[Federal Register Volume 81, Number 194 (Thursday, October 6, 2016)]
[Rules and Regulations]
[Pages 69580-69658]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-22690]
[[Page 69579]]
Vol. 81
Thursday,
No. 194
October 6, 2016
Part II
Department of Health and Human Services
-----------------------------------------------------------------------
Food and Drug Administration
-----------------------------------------------------------------------
21 CFR Parts 314 and 320
Abbreviated New Drug Applications and 505(b)(2) Applications; Final
Rule
Federal Register / Vol. 81 , No. 194 / Thursday, October 6, 2016 /
Rules and Regulations
[[Page 69580]]
-----------------------------------------------------------------------
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: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final rule 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 final rule implements 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 final rule also amends
certain regulations regarding 505(b)(2) applications and ANDAs to
facilitate compliance with and efficient enforcement of the FD&C Act.
DATES: This rule is effective December 5, 2016.
ADDRESSES: 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 final rule 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:
With regard to the final rule: 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.
With regard to the information collection: FDA PRA Staff, Office of
Operations, Food and Drug Administration, Three White Flint North
10A63, 11601 Landsdown St., North Bethesda, MD 20852,
[email protected].
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Final Rule
B. Summary of the Major Provisions of the Final Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations and Acronyms Commonly Used in This
Document
III. Background
A. History of This Rulemaking
B. General Overview of the Final Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
A. Definitions (Sec. 314.3(b))
B. Submission of Patent Information (Sec. 314.53)
C. Patent Certification (Sec. Sec. 314.50(i) and 314.94(a)(12))
D. Notice of Paragraph IV Certification (Sec. Sec. 314.52 and
314.95)
E. Amended Patent Certifications (Sec. Sec. 314.50(i)(6) and
314.94(a)(12)(viii))
F. Patent Certification Requirements for Amendments and
Supplements to 505(b)(2) Applications and ANDAs (Sec. Sec. 314.60,
314.70, 314.96, and 314.97)
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 (Sec. Sec. 314.60, 314.70,
314.96, and 314.97)
H. 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 (Sec. 314.54)
I. Petition to Request a Change From a Listed Drug (Sec.
314.93)
J. Filing an NDA and Receiving an ANDA (Sec. 314.101)
K. Approval of an NDA and ANDA (Sec. 314.105)
L. Refusal To Approve an NDA or ANDA (Sec. Sec. 314.125 and
314.127 and Related Provisions in Sec. Sec. 314.90 and 314.99)
M. Date of Approval of a 505(b)(2) Application or ANDA (Sec.
314.107)
N. Assessing Bioavailability and Bioequivalence for Drugs Not
Intended To Be Absorbed Into the Bloodstream (Sec. 320.23)
O. Miscellaneous
P. Technical Amendments
VI. Effective Date
VII. Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. References
I. Executive Summary
I.A. Purpose of the Final Rule
This rule implements portions of Title XI of the MMA and revises
and clarifies 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.
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 since its enactment. Based on this experience, FDA is amending
its regulations to implement portions of the MMA that pertain to 30-
month stays and other matters not related to forfeiture of 180-day
exclusivity.
FDA is amending 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 clarifying requirements for the NDA holder's
description of the specific approved method of use claimed by the
patent (the ``use code'') required for publication in FDA's ``Approved
Drug Products With Therapeutic Equivalence Evaluations'' (commonly
known as the Orange Book) to address overbroad or ambiguous use codes
that may delay approval of generic drugs. This clarification 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. We also are revising the regulations to codify the types
of court decisions and other actions that will terminate a 30-month
stay of approval on a 505(b)(2) application or ANDA. Finally, we are
updating the regulations to codify FDA's current practice and policy
and thereby promote transparency.
[[Page 69581]]
I.B. Summary of the Major Provisions of the Final Rule
I.B.1. Submission of Patent Information
The rule revises and streamlines 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.
We are codifying our longstanding 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 address overbroad or ambiguous use codes, we
are expressly requiring that if the method(s) of use claimed by the
patent does not cover an indication or other approved condition of use
in its entirety, the NDA holder's use code must describe only the
specific approved method of use claimed by the patent for which a claim
of patent infringement could reasonably be asserted if a person not
licensed by the patent owner engaged in the manufacture, use, or sale
of the drug product.
I.B.2. Timing of Submission of Patent Information
We are expressly describing 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 (21 U.S.C. 355(c)(2)), 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 expanding 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 are
not submitted: (1) Within 30 days of patent issuance; (2) within 30
days of approval of a corresponding change to product labeling; or (3)
within 30 days of a decision by the U.S. Patent and Trademark Office
(USPTO) or a Federal court that is specific to the patent and alters
the construction of a method-of-use claim(s) of the patent. This
revision to our regulations is intended to reduce delays in approval
related to overbroad or ambiguous patent use codes.
In addition, we are establishing that the submission date of patent
information provided by an NDA holder after approval will be the
earlier of the date on which Form FDA 3542 is date-stamped by the
Central Document Room or officially received by FDA in an electronic
format. These revisions are intended to facilitate prompt listing in
the Orange Book and to remove any ambiguity about the date of
submission in light of the implications of untimely filed patent
information for the patent certification obligations of 505(b)(2) and
ANDA applicants that rely upon the listed drug.
I.B.3. Correction or Change of Patent Information
We are clarifying and improving the procedures that govern
challenges to the accuracy or relevance of the NDA holder's submission
of patent information to the Agency. These procedures allow a person
(including a 505(b)(2) or ANDA applicant) to request, for example, that
an NDA holder confirm that a previously submitted use code complies
with current requirements. We are establishing a 30-day timeframe in
which the NDA holder will be required to substantively respond to the
patent listing dispute and verify the accuracy and completeness of the
response. We intend to take an incremental approach and evaluate
whether FDA's revisions to the regulations on submission of method-of-
use patent information and patent listing dispute procedures adequately
address the problem of overbroad and ambiguous use codes before we
determine whether a process to review a proposed labeling carve-out
with deference to the 505(b)(2) and/or ANDA applicant(s)'
interpretation of the scope of the patent is also needed.
In addition, we are expressly requiring 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 revisions
facilitate implementation of the MMA provision related to patent
withdrawal and efficient enforcement of the FD&C Act.
I.B.4. Notice of Paragraph IV Certification--Timing
We are revising our regulations to clearly delineate the two
limitations on the timeframe 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
longstanding practice regarding premature notice) and (2) the date,
established by MMA, by which notice must be given to be considered
timely.
For an original application, a 505(b)(2) applicant must send notice
of a paragraph IV certification on or after the date on which the
505(b)(2) application is filed and an ANDA applicant must send notice
of a paragraph IV certification on or after the date on which it
receives a ``paragraph IV acknowledgment letter'' from FDA stating that
the application is sufficiently complete to permit a substantive
review. Both 505(b)(2) and ANDA applicants must send notice of a
paragraph IV certification not later than 20 days after the date of the
``postmark'' (as defined in this final rule) on the paragraph IV
acknowledgment letter.
For an amendment or supplement, an applicant must send notice of a
paragraph IV certification contained in an amendment to a 505(b)(2)
application (that has been filed) or ANDA (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 establishing 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. 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. 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.
I.B.5. Notice of Paragraph IV Certification--Content and Methods
We are revising 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 are also
expanding the acceptable methods of sending notice of a paragraph IV
[[Page 69582]]
certification beyond registered or certified mail to include
``designated delivery services.'' This reduces the burden on 505(b)(2)
and ANDA applicants who currently must submit requests to the Agency to
send notice by common alternate delivery methods.
I.B.6. Amended Patent Certifications
We are clarifying 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 are also clarifying the circumstances and timeframe 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 rule codifies 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 the 180-
day exclusivity period based on that patent has expired or has been
extinguished, and exempting 505(b)(2) applicants from providing or
maintaining a certification to withdrawn patents. In addition, the rule
expressly codifies the current requirement for a 505(b)(2) or ANDA
applicant to submit a patent certification to a timely filed, newly
issued patent that claims the listed drug or an approved method of
using such drug.
I.B.7. Patent Certification Requirements for Amendments
We are clarifying and augmenting the patent certification
requirements for amendments to 505(b)(2) applications and ANDAs to
ensure that certain types of changes to the drug product are
accompanied by an appropriate patent certification (or recertification)
or statement. An appropriate patent certification (or recertification)
or statement is required to accompany an amendment to add a new
indication or other condition of use, to add a new strength, to make
other-than-minor changes in product formulation, or to change the
physical form or crystalline structure of the active ingredient. The
regulations continue to require that a patent certification be amended
if, at any time before approval, the applicant learns that the
previously submitted patent certification or statement is no longer
accurate.
I.B.8. Limitation on Submission of Certain Amendments and Supplements
to a 505(b)(2) Application or ANDA
We are codifying 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.
I.B.9. 505(b)(2) Applications
We are requiring a 505(b)(2) applicant to identify one
pharmaceutically equivalent drug product approved in an NDA, if one or
more is approved before the original 505(b)(2) application is
submitted, 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
certification obligations that would have applied if the proposed
product could have been approved in an ANDA.
I.B.10. Date of Approval of a 505(b)(2) Application or ANDA
The rule describes, 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 revising 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.
We are clarifying 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 (or its
representative(s)). This 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 codifying 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 are
also addressing other scenarios in which a 30-month 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 in each
pending suit for patent infringement brought within 45 days of receipt
of the notice of paragraph IV certification. These clarifications are
intended to avoid unnecessary delays in approval of 505(b)(2)
applications and ANDAs 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).
I.B.11. Notification of Commercial Marketing
We are updating 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 is required to submit
correspondence to its ANDA notifying FDA within 30 days of the date of
first commercial marketing of the drug product. If a first applicant
does not notify FDA within this timeframe, we are deeming 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.
