), (b)(10), (b)(12), and (b)(14) through (b)(18) and
adding in its place ``NDA'';
0
b. Revising paragraph (b) introductory text; and
0
c. Adding paragraph (b)(19).
The revisions read as follows:
Sec. 314.125 Refusal to approve an NDA.
* * * * *
(b) FDA may refuse to approve an NDA for any of the following
reasons, unless the requirement has been waived under Sec. 314.90:
* * * * *
(19) The 505(b)(2) application failed to contain a patent
certification or statement with respect to each listed patent for an
approved drug product that:
(i) Is pharmaceutically equivalent to the drug product for which
the 505(b)(2) application is submitted; and
(ii) Was approved before the 505(b)(2) application was submitted.
* * * * *
0
21. Section 314.127 is amended by:
0
a. Removing the words ``abbreviated application'' and ``abbreviated new
drug application'' wherever they appear in paragraphs (a) and (b) and
adding in their place ``ANDA'';
0
b. Revising the section heading and paragraph (a) introductory text;
and
0
c. Adding paragraph (a)(14).
The revisions read as follows:
Sec. 314.127 Refusal to approve an ANDA.
(a) FDA will refuse to approve an ANDA for a new drug under section
505(j) of the Federal Food, Drug, and Cosmetic Act for any of the
following reasons, unless the requirement has been waived under Sec.
314.99:
* * * * *
(14) For an ANDA submitted pursuant to an approved suitability
petition, an NDA subsequently has been approved for the change
described in the suitability petition.
* * * * *
PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
0
22. The authority citation for part 320 continues to read as follows:
Authority: 21 U.S.C. 321, 351, 352, 355, 371.
0
23. Section 320.1 is revised to read as follows:
Sec. 320.1 Definitions.
The definitions contained in Sec. 314.3 of this chapter apply to
those terms when used in this part.
0
24. Section 320.23 is amended by:
0
a. Revising the last sentence in paragraph (a)(1);
0
b. Removing the word ``shall'' in paragraph (a)(2) and adding in its
place the word ``must'';
0
c. Redesignating paragraph (b) as paragraph (b)(1); and
0
d. Adding new paragraph (b)(2).
The revisions read as follows:
Sec. 320.23 Basis for measuring in vivo bioavailability or
demonstrating bioequivalence.
(a)(1) * * * For drug products that are not intended to be absorbed
into the bloodstream, bioavailability may be assessed by scientifically
valid measurements intended to reflect the rate and extent to which the
active ingredient or active moiety becomes available at the site of
action.
* * * * *
(b) * * *
(2) For drug products that are not intended to be absorbed into the
bloodstream, bioequivalence may be demonstrated by scientifically valid
methods that are expected to detect a significant difference between
the drug and the listed drug in safety and therapeutic effect.
Dated: January 23, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-01666 Filed 2-5-15; 8:45 am]
BILLING CODE 4164-01-P