I.B.12. Notification of Court Actions or Written Consent to Approval
We are expanding the scope of documentation that an applicant must
submit to FDA regarding patent-related court actions and written
consent to approval to ensure that FDA is promptly advised of
information that may affect the timing of approval of a 505(b)(2)
application or ANDA.
I.C. Legal Authority
Title XI of the MMA and sections 505, 505A, 505E, and 527 of the
FD&C Act (21 U.S.C. 355, 355a, 355f, 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 rule.
I.D. Costs and Benefits
Many provisions of this final rule codify current practice, but
some elements will lead to changes that generate additional benefits
and costs. The table summarizes the benefits and costs of this final
rule. The estimated annualized monetized benefits of this final rule
are $215,247 at a 3 percent or 7 percent discount rate, while the
estimated annualized monetized costs are $266,947 at a 3 percent
discount rate and $275,925 at a 7 percent discount rate. We have also
identified, but are
[[Page 69583]]
unable to quantify, additional impacts from changes to submitted patent
information.
Summary of Benefits and Costs
------------------------------------------------------------------------
Benefits Costs
------------------------------------------------------------------------
One-time (Year 1) Cost for Reading the NA $466,450
Rule...................................
Annually Recurring Compliance Costs or $215,247 213,858
Savings (Years 1-10)...................
Present Value at 3 Percent.............. 1,836,098 2,277,116
Present Value at 7 Percent.............. 1,511,803 1,937,983
Annualized Value at 3 Percent........... 215,247 266,947
Annualized Value at 7 Percent........... 215,247 275,925
------------------------------------------------------------------------
NA = Not Applicable.
II. Table of Abbreviations and Acronyms Commonly Used in This Document
------------------------------------------------------------------------
Abbreviation What it means
------------------------------------------------------------------------
ANDA............................. Abbreviated New Drug Application.
CDER............................. Center for Drug Evaluation and
Research.
CFR.............................. Code of Federal Regulations.
CSA.............................. Controlled Substances Act.
ESG.............................. Electronic Submissions Gateway.
FD&C Act......................... Federal Food, Drug, and Cosmetic Act.
FDA.............................. U.S. Food and Drug Administration.
FDASIA........................... Food and Drug Administration Safety
and Innovation Act.
FOIA............................. Freedom of Information Act.
FR............................... Federal Register.
FTC.............................. U.S. Federal Trade Commission.
GAIN............................. Generating Antibiotic Incentives Now.
GDUFA............................ Generic Drug User Fee Amendments of
2012.
IRTNMTA.......................... Improving Regulatory Transparency for
New Medical Therapies Act.
MMA.............................. Medicare Prescription Drug,
Improvement, and Modernization Act
of 2003.
NDA.............................. New Drug Application.
OGD.............................. Office of Generic Drugs (in FDA's
Center for Drug Evaluation and
Research).
OMB.............................. U.S. Office of Management and Budget.
OND.............................. Office of New Drugs (in FDA's Center
for Drug Evaluation and Research).
Orange Book...................... FDA's ``Approved Drug Products With
Therapeutic Equivalence
Evaluations''.
OTC.............................. Over-the-counter.
RLD.............................. Reference Listed Drug.
U.S.............................. United States.
U.S.C............................ United States Code.
USPS............................. United States Postal Service.
USPTO............................ U.S. Patent and Trademark Office.
------------------------------------------------------------------------
III. Background
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).
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 relied upon by the applicant for approval of the NDA comes
from investigations that were 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) (see section 505(b)(2) of
the FD&C Act; compare section 505(b)(1) of the FD&C Act for ``stand-
alone'' NDAs).
An ANDA contains 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, conditions of use, dosage form,
route of administration, strength, and (with certain permissible
differences) labeling, among other characteristics. An ANDA applicant
also must demonstrate that its proposed drug product is bioequivalent
to the RLD (see section 505(j) of the FD&C Act; compare section
505(j)(2)(C) for ``petitioned ANDAs''). 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 submitted under section
505(b)(1) of the FD&C Act.
The timing of approval for a 505(b)(2) application and an ANDA
(including a petitioned ANDA) is subject to certain patent and
marketing exclusivity protections. An NDA applicant is required to
submit information on any patent that claims the drug that is the
subject of the NDA or that 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) and (c)(2) of
the FD&C Act). Upon approval of an NDA under section 505(c) of the FD&C
Act, we publish certain patent information provided by the NDA holder
in the Orange Book, available electronically on FDA's Web site at
http://www.fda.gov/cder.
A 505(b)(2) application and ANDA must include an appropriate patent
certification or statement for each patent that claims the listed
drug(s) relied upon or RLD, respectively, or a method of using such
drug and for which information is required to be filed under section
505(b) or 505(c) of the FD&C Act. The 505(b)(2) or ANDA applicant must
submit one or more of the following certifications or statements:
That such patent information has not been filed (a
paragraph I certification);
that such patent has expired (a paragraph II
certification);
the date on which such patent will expire (a paragraph III
certification);
that such 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 or ANDA is submitted (a paragraph IV
certification);
that there are no patents that claim the listed drug(s) or
that claim a use of such drug (a ``no relevant patents'' statement,
which is submitted instead of a patent certification); or
that a method-of-use patent does not claim a use for which
the 505(b)(2) or ANDA applicant is seeking approval (a 505(b)(2)(B) or
(j)(2)(A)(viii) statement).
An applicant that submits a paragraph IV certification is required
to give notice of the paragraph IV certification to the NDA holder 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
[[Page 69584]]
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)(iii) 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).
III.A. History of This Rulemaking
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 505(b)(2) applications and ANDAs. Title XI
of the MMA addressed two key concerns identified in an FTC report on
``Generic Drug Entry Prior to Patent Expiration: An FTC Study'' (July
2002) (Ref. 1) 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
505(b)(2) application or ANDA). 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
certain 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.
Section 1102 of the MMA altered the conditions under which a 180-
day period of marketing exclusivity attaches 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),
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.
On February 6, 2015, we published a proposed rule to implement
portions of the MMA that pertain to 30-month stays and other matters
not related to forfeiture of 180-day exclusivity, and make our
regulations governing 505(b)(2) applications and ANDAs consistent with
the MMA's amendments to the FD&C Act (80 FR 6802, February 6, 2015; see
also ``Abbreviated New Drug Applications and 505(b)(2) Applications;
Correction,'' 80 FR 13289, March 13, 2015). In addition, the proposed
rule would amend the regulations in parts 314 and 320 (21 CFR parts 314
and 320) 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. We will determine whether additional rulemaking
related to 180-day exclusivity is necessary in the future.
FDA provided 120 days for public comment on the proposed rule,
including a 30-day extension of the original comment period (see
``Abbreviated New Drug Applications and 505(b)(2) Applications;
Extension of Comment Period,'' 80 FR 22953, April 24, 2015). We
received 13 comment letters on the proposed rule by the close of the
comment period, each containing 1 or more comments on 1 or more issues.
We received comments from pharmaceutical industry associations, brand
and generic drug manufacturers, law firms, and a law student. Based on
the comments received, FDA is finalizing the proposed rule with certain
revisions and technical amendments.
III.B. General Overview of the Final Rule
This final rule implements portions of Title XI of the MMA and
revises and clarifies FDA regulations relating to 505(b)(2)
applications and ANDAs. The final rule reflects our consideration of
comments on the proposed rule, recent court decisions, and legislative
enactments, and incorporates several clarifying revisions and technical
amendments. Table 1 summarizes the substantive changes from the
proposed rule to the final rule.
BILLING CODE 4164-01-P
[[Page 69585]]
[GRAPHIC] [TIFF OMITTED] TR06OC16.000
[[Page 69586]]
[GRAPHIC] [TIFF OMITTED] TR06OC16.001
[[Page 69587]]
[GRAPHIC] [TIFF OMITTED] TR06OC16.002
[[Page 69588]]
[GRAPHIC] [TIFF OMITTED] TR06OC16.003
[[Page 69589]]
[GRAPHIC] [TIFF OMITTED] TR06OC16.004
[[Page 69590]]
[GRAPHIC] [TIFF OMITTED] TR06OC16.005
BILLING CODE 4164-01-C
IV. Legal Authority
The MMA and sections 505, 505A, 505E, 527, and 701 (21 U.S.C. 355,
355a, 355f, 360cc, and 371) of the FD&C Act provide the principal legal
authority for this final rule. Section 505(b) of the FD&C Act describes
the contents of an NDA, including a 505(b)(2) application, and
describes patent listing and patent certification requirements for
NDAs. 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 certain patent and marketing exclusivity
protections. Section 505(j) also describes the availability of 180-day
exclusivity for a first applicant. Section 505(x) describes the date of
approval of an NDA for which FDA intends to recommend controls under
the Controlled Substances Act (CSA). Section 701(a) of the FD&C Act
provides FDA with the authority to issue regulations for the efficient
enforcement of the FD&C Act.
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 505E of the FD&C
Act describes the availability of an exclusivity period extension for
certain designated qualified infectious disease products. 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, 505E, 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 final
rule.
V. Comments on the Proposed Rule and FDA Response
We received 13 comment letters on the proposed rule by the close of
the comment period, each containing 1 or
[[Page 69591]]
more comments on 1 or more issues. We received comments from
pharmaceutical industry associations, brand and generic drug
manufacturers, law firms, and a law student. Several comments made
general remarks supporting the proposed rule without focusing on a
particular proposed provision.
We describe and respond to specific comments in sections V.A
through V.O. We have numbered each comment to help distinguish between
different comments. We have grouped similar comments together under the
same number, and, in some cases, we have separated different issues
discussed in the same comment and designated them as distinct comments
for purposes of our responses. The number assigned to each comment or
comment topic is purely for organizational purposes and does not
signify the comment's value or importance or the order in which
comments were received. We also received comments on topics related to
505(b)(2) applications and ANDAs that are outside the scope of the
proposed rule, including, for example, issues related to forfeiture of
eligibility for 180-day exclusivity and the Drug Efficacy Study
Implementation, and we are not addressing these comments at this time.
We are currently implementing the 180-day exclusivity provisions of the
MMA directly from the statute and will determine whether additional
rulemaking is necessary in the future.
V.A. Definitions (Sec. 314.3(b))
We proposed 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 in the context of implementing
section 505(b) and (j) of the FD&C Act. We also proposed amendments to
Sec. 314.3(b) to conform with other changes in the proposed rule (80
FR 6802), and to incorporate new definitions. We received a general
comment expressing support for FDA's efforts to clarify and update
various definitions that are necessary for the efficient enforcement of
the Hatch-Waxman Amendments. We received no comments on our proposed
definitions of ``180-day exclusivity period,'' ``abbreviated new drug
application or ANDA,'' ``active ingredient,'' ``ANDA holder,''
``component,'' ``inactive ingredient,'' ``NDA holder,'' ``new drug
application or NDA,'' ``original NDA,'' ``paragraph IV certification,''
``patent owner,'' ``reference standard,'' ``strength,'' and
``therapeutic equivalents.'' We also received no comments on our
proposed revisions to the current definitions of ``abbreviated
application,'' ``act,'' ``applicant,'' ``application,'' ``listed
drug,'' and ``the list.'' In addition, we received no comments on our
proposed relocation of the definition of ``active moiety'' that
currently is in Sec. 314.108(a) to Sec. 314.3(b). Finally, we
received no comments on our proposed relocation of the definitions that
currently are in Sec. 320.1(a) and (c) through (g) to Sec. 314.3(b),
our proposed deletion of Sec. 320.1(b), and our proposed revisions to
the definitions of ``bioavailability'' and ``bioequivalence.''
Therefore, we are finalizing these definitions without change, except
for the technical amendment to the definition of ``listed drug''
described in section V.A.3 (Response 4) and the technical amendments to
the definitions of ``original NDA,'' ``resubmission,'' and
``therapeutic equivalents'' described in section V.P.1. We also
describe a technical amendment to the definition of ``505(b)(2)
application'' in section V.P.3 and the addition of the defined term
``Agency'' in section V.P.1.
V.A.1. Definitions of ``Acknowledgment Letter'' and ``Paragraph IV
Acknowledgment Letter''
We proposed to establish a definition of the term ``paragraph IV
acknowledgment letter'' and the related term ``acknowledgment letter''
to facilitate implementation of the MMA's requirement for a 505(b)(2)
or ANDA applicant 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 application has been filed (see section
505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the FD&C Act and section
V.A.6). We proposed to define ``paragraph IV acknowledgment letter'' to
mean 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. For 505(b)(2) applications and ANDAs
that do not contain a paragraph IV certification, we proposed to define
``acknowledgment letter'' to mean 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 ``acknowledgment letter'' or
``paragraph IV acknowledgment letter'' would indicate that the
505(b)(2) application is regarded as filed or the ANDA is regarded as
received (see proposed Sec. 314.3(b)).
As explained in the proposed rule, the ``paragraph IV
acknowledgment letter'' for 505(b)(2) applications that rely on the
Agency's finding of safety and/or effectiveness for a listed drug and
contain a paragraph IV certification would be the filing communication
that generally is sent to the 505(b)(2) applicant not later than 14
calendar days after the 60-day filing date and sometimes is referred to
as the ``74-day letter'' (see 80 FR 6802 at 6811 and 6814 to 6815).
Unlike the paragraph IV acknowledgment letter for ANDAs, the filing
communication is typically sent by the Office of New Drugs (OND) in the
Center for Drug Evaluation and Research (CDER) in a franked envelope
that may not bear a postmark made by the U.S. Postal Service (USPS).
For purposes of Sec. 314.52(b) and (c) only, we proposed that the
``date of the postmark'' on the ``paragraph IV acknowledgment letter''
would be considered to be four 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 USPS (see definition of ``postmark'' in proposed Sec.
314.3). In the proposed rule, we explained that if OND were to send the
filing communication via electronic transmission in the future, then
our proposed definition of a ``postmark'' that documents an electronic
event would apply (see proposed Sec. 314.3(b) and section V.A.6).
In the following paragraphs, we discuss a comment on these proposed
definitions. We also received a comment that agrees with the proposed
definition of ``paragraph IV acknowledgment letter'' and the inclusion
of this term in revised Sec. 314.101(b)(2). After considering these
comments, we are revising the definition of ``acknowledgment letter''
to delete the reference to 505(b)(2) applications, thereby limiting the
applicability of this term to ANDAs. We are finalizing the definition
of ``paragraph IV acknowledgment letter'' without change.
(Comment 1) One comment requests that FDA clarify whether the terms
``acknowledgment letter,'' ``acceptance for filing letter,'' and
``paragraph IV acknowledgment letter'' can be used interchangeably to
refer to the letter sent to applicants for ANDAs that contain a
paragraph IV certification.
(Response 1) FDA separately defines the terms ``acknowledgment
letter'' and ``paragraph IV acknowledgment letter'' for ANDAs because
the ``paragraph IV acknowledgment letter'' contains
[[Page 69592]]
information on certain regulatory requirements associated with a
paragraph IV certification. For administrative reasons, it had been
FDA's practice to send an ``acknowledgment letter'' rather than a
``paragraph IV acknowledgment letter'' to an ANDA applicant if an
original ANDA contained a patent certification or statement other than
a paragraph IV certification, and the applicant submitted an amendment
containing a paragraph IV certification before the ANDA has been
received for substantive review. Accordingly, we proposed to use both
terms in the regulations where appropriate (see proposed Sec. 314.95).
Upon further consideration, we are modifying our administrative
practices to send a ``paragraph IV acknowledgment letter'' to an ANDA
applicant if the ANDA contains a paragraph IV certification at any time
prior to receipt of the ANDA. We are making conforming revisions to
Sec. 314.95(b)(1) and (2), (c)(3), and (d)(2) to remove the reference
to an ``acknowledgment letter.'' We are retaining a revised definition
of the term ``acknowledgment letter'' in Sec. 314.3(b) because FDA's
Office of Generic Drugs (OGD) will continue to send ``acknowledgment
letters'' for ANDAs that do not contain a paragraph IV certification at
the time of receipt (see, e.g., section V.D.1.b). (The defined term
``acknowledgment letter'' for ANDAs differs from the informal use of
this term for NDAs, which acknowledges the submission of an NDA before
the Agency has determined whether the NDA can be filed.) FDA no longer
uses the term ``acceptance for filing letter,'' which is an informal
term that previously was used to describe an acknowledgment letter for
an ANDA.
FDA has concluded that that it is unnecessary to distinguish
between an ``acknowledgment letter'' and a ``paragraph IV
acknowledgment letter'' for a 505(b)(2) application. If the 505(b)(2)
application contains a paragraph IV certification at any time before
the 505(b)(2) application is filed, the filing communication that FDA
sends to NDA applicants also will be the ``paragraph IV acknowledgment
letter'' for 505(b)(2) applicants for purposes of determining the date
by which notice of paragraph IV certification must be sent (see Sec.
314.52). We are making a conforming revision to Sec. 314.52(d) to
remove the reference to an ``acknowledgment letter'' (see section
V.D.1.b).
V.A.2. Definition of ``Commercial Marketing''
We proposed 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 (21 CFR part 312), but that does not include transfer of the
drug product for reasons other than sale to parties identified in the
approved ANDA (see proposed Sec. 314.3(b)). In the following
paragraphs, we discuss three comments on this proposed definition.
After considering these comments, we are making editorial corrections
to clarify the types of transfers of the drug product for reasons other
than sale that fall within the exception to commercial marketing. We
also are making amendments to clarify that the definition of commercial
marketing includes the introduction or delivery for introduction into
interstate commerce of the reference listed drug by the ANDA applicant.
(Comment 2) One comment recommends clarifying that commercial
marketing does not include transfer of the drug product to a third-
party logistics provider or contractor who is not identified in the
ANDA, provided that the transfer does not take the drug product outside
the control of the ANDA holder (e.g., transfer of the drug product for
storage or further distribution only as the ANDA holder may direct in
the future). This comment also suggests revising the structure of the
definition to improve clarity. Another comment maintains that the
proposed definition would limit business flexibility, given that an
ANDA applicant's transfer of the drug product to a re-packager (e.g.,
to facilitate packaging validation or preparation for product launch)
would be considered commercial marketing because re-packagers are not
identified in ANDAs.
(Response 2) FDA declines to expand the exception to commercial
marketing to include transfer of the drug product, outside the control
of the ANDA applicant, for reasons other than sale to third parties not
identified in the ANDA. FDA's amended definition of ``commercial
marketing'' creates a bright-line rule for establishing the date of
first commercial marketing of the drug by any first applicant for
purposes of determining the start of the 180-day exclusivity period
(see section 505(j)(5)(B)(iv)(I) of the FD&C Act and Sec.
314.107(c)(2)). The amended definition also facilitates implementation
of the statutory provision by which a first applicant may forfeit
eligibility for 180-day exclusivity due to failure to market the drug
by the timeframe described in the statute (see section
505(j)(5)(D)(i)(I) of the FD&C Act).
Under the amended definition in Sec. 314.3(b), ``commercial
marketing'' of the drug product refers to a transfer of the drug
product outside the control of the ANDA applicant, subject to specified
exceptions, and thus does not include a transfer of the drug product
within the control of the ANDA applicant. As we explained in the
proposed rule, the amended definition is intended to clarify that the
ANDA applicant's shipment of a drug product described in an 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 (80 FR 6802 at
6812). Among other things, an ANDA holder would be required to identify
a packager or re-packager in a supplement to the ANDA if different
equipment or facilities are used that have a moderate potential to have
an adverse effect on factors that may relate to the safety and
effectiveness of the drug product (see 21 U.S.C. 356a and Sec.
314.70(c); compare Sec. 314.70(d)). We also note that storage and
distribution facilities often are identified in ANDAs (see, e.g., draft
guidance for industry entitled ``Pre-Launch Activities Importation
Requests (PLAIR)'' (July 2013) at 3, available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
Accordingly, we do not expect the amended definition to have a
significant impact on ANDA applicants' business arrangements with third
parties.
FDA agrees that the definition of ``commercial marketing'' should
be revised further for clarity. We also are making amendments to remove
the reference to an ``approved'' ANDA and to further clarify that the
definition of commercial marketing includes an ANDA applicant's
commercial marketing of the reference listed drug, including an
authorized generic drug (see section 505(j)(5)(B)(iv)(I) of the FD&C
Act). As revised, commercial marketing is the introduction or delivery
for introduction into interstate commerce of a drug product described
in an ANDA, outside the control of the ANDA applicant, except that the
term does not include transfer of the drug product for investigational
use under part 312 of this chapter or transfer of the
[[Page 69593]]
drug product to parties identified in the ANDA for reasons other than
sale. Commercial marketing includes the introduction or delivery for
introduction into interstate commerce of the reference listed drug by
the ANDA applicant.
(Comment 3) One comment agrees with the proposed definition of
``commercial marketing'' but recommends specifically excluding
charitable donations of drug product.
(Response 3) FDA disagrees with the recommendation to exclude
charitable donations of drug product from the definition of
``commercial marketing.'' A drug product is introduced or delivered for
introduction into interstate commerce, outside the control of the ANDA
applicant, when an ANDA applicant donates the drug product to a
charitable institution or organization (e.g., a nonprofit hospital or
health care entity). This introduction or delivery for introduction
into interstate commerce subjects the donated drug product to
applicable statutory and regulatory requirements, including, but not
limited to, requirements intended to ensure that the drug product is
not adulterated or misbranded (see, e.g., 21 U.S.C. 331, 351, and 352).
Moreover, even if the charitable institution or organization is
identified in the ANDA, a charitable donation of drug product is not
necessarily a transfer of the drug product for reasons other than sale,
given that there are circumstances in which a donated drug product may
be sold (see 21 U.S.C. 353(c)(3)(B) and 21 CFR 203.22). FDA does not
believe the definition of ``commercial marketing'' will impact
charitable donation of drug product, given that charitable donation of
drug product met the criteria for commercial marketing under the
previous definition in Sec. 314.107(c)(4). The comment does not
provide any explanation for the proposed change, and we do not believe
that the proposed change is necessary.
V.A.3. Definition of ``Date of Approval''
We proposed to move the definition of ``date of approval'' from
Sec. 314.108(a) to Sec. 314.3(b) with several revisions. We proposed
that the date of approval would mean the date on the approval letter
from FDA stating that the NDA or ANDA is approved (see proposed Sec.
314.3(b)). Our proposed revisions broadened the definition to include
the date of approval for an ANDA, and incorporated the defined term
``approval letter.'' We also proposed to remove the caveat that the
date of approval is the date on the approval 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.
In the following paragraphs, we discuss two comments that disagree
with these proposed changes. After these comments were submitted,
Congress enacted the Improving Regulatory Transparency for New Medical
Therapies Act (IRTNMTA) (Pub. L. 114-89), which addresses the primary
concern expressed by comments regarding the proposed revision to the
definition. We are finalizing the definition with technical amendments
to incorporate IRTNMTA.
(Comment 4) Two comments recommend that FDA retain the former
definition of ``date of approval'' in Sec. 314.108 because the
definition addresses circumstances in which the date on the approval
letter for an NDA is not the same as the date on which an applicable
exclusivity period begins to run. The comments contend that the
qualifying phrase ``as long as approval of such [final printed]
labeling or materials is not expressly required'' in the former
definition of ``date of approval'' is not reflected elsewhere in the
Agency's regulations. Moreover, the comments assert that the proposed
revision to the definition would effectively reduce the exclusivity
period for certain approved drug products that cannot be commercially
marketed until the Drug Enforcement Administration (DEA) has scheduled
the drug as a controlled substance or until FDA has approved a
proprietary name (where the name is necessary for the safe use of the
drug). The comments maintain that FDA did not clearly describe and
invite comment on these effects of the proposed revision to the
definition.
(Response 4) We disagree with comments recommending that we retain
the former definition of ``date of approval'' in Sec. 314.108. As we
explained in the proposed rule, FDA's regulations in Sec. 314.105(b)
specifically address the circumstances in which FDA will approve an NDA
and issue the applicant an approval letter on the basis of draft
labeling. Since publication of the proposed rule, FDA has determined
that an ANDA also may be approved on the basis of draft labeling,
provided that the only deficiencies in the draft labeling are editorial
or similarly minor in nature (see guidance for industry entitled
``Acceptability of Draft Labeling to Support ANDA Approval'' (October
2015), available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm)
(superseding FDA's former policy that final printed labeling is
required for approval of an ANDA). If draft labeling deficiencies have
not yet been resolved and are more than ``editorial or similar minor
deficiencies,'' then the appropriate action is a complete response
letter (see Sec. Sec. 314.125(b) and 314.110). In the exceptional
circumstances in which FDA has not yet approved a proprietary name for
a proposed drug product and determines that the product cannot be
marketed without a proprietary name, the applicant should receive a
complete response letter (compare Letter from Janet Woodcock, M.D.,
Director, CDER, to Anil Hiteshi, Spectrum Pharmaceuticals, Inc., dated
February 24, 2015, regarding Docket No. FDA-2014-P-1615, available at
http://www.regulations.gov) (denying request for revision of the
approval date because the approval letter expressly stated that
Spectrum could market the product with labeling bearing only the
established name until a proprietary name could be agreed upon).
Accordingly, it is unnecessary to address any requirements for approval
of final printed labeling in the definition of ``date of approval.''
On November 25, 2015, Congress enacted IRTNMTA, which addresses
concerns that delays in scheduling a newly approved drug may reduce an
applicable exclusivity period that commences on the ``date of
approval.'' IRTNMTA provides that the date of approval for an NDA for
which FDA intends to recommend controls under the CSA is the later of
the date an NDA is approved under section 505(c) of the FD&C Act or the
date of issuance of the interim final rule controlling the drug (see
section 505(x)(1) and (2) of the FD&C Act). To incorporate IRTNMTA, we
are revising the definition of ``date of approval'' to mean the date on
the approval letter from FDA stating that the NDA or ANDA is approved,
except that the date of approval for an NDA described in section
505(x)(1) of the FD&C Act is determined as described in section
505(x)(2) of the FD&C Act (see Sec. 314.3(b)).
As reflected in the revised definition, we are currently
implementing IRTNMTA directly from the statute and will determine
whether additional rulemaking is necessary in the future. However,
given the broader relevance of the term ``date of approval'' to matters
covered in part 314, we are making other technical amendments to align
with the revised definition and enhance clarity. These technical
amendments are described in the following paragraphs.
We are further revising the proposed definition of ``listed drug''
to establish that a drug product is deemed to be a listed drug on the
``date of approval'' for the NDA or ANDA for that drug
[[Page 69594]]
product, rather than on the ``date of the approval letter'' (see Sec.
314.3(b)). This technical amendment clarifies the listed drug status of
a drug product described in section 505(x)(1) of the FD&C Act, and the
corresponding date on which the drug product will be identified in the
Orange Book (the list) as a listed drug. We are revising Sec.
314.105(a) to remove the proposed statement that an NDA is approved on
the date of the issuance of the approval letter. This statement may be
inaccurate with respect to drug products described in section 505(x)(1)
of the FD&C Act, and the text is unnecessary in light of the revised
definition of ``date of approval'' (see Sec. 314.3(b)). We also are
revising Sec. 314.105(a) to state that a new drug product may not be
marketed until the date of approval, rather than the date of the
approval letter, for consistency with IRTNMTA. Although section
505(x)(1) of the FD&C Act does not apply to ANDAs, we are making the
same revisions to Sec. 314.105(d) for consistency. In addition, we are
revising Sec. 314.107(b) to clarify that this provision describes how
to determine the first possible date on which a 505(b)(2) application
or ANDA can be approved, rather than the ``date of approval.'' We also
are replacing the phrase ``the date the patented drug was approved''
with ``the date of approval'' in Sec. 314.107(b)(3)(i)(B) to
incorporate the revised definition. Finally, in the paragraph heading
for Sec. 314.108(b), we are replacing the phrase ``date of approval''
with ``timing of approval'' to more accurately characterize the content
of this paragraph.
In the sections of parts 314 and 320 that are the subject of this
rulemaking, the references to the ``date of approval'' are intended to
refer to the revised definition in Sec. 314.3(b). For example, we are
maintaining the reference to ``date of approval'' in Sec.
314.53(c)(2)(ii) to ensure that there is no ambiguity post-IRTNMTA
about the required timeframe for submission of patent information after
approval, given 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)). Accordingly, for an NDA
subject to IRTNMTA, the NDA holder must submit Form FDA 3542 within 30
days of the later of the date on which the NDA is approved under
section 505(c) of the FD&C Act or the date of issuance of the interim
final rule controlling the drug for the patent information to be
considered timely filed.
V.A.4. Definition of ``Dosage Form''
We proposed to define ``dosage form'' to mean the physical
manifestation containing the active and inactive ingredients that
delivers a dose of the drug product. The physical manifestation
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) design
features that affect frequency of dosing (see proposed Sec. 314.3(b)).
In the following paragraphs, we discuss a comment on this proposed
definition. After considering this comment, we are finalizing the
definition without change.
(Comment 5) One comment recommends that FDA broaden the definition
of ``dosage form'' by including an additional factor to describe the
physical manifestation of a drug product. The comment requests that FDA
establish that a drug product with features that impart properties
designed to deter tampering, abuse, or misuse of the drug product does
not have the same dosage form as a similar version of the drug product
that does not have such properties. The comment suggests that this
would clarify that abuse-deterrent formulations and non-abuse-deterrent
formulations of a drug product cannot be considered pharmaceutical
equivalents or therapeutic equivalents.
(Response 5) FDA declines to adopt the comment's suggestion at this
time. FDA may address issues related to the pharmaceutical equivalence
and therapeutic equivalence of abuse-deterrent formulations of a drug
product through rulemaking or other regulatory mechanisms.
V.A.5. Definitions of ``First Applicant'' and ``Substantially Complete
Application''
We proposed to define the terms ``first applicant'' and
``substantially complete application'' to incorporate into our
regulations the definitions established by the MMA, with minor
editorial changes and additional clarifying text (see section
505(j)(5)(B)(iv)(II)(bb) and (cc) of the FD&C Act). We proposed to
define ``first applicant'' 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 (see
proposed Sec. 314.3(b)). We proposed to delete the definition of
``applicant submitting the first application'' in former Sec.
314.107(c)(2) because that definition was superseded by the statutory
definition.
We also proposed to define ``substantially complete application''
to 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 (see proposed
Sec. 314.3(b)). We clarified that any information referenced in the
ANDA must have been provided to FDA for the ANDA to be substantially
complete, and we provided examples of other bases for finding that an
ANDA is not substantially complete (see 80 FR 6802 at 6816 to 6817).
In the following paragraphs, we discuss a comment on these proposed
definitions. After considering this comment, we are revising the
definition of ``substantially complete application'' for consistency
with Sec. 314.101 and making an editorial correction for clarity. We
are finalizing the definition of ``first applicant'' with editorial
changes to more clearly incorporate the defined term ``substantially
complete application.''
(Comment 6) One comment recommends that FDA revise the definitions
of ``first applicant'' and ``substantially complete application'' to
clarify the content required to support a decision that an ANDA is
substantially complete ``on its face'' in order to distinguish
deficiencies that may preclude receipt of an ANDA from review issues.
(Response 6) FDA is revising the definition of ``substantially
complete application'' for consistency with other regulations outlining
the required content of an ANDA and to enhance clarity. Under existing
Sec. 314.101(b), FDA will receive an ANDA if FDA finds that none of
the reasons in Sec. 314.101(d) and (e) applies for considering the
ANDA not to have been received. The deficiencies described in Sec.
314.101(d) that may result in refusal to receive an ANDA include, but
are not limited to, an ANDA that is incomplete ``because it does not on
its face contain information required'' under section 505(j) of the
FD&C Act and Sec. 314.94 (see Sec. 314.101(d)(3)).
We are revising the definition of ``substantially complete
application'' to include an express definition of ``sufficiently
complete'' to permit a substantive review that aligns with our standard
for receiving an ANDA. As revised, a ``substantially complete
application'' is an ANDA that on its face is sufficiently complete to
permit a substantive review. ``Sufficiently
[[Page 69595]]
complete'' to permit a substantive review means that the ANDA contains
all the information required under section 505(j)(2)(A)(i) through
(viii) of the FD&C Act and does not contain a deficiency described in
Sec. 314.101(d) and (e) (see Sec. 314.3(b)). The phrase ``on its
face'' describes FDA's threshold determination that the ANDA includes
the information required to make it sufficiently complete to permit a
substantive review (i.e., information corresponding to the statutory
and regulatory requirements for an ANDA). This evaluation does not
involve a substantive review of the data in the ANDA (see Sec.
314.101(b)(1)). As discussed in section V.J.2, we are supplementing
Sec. 314.101(d)(3) to more precisely describe the factors that FDA
considers in determining whether an ANDA is incomplete on its face.
FDA is revising the definition of ``first applicant'' to more
clearly incorporate the defined term ``substantially complete
application.'' As revised, a first applicant is an ANDA applicant that,
on the first day on which a substantially complete application
containing a paragraph IV certification is submitted for approval of a
drug, submits a substantially complete application that contains, and
for which the applicant lawfully maintains, a paragraph IV
certification for the drug.
V.A.6. Definition of ``Postmark''
We proposed to define the term ``postmark'' 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 proposed Sec. 314.3(b) and section 505(b)(3)(B)(i) and
505(j)(2)(B)(ii)(I) of the FD&C Act). The purpose of the postmark is to
establish a verifiable date from which the 20-day notice period runs.
In light of the transition by FDA and regulated industry to electronic
communications, FDA proposed to define 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 USPS 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 USPS 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. In the following
paragraphs, we discuss two comments on this proposed definition. After
considering these comments, we are finalizing the definition without
change.
(Comment 7) One comment recommends that FDA provide ANDA applicants
with the option to receive a paragraph IV acknowledgment letter by
electronic transmission rather than first class mail to help ensure
prompt receipt by the ANDA applicant irrespective of location. The
comment suggests that this option may reduce the likelihood that an
ANDA applicant would fail to send notice of paragraph IV certification
within 20 days after the date of the postmark on the paragraph IV
acknowledgment letter, and thereby avoid the administrative consequence
described in proposed Sec. 314.101(b)(4). Another comment notes that
the proposed definition of postmark clarifies the date by which notice
of paragraph IV certification must be sent when ANDA applicants receive
a paragraph IV acknowledgment letter from FDA both by electronic mail
and the USPS.
(Response 7) We agree that electronic transmission of a paragraph
IV acknowledgment letter to an ANDA applicant may facilitate timely
sending notice of paragraph IV certification. Our definition of
``postmark'' is intended to accommodate the electronic transmission of
paragraph IV acknowledgment letters from FDA to 505(b)(2) and ANDA
applicants in the future.
OGD currently sends an ANDA applicant or its authorized
representative a paragraph IV acknowledgment letter (or an
acknowledgment letter, if appropriate) in an envelope bearing a
postmark made by the USPS. If the ANDA applicant or its authorized
representative has provided an electronic mail address on Form FDA
356h, which accompanies each submission to the ANDA, OGD also sends a
courtesy copy of the paragraph IV acknowledgment letter (or an
acknowledgment letter, if appropriate) by electronic mail and
subsequently archives the electronic communication. Upon the effective
date of this final rule (see section VI), the date of FDA's electronic
transmission of a paragraph IV acknowledgment letter to an ANDA
applicant also will be the postmark described in section
505(j)(2)(B)(ii)(I) of the FD&C Act. We no longer intend to send a
paragraph IV acknowledgment letter to an ANDA applicant by the USPS.
Accordingly, we expect few circumstances in which there will be a
question about which postmark controls for purposes of determining the
date by which notice of paragraph IV certification must be sent.
However, if an ANDA applicant (or, in the future, a 505(b)(2)
applicant) receives a paragraph IV acknowledgment letter from FDA both
by electronic mail and the USPS, the earlier postmark provides the
controlling postmark.
Although the comment did not discuss 505(b)(2) applications, we
note that FDA is committed to adapting its business practices to
evolving technology and anticipates electronically transmitting
paragraph IV acknowledgment letters to 505(b)(2) applicants in a manner
that meets the requirements of the definition of postmark in the
future.
V.A.7. Definition of ``Tentative Approval''
We proposed to define ``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 a listed drug has unexpired orphan drug
exclusivity, 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 the listed drug has a period of exclusivity under
Sec. 314.108 or section 505A of the FD&C Act, or because a court order
under 35 U.S.C. 271(e)(4)(A) orders that the application may be
approved no earlier than the date specified (see proposed Sec.
314.3(b) and section 505(j)(5)(B)(iv)(II)(dd)(AA) of the FD&C Act). The
proposed definition clarified 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. In the following paragraphs, we discuss a
comment on this proposed definition. After considering this comment, we
are revising the definition to describe an additional basis for
tentative approval and making conforming revisions to Sec. Sec.
314.101(e)(2), 314.105(a) and (d), and 314.107(b)(4) and (d).
(Comment 8) A comment requests that FDA update proposed Sec.
314.107(d) to reflect that Generating Antibiotic Incentives Now (GAIN)
exclusivity may delay approval of a 505(b)(2) application or ANDA, and
that FDA make any other
[[Page 69596]]
necessary conforming revisions to the regulations.
(Response 8) We agree with the comment. Title VIII of the Food and
Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-
144), entitled GAIN, provides an exclusivity period extension for
certain designated qualified infectious disease products in section
505E of the FD&C Act. We are revising the definition of ``tentative
approval'' to indicate that approval of a 505(b)(2) application or ANDA
also may be delayed by a period of exclusivity for the listed drug
under section 505E of the FD&C Act. We are making similar revisions to
our regulations on approval of an NDA or ANDA (Sec. 314.105(a) and
(d)) and delay due to exclusivity (Sec. 314.107(d)). We are also
revising our regulations on tentative approval to explain that FDA will
issue a tentative approval letter when tentative approval is
appropriate in accordance with Sec. 314.107 (see Sec. 314.107(b)(4)).
GAIN also extends by 5 years the 4-year period described in section
505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the FD&C Act after which certain
505(b)(2) applications or ANDAs containing a paragraph IV certification
may be submitted. Accordingly, we are revising Sec. 314.101(e)(2) to
remove the cross-reference to Sec. 314.108(b)(2) and expressly state
that FDA will refuse to file an NDA or will consider an ANDA not to
have been received if submission of a 505(b)(2) application or an ANDA
is not permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), or
505E(a) of the FD&C Act. For completeness, we are making a technical
amendment to Sec. 314.101(e)(2) to reference pediatric exclusivity
under section 505A(b)(1)(A)(i)(I) and (c)(1)(A)(i)(I) of the FD&C Act,
which extends by 6 months the 4-year period described in section
505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the FD&C Act.
V.B. Submission of Patent Information (Sec. 314.53)
V.B.1. General Requirements for Submission of Patent Information (Sec.
314.53(b) and (c))
Section 314.53(b) of our regulations requires that an applicant
submitting an NDA, 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) to its NDA on Forms FDA
3542a and 3542 with the filing or upon and after approval,
respectively. The information requested in Form FDA 3542 must be
provided for any patent that claims the approved drug substance,
approved drug product, or any approved 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. FDA publishes certain
information from Form FDA 3542 in the Orange Book after approval of the
NDA or the supplement. The following sections describe our proposed
revisions to these regulations and our responses to the comments that
we received on the proposed rule.
V.B.1.a. Drug substance (active ingredient) and drug product
(formulation or composition) patents. We proposed to revise Sec.
314.53(c)(1) to omit the reference to ``complete'' patent information
and clarify that FDA will accept a submission of patent information on
Forms FDA 3542a or 3542, as appropriate, that omits requested patent
information if the omission is permitted under an exception in Sec.
314.53(c)(2). We proposed 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 the requirements for submission
of method-of-use patent information, need not identify each basis on
which the patent claims the drug (see proposed Sec. 314.53(c)(2)(i)(S)
and (c)(2)(ii)(T)). Accordingly, if a patent is eligible for listing as
claiming both the drug substance and the drug product, an applicant
only would be required to identify one of these two bases for listing.
We proposed to clarify that these proposed exceptions to the required
submission of patent information do not alter the requirements for
submission of method-of-use patent information (see proposed Sec.
314.53(c)(2)(i)(O)(3) and (c)(2)(ii)(P)(4)).
One comment supports these streamlined requirements for listing
patents that claim the drug substance and/or drug product in the Orange
Book. In the following paragraphs, we discuss two other comments on
these proposed revisions. After considering these comments, we are
finalizing these requirements without change. We are making conforming
revisions to Sec. 314.53(c)(2)(ii) to replace the phrase ``the patent
declaration is incomplete'' with ``the patent declaration does not
contain the required information.''
(Comment 9) One comment requests that FDA revise Sec. 314.53(c)(1)
to state that FDA will not accept patent information ``unless and
until'' it is submitted on the appropriate form and contains the
required information. The comment maintains that this revision would
clarify that submission of patent information is considered complete
only as of the date on which all required information has been
submitted to FDA.
(Response 9) We decline to revise Sec. 314.53(c)(1) as requested.
FDA's existing regulations already require that if an NDA holder timely
submits the required patent information, but FDA notifies the NDA
holder that its Form FDA 3542 is incomplete or shows that the patent is
not eligible for listing, the NDA holder must submit an acceptable Form
FDA 3542 within 15 days of FDA's notification to be considered timely
filed as of the date of the original submission of patent information
(see Sec. 314.53(c)(2)(ii)). FDA believes the current procedure is
adequate to ensure timely and complete submission of patent
information.
(Comment 10) One comment requests that FDA require additional
detail regarding drug substance claims, where the drug product's active
ingredient may not be self-evident. The comment also suggests that FDA
require more detail regarding drug product claims to enable FDA to
determine whether a new patent certification is required for a
505(b)(2) or ANDA applicant's change in product formulation and avoid
an unwarranted opportunity for a 30-month stay.
(Response 10) The comment does not clearly describe the additional
information requested or provide adequate support for any proposed
change. FDA previously has explained that ``identification of the
relevant patent(s), as opposed to the individual patent claims (other
than for method-of-use patents), satisfies the [FD&C Act's] explicit
requirements [and] provides sufficient information to potential
applicants to determine if a more thorough patent search or analysis is
warranted'' (``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; Final Rule'' 68 FR 36676 at 36685,
June 18, 2003). (The MMA superseded certain provisions of the 2003
Final Rule related to 30-month stays of approval; 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)).) Moreover, it is unnecessary for an NDA holder to
submit more detailed patent information regarding drug product claims
for purposes of determining whether a 505(b)(2) or
[[Page 69597]]
ANDA applicant must amend a previously submitted patent certification
due to a change in the formulation of its proposed product because the
505(b)(2) or ANDA applicant has an independent duty to evaluate whether
a previously submitted patent certification continues to be accurate
after any change in the formulation of its proposed drug product. We
also are adding Sec. Sec. 314.60(f)(3) and 314.96(d)(3) to expressly
describe when a change in product formulation requires an appropriate
patent certification or a recertification (see section V.F.1).
V.B.1.b. Drug substance patents that claim only a polymorph of the
active ingredient. We proposed to revise Sec. 314.53(c)(2)(i)(M)(2)
and (c)(2)(ii)(N)(2) to only require an applicant to provide
information on whether the patent claims a polymorph (generally, a
different crystalline or amorphous form of the same drug substance)
that is the same active ingredient described in the NDA, amendment, or
supplement if the only basis on which the patent is eligible for
listing is that it claims the polymorph. We proposed conforming
revisions to Sec. 314.53(b)(1) and (2), (c)(2)(i)(M)(3), and
(c)(2)(ii)(N)(3) to provide that the applicant's certification
regarding test data required by Sec. 314.53(b) applies only to patents
that claim only a polymorph.
We received two comments that agreed with the proposed provision.
In the following paragraphs, we discuss another comment on this
proposed revision. After considering the comment, we are finalizing
these revisions without change.
(Comment 11) One comment suggests that FDA require more specific
information about the polymorph claimed in the patent that is the same
active ingredient in the approved drug product to guide development of
proposed products intended for submission in a 505(b)(2) application or
ANDA.
(Response 11) The comment does not clearly describe the additional
information requested; however, we disagree with the premise of the
comment. FDA requires the NDA holder to submit information on Form FDA
3542 to enable the Agency to determine whether the patent or patent
information is eligible for listing in the Orange Book based on the
criteria in our regulations, to enable the Agency to implement section
505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, and to assist the
Agency with its administrative listing responsibilities. The drug
substance and drug product designation for listing of a patent in the
Orange Book is not intended to define the scope of patent claims that
an NDA holder or patent owner may assert in patent infringement
litigation against a 505(b)(2) or ANDA applicant (see Sec.
314.53(c)(2)(ii)(T)). Each 505(b)(2) or ANDA applicant is responsible
for conducting its own analysis of the scope of relevant patents.
V.B.1.c. Method-of-use patents. We proposed to revise Sec.
314.53(b)(1) to further clarify that an NDA applicant or holder may
submit a single Form FDA 3542a or Form FDA 3542, as appropriate, for 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) of
the patent claim(s) that corresponds to the pending or approved method
of use.
We also proposed to revise our regulations to enhance compliance by
NDA applicants and holders with the requirements for identifying the
specific section(s) of product labeling that corresponds to the method
of use claimed by the patent and, upon approval, describing the
approved method of use claimed by the patent (the ``use code'')
required for publication in the Orange Book (see proposed Sec.
314.53(b)(1), (c)(2)(i)(O)(2), (c)(2)(ii)(P)(2) and (3)). To address
situations in which the scope of the method of use claimed by the
patent is narrower than an indication or other condition of use
described in product labeling, we proposed to 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 (see
proposed Sec. 314.53(b)(1)). We also proposed 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 (see proposed Sec. 314.53(c)(2)(ii)(P)(3)). Finally, we
proposed to codify the Agency's longstanding requirement that the NDA
holder's use code 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 (see proposed Sec. 314.53(c)(2)(ii)(P)(3)).
Several comments support FDA's proposed revisions to the
regulations regarding the submission of information on method-of-use
patents. In the following paragraphs, we discuss other comments on the
submission of information on method-of-use patents. After considering
all of these comments, we are making clarifying revisions to Sec.
314.53(b)(1), (c)(2)(i)(O)(1) and (2), (c)(2)(ii)(P)(1) through (3),
and (e), and conforming revisions to Forms FDA 3542a and 3542.
(Comment 12) One comment suggests that the Agency's proposal
regarding the required content of the use code appears to shift to the
NDA holder the Agency's burden of determining whether a 505(b)(2) or
ANDA applicant is not seeking approval for a protected use. Another
comment objects to FDA's requirement that the NDA holder's use code
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. The
comment contends that this approach would require NDA holders to
speculate about the protected uses that a prospective 505(b)(2) or ANDA
applicant may seek to omit from labeling. Moreover, the comment asserts
that this proposal is unworkable given that a 240-character use code
may not adequately describe a series of patent claims of varying scope.
The comment further notes that the use code does not obviate the need
for the 505(b)(2) or ANDA applicant to evaluate the scope of the
patent.
(Response 12) FDA disagrees with these comments regarding the
content requirements for the use code. Given the Agency's ministerial
role in patent listing, we require an NDA holder to provide adequate
information about the scope of a listed method-of-use patent to assist
505(b)(2) and ANDA applicants in assessing whether the listed patent
claims a use for which the 505(b)(2) or ANDA applicant is not seeking
approval and to enable FDA to evaluate whether a proposed labeling
carve-out is appropriate (see section 505(b)(2)(B) and (j)(2)(A)(viii)
of the FD&C Act, respectively; see also Caraco Pharm. Labs. v. Novo
Nordisk A/S, 132 S. Ct. 1670, 1684 (2012) (``Use codes are pivotal to
the FDA's implementation of the Hatch-Waxman Amendments'')).
We are finalizing the requirement in Sec. 314.53(c)(2)(ii)(P)(3)
that the NDA holder's description of the patented method of use
required for publication 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, with punctuation changes and clarifying revisions
to the parenthetical example. We also are
[[Page 69598]]
expressly requiring that the NDA holder's description of the patented
method of use meets the statutory standard for an NDA holder's
submission of patent information (see section 505(b)(1) and (c)(2) of
the FD&C Act). As revised, the parenthetical text explains that if the
method(s) of use claimed by the patent does not cover an indication or
other approved condition of use in its entirety, then the NDA holder
must describe only the specific approved method of use claimed by the
patent for 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 (see Sec.
314.53(c)(2)(ii)(P)(3)). We are making conforming revisions to Sec.
314.53(b)(1). The use code must only describe a patented method of use
that is described in FDA-approved product labeling because the scope of
the approved conditions of use of a drug product is described in the
FDA-approved product labeling. We generally describe this content
requirement for the use code as the ``specific approved method of use
claimed by the patent.'' The development of the use code does not
require speculation about the protected uses that a prospective
505(b)(2) or ANDA applicant may seek to omit from labeling; rather, it
simply requires the NDA holder to describe only the specific approved
method(s) of use claimed by the patent. This requirement also does not
shift to the NDA holder the Agency's burden of determining whether a
505(b)(2) or ANDA applicant is not seeking approval for a protected
use. Based on the use code provided by the NDA holder, FDA determines
the specific labeling that describes the protected use and decides
whether a 505(b)(2) application can be approved with that information
omitted from the labeling or, in the case of an ANDA, whether an ANDA
that omits the protected information from the labeling will be rendered
less safe or effective for its remaining non-protected conditions of
use (see Sec. 314.127(a)(7)).
Given that the majority of use codes listed in the Orange Book do
not approach 240 characters, this limitation is not expected to affect
the accuracy of the NDA holder's description of the specific approved
method(s) of use claimed by the patent. Nevertheless, FDA is expanding
the use code character limit to 250 characters because FDA's database
system can accommodate this additional text. We agree that the use code
is not intended to substitute for the 505(b)(2) or ANDA applicant's
review of the patent and the approved labeling in making decisions
about whether to challenge a listed patent, request a delay in approval
until expiry of the listed patent, or not request approval for a use
claimed by the listed patent.
(Comment 13) One comment recommends that FDA clarify the directions
on Form FDA 3542 for submitting the use code to avoid potential
confusion about whether the NDA holder's use code should be based on
language from the approved labeling or from the patent claim(s).
(Response 13) FDA agrees with the recommendation to clarify the
instructions on Form FDA 3542 and the related regulations regarding the
use code. We are revising Sec. 314.53(b)(1) to clarify the general
requirement that the NDA holder's description of the patented method of
use required by Sec. 314.53(c)(2)(ii)(P)(3) must describe only the
approved method(s) of use claimed by the patent (see Response 12 for a
discussion of the ``specific approved method of use claimed by the
patent''). We also are revising Sec. 314.53(c)(2)(i)(O)(1) and
(c)(2)(ii)(P)(1) to remove the phrases ``or related indication'' and
``or indication,'' respectively, and supplementing Sec.
314.53(c)(2)(ii)(P)(3) to clarify that the use code must describe only
the specific approved method of use claimed by the patent. In other
words, the scope of the use code must not extend beyond the scope of
the patent claim(s) and, within the boundary established by the patent
claim(s), the use code must only describe a patented method of use that
has been approved by FDA as reflected in approved product labeling (see
Caraco Pharm. Labs., 132 S. Ct. 1670 at 1683, n.7 (rejecting an
argument that the use code may sweep more broadly than the patent based
on the requirement to provide a description of each approved method of
use or indication) (emphasis added)). Consistent with our clarifying
revisions to Sec. 314.53(c)(2)(ii)(P)(3), we are revising section 4.2b
of Form FDA 3542 to state that the NDA holder must submit the
description of the specific approved method of use claimed by the
patent that is proposed for inclusion as the ``use code'' in the Orange
Book. We also are making conforming revisions to Sec. 314.53(e) to
replace the phrase ``approved indications or other conditions of use
covered by a patent'' with the ``description of the method of use
claimed by the patent as required by Sec. 314.53(c)(2)(ii)(P)(3).''
(Comment 14) One comment proposes that FDA standardize use codes
rather than relying on the NDA holder's description of the approved
method of use claimed by the patent. Another comment recommends that
FDA further describe its expectations for the content of use codes by
providing hypothetical examples in which the patented method-of-use
claim is broader, narrower, or co-extensive with an approved indication
or other condition of use or that uses different terminology. The
comment also suggests that FDA provide advice on the content of the use
code where the method of use claimed by the patent is described in a
section of labeling other than Indications and Usage.
(Response 14) We decline to adopt standardized use codes because we
do not believe that standardized use codes would accurately capture the
nuances of the method-of-use patent claims that NDA holders may submit
to FDA for listing. FDA's role in listing patents remains ministerial
(see ``Abbreviated New Drug Application Regulations; Patent and
Exclusivity Provisions; Final Rule,'' 59 FR 50338 at 50349, October 3,
1994; see also 68 FR 36676 at 36687), and we continue to believe that
there is a need for accurate and detailed information related to the
approved methods of use claimed in the patent being submitted for
listing (see 68 FR 36676 at 36682). Since 2003, when we began requiring
NDA holders to submit the use code for publication in the Orange Book
(see 68 FR 36676 at 36683), the Agency has gained significant
experience in implementing section 505(b)(2)(B) and (j)(2)(A)(viii) of
the FD&C Act based on the NDA holder's use code. Based on our
experience, we are clarifying the use code requirements through this
rulemaking. We expect that these clarifying revisions to our
regulations will improve the accuracy of use codes. As the U.S. Supreme
Court noted in Caraco Pharm. Labs.: ``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). Although we decline
to provide hypothetical examples, the following general principles
illustrate the clarifying revisions to the regulations regarding the
content of use codes.
Patented method of use is broader than an indication or
other approved condition of use: The use code must only describe a
patented method of use that is described in FDA-approved product
labeling. If the method of use claimed by the patent uses different
terminology than the approved labeling and/or is broader than an
indication or other approved condition of use, then the use code would
need to be phrased more narrowly than the patent claim to
[[Page 69599]]
only describe the specific patented method of use that is described in
FDA-approved product labeling.
Patented method of use is co-extensive with an indication
or other approved condition of use: The use code must describe only the
specific approved method of use claimed by the patent.
Patented method of use is narrower than an indication or
other approved condition of use: If the method of use claimed by the
patent does not cover an indication or other approved condition of use
in its entirety, then the NDA holder must describe only the specific
approved method of use claimed by the patent--not the broader
indication or other approved condition of use that may include, but is
broader than, the use claimed by the patent.
For example, Prandin (repaglinide) tablets currently are indicated
as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus, and U.S. Patent No. 6,677,358
(358 patent) was listed in the Orange Book as claiming a method of
using Prandin. In Novo Nordisk A/S v. Caraco Pharm. Labs., the Federal
Circuit explained that claim 4 of the 358 patent ``claims `[a] method
for treating non-insulin dependent diabetes mellitus (NIDDM) comprising
administering to a patient in need of such treatment repaglinide in
combination with metformin.' . . . An appropriate use code therefore
must be limited to use of `repaglinide in combination with metformin'
to treat NIDDM'' (688 F.3d 766 at 768 (Fed. Cir. 2012)) (internal
citation omitted). A similar approach would apply if the patented
method of use is described in a section of labeling other than
Indications and Usage. For example, if the patent claims a novel dosing
regimen for a particular indication, the use code must specifically
describe the protected dosing regimen for that indication and not only
the indication to which the dosing regimen relates. Thus, if the
method(s) of use claimed by the patent does not cover an indication or
other approved condition of use in its entirety, an NDA holder's
submission of a use code that describes an entire indication or other
approved condition of use would violate FDA's regulations.
FDA requires the NDA holder to submit an accurate description,
subject to the verification under penalty of perjury required by Sec.
314.53(c)(2)(ii)(R), of the specific approved method of use claimed by
the patent to implement section 505(b)(2)(B) and (j)(2)(A)(viii) of the
FD&C Act. An inaccurate description of the approved method of use
claimed by the patent (e.g., one that incorrectly describes the entire
indication or condition of use to which the patented method of use
relates rather than the specific approved method of use claimed by the
patent) would impede FDA's ability to make a scientific determination
about whether a 505(b)(2) application or ANDA may be approved with
labeling that omits the protected information corresponding to the use
code.
As described in Sec. 314.53(b)(1), each approved method of use
claimed by the patent must be separately identified and thus will
require separate listing(s) of method-of-use information in section 4
of Form FDA 3542. We are revising Forms FDA 3542 and 3542a to
facilitate separate listings of method-of-use information. We also are
revising Sec. 314.53(c)(2)(ii) to clarify the Agency will not list or
publish patent information if it is not provided on Form FDA 3542.
(Comment 15) One comment requests that FDA clarify the level of
detail with which an NDA applicant must identify 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. Another
comment recommends that FDA replace the term ``specific sections'' with
``specific language'' and eliminate the parenthetical text in proposed
Sec. 314.53(c)(2)(i)(O)(2) and (c)(2)(ii)(P)(2) to clarify that the
protected use may encompass less than the entirety of one of the
``sections'' of the product labeling. This comment also recommends that
FDA replace the phrase ``corresponds to the method of use claimed by
the patent'' with ``is claimed by the method of use claimed by the
patent'' in proposed Sec. 314.53(b)(1), (c)(2)(i)(O)(2), and
(c)(2)(ii)(P)(2) to result in a more accurate identification of the
specific labeling that describes a protected method of use.
(Response 15) FDA agrees that the regulations should clearly define
the requirement to identify the specific labeling that describes the
method of use claimed by the patent. FDA is revising its regulations to
clarify that, for approved NDAs, the NDA holder submitting information
on the method-of-use patent must identify with specificity the
section(s) and subsection(s) of the approved labeling that describe the
method(s) of use claimed by the patent submitted (see Sec.
314.53(b)(1)). FDA is making conforming revisions to Sec.
314.53(c)(2)(ii)(P)(2) and section 4.2a of Form FDA 3542 with respect
to approved labeling, and to Sec. 314.53(c)(2)(i)(O)(2) and section
4.2a of Form FDA 3542a with respect to proposed labeling.
Identifying the section(s) and subsection(s) of the approved
labeling with specificity means listing on Form FDA 3542 (or, with
respect to proposed labeling, Form FDA 3542a) each section and
subsection of labeling that contains information describing the
patented method of use.
For prescription drug products with labeling in the
``physician labeling rule'' (PLR) format (see ``Requirements on Content
and Format of Labeling for Human Prescription Drug and Biological
Products,'' 71 FR 3922, January 24, 2006), the section(s) and
subsection(s) of the approved labeling should be identified by the
section and subsection number (see 21 CFR 201.56(d) and 201.57). For
example, ``section 1, subsection 1'' refers to the first indication
listed in approved product labeling (see Sec. 201.57(c)(2)).
For prescription drug products with labeling not in PLR
format, the section(s) and subsection(s) of the approved labeling
should be identified by the section and subsection title (see
Sec. Sec. 201.56(b) and (e) and 201.80).
For nonprescription drug products, the section(s) and
subsection(s) of the approved labeling should be identified by the
section and subsection title (see 21 CFR 201.66).
An NDA holder should evaluate whether FDA-approved revisions to
product labeling (e.g., conversion to PLR format) warrant submission of
a revised Form FDA 3542 for the purpose of updating section 4.2a.
FDA agrees that the protected use may comprise less than the
entirety of a section or subsection of the approved product labeling.
However, it is unnecessary to require an NDA holder to identify the
specific language in approved product labeling that describes the
patented method of use because the use code and identification of the
specific section(s) and subsection(s) of labeling that describe the
patented method of use are sufficient for FDA to evaluate a 505(b)(2)
or ANDA applicant's proposed labeling. Accordingly, FDA declines to
replace the term ``specific sections'' with ``specific language'' in
Sec. 314.53(c)(2)(i)(O)(2) and (c)(2)(ii)(P)(2). FDA is removing the
parenthetical text in proposed Sec. 314.53(c)(2)(i)(O)(2) and
(c)(2)(ii)(P)(2) because it is unnecessary in light of other clarifying
revisions to the regulations regarding the use code.
If a 505(b)(2) or ANDA applicant submits a statement under section
505(b)(2)(B) and (j)(2)(A)(viii) of the FD&C Act, FDA evaluates the
505(b)(2) or ANDA applicant's proposed labeling
[[Page 69600]]
to determine whether the applicant is not seeking approval for the
protected use based on the use code submitted by the NDA holder and
with reference to the labeling section(s) and subsection(s) identified
by the NDA holder. FDA determines the specific labeling that describes
the patented method of use, and decides whether the 505(b)(2)
application can be approved with that information omitted from the
labeling or, in the case of an ANDA, whether an ANDA that carves out
the protected information from the labeling would be rendered less safe
or effective than the listed drug for the remaining non-protected
conditions of use and preclude approval (see Sec. 314.127(a)(7)). For
example, FDA has determined that it can approve ANDAs for broad,
general indications that may partially overlap with a protected method
of use, as long as any express references to the protected use are
omitted from the labeling (see Hospira, Inc. v. Burwell, 2014 WL
4406901 at *17 (D. Md., Sept. 5, 2014) (upholding FDA's interpretation
of section 505(j)(2)(A)(viii) of the FD&C Act)). Although
identification of the section(s) and subsection(s) of labeling
identified by the NDA holder may assist FDA in exercising its
scientific judgment to implement section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act, FDA is not bound by the section(s) and
subsection(s) identified by the NDA holder in section 4.2a of Form FDA
3542 in making its determination. FDA will use its independent
scientific judgment to determine which section(s) and/or subsection(s)
of labeling contain language that must be carved out based on the use
code provided.
FDA agrees that the identified section(s) and subsection(s) of
labeling should not merely ``correspond'' to the method of use claimed
by the patent because the term ``correspond'' could be interpreted in
an inappropriately broad manner. To enhance accuracy, FDA is revising
Sec. 314.53(b)(1), (c)(2)(i)(O)(2), and (c)(2)(ii)(P)(2) to require
that the identified section(s) and subsection(s) of labeling
``describe'' the method of use claimed by the patent.
(Comment 16) One comment recommends that FDA require NDA holders to
resubmit patent information on the updated Form FDA 3542 for all
currently listed patents to maintain or revise the Orange Book listing.
This comment also suggests that FDA request public comment on revisions
to Forms FDA 3542a and 3542 to conform with the changes described in
the proposed rule.
(Response 16) We disagree with the recommendation to require NDA
holders to resubmit Form FDA 3542 for all currently listed patents to
maintain their current Orange Book listings. Given that over 10,000
patent listings appear in the Orange Book, this recommendation would
impose a significant burden on NDA holders and the Agency without a
commensurate benefit. If a person seeks to confirm the accuracy or
relevance of patent information currently listed in the Orange Book in
light of the patent listing requirements set forth in Sec.
314.53(b)(1) and (c), the person may submit a patent listing dispute
under Sec. 314.53(f)(1) (see section V.B.4.a). NDA applicants and
holders will be required to submit patent information on the updated
Forms FDA 3542a and 3542 on a prospective basis.
FDA requested public comment on its proposed revisions to the
regulations and has made certain changes to the regulations in response
to those comments. FDA is revising Forms FDA 3542a and 3542 to conform
to the requirements established by this final rule.
V.B.1.d. Patents previously submitted for listing. We proposed to
revise Sec. 314.53(c)(2)(i)(J) and (c)(2)(ii)(K) to remove the
requirement that an applicant provide information on whether the patent
has been submitted previously for the NDA or supplement. We received no
comments regarding this proposed revision; however, we have decided not
to finalize this proposed change. Instead, we have decided to retain
the existing requirement to assist the Orange Book staff with updating
listed patent information where appropriate (see 68 FR 36676 at 36686
and ``Agency Information Collection Activities; Submission for [OMB]
Review; Comment Request; Applications for [FDA] Approval to Market a
New Drug . . . ,'' 72 FR 21266 at 21269, April 30, 2007).
V.B.1.e. Reissued patents. We proposed to require an NDA holder to
submit additional information on patents that have been reissued by the
USPTO under 35 U.S.C. 251. We proposed that an NDA applicant or holder
must include information on whether a patent submitted for listing is a
reissuance of a patent previously submitted for listing for the NDA or
supplement (see proposed Sec. 314.53(c)(2)(i)(J) and (c)(2)(ii)(K)).
Our proposal reflected our consideration of 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. In the following
paragraphs, we discuss three comments on this proposal (see section
V.E.3 for a discussion of comments on patent certification requirements
for reissued patents). After considering these comments, we are not
finalizing this proposal.
(Comment 17) The first comment recommends that FDA reevaluate its
proposed regulations on reissued patents in light of a recent court
decision rejecting FDA's ``single bundle of patent rights'' approach in
a case involving the pre-MMA version of the FD&C Act. The second
comment suggests that FDA further consider its ``single bundle of
patent rights'' approach given the possibility for issuance of multiple
patents based on continuing applications referring to the original
patent application. The third comment supports the business certainty
provided by FDA's ``single bundle of patent rights'' approach because
the requirement for a 505(b)(2) or ANDA applicant to provide an
appropriate patent certification or statement for a reissued patent
would be governed by the provisions regarding untimely filed patents if
either the original patent or the reissued patent was late-listed as to
a pending 505(b)(2) application or ANDA.
(Response 17) FDA agrees that the ``single bundle of patent
rights'' approach reflected in its proposed regulations on reissued
patents should not be finalized in light of the recent decision in
Mylan Pharms., Inc. v. FDA, 594 Fed. Appx. 791 (4th Cir. Dec. 16,
2014). In Mylan, the Court determined that a reissued patent ``is a
separate grant of rights, even if elements of the reissued patent
overlap with those of the original patent'' (see 594 Fed. Appx. 791 at
797). The Court held that the statutory reference to ``the patent which
is the subject of the certification'' in the pre-MMA version of section
505(j)(5)(B)(iv) of the FD&C Act means that each patent (original and/
or reissued) that is the subject of a paragraph IV certification may be
a basis for eligibility for 180-day exclusivity.
Although the Mylan decision involved the pre-MMA version of the
FD&C Act (in which eligibility for 180-day exclusivity was evaluated on
a patent-by-patent basis), the Court's interpretation of ``the patent
which is the subject of the certification'' is relevant to the current
version of the FD&C Act when determining eligibility for first
applicant status under the MMA's 180-day exclusivity scheme (see
[[Page 69601]]
section 505(j)(5)(B)(iii) of the FD&C Act). Accordingly, the Agency now
considers reissued patents as separate and distinct from the original
patent for purposes of administering the patent certification
requirements of the FD&C Act and any 30-month stay of approval or 180-
day exclusivity. Given that a reissued patent will be treated no
differently than an original patent, it is unnecessary for FDA to
require that an NDA holder's submission of patent information include
information on whether the patent is a reissued patent of a patent
previously submitted for listing, and we are not finalizing proposed
Sec. 314.53(c)(2)(i)(J) and (c)(2)(ii)(K).
Upon patent reissuance, the original patent is surrendered and
ceases to have legal effect (see 37 CFR 1.178(a)). Thus, an NDA holder
is required to withdraw the original patent and request that the
original patent be removed from listing in the Orange Book after patent
reissuance (see Sec. 314.53(f)(2)). Consistent with our policy for any
request to remove a patent from listing in the Orange Book, an original
patent that has been reissued would remain listed in the Orange Book
until FDA determined that no first applicant is eligible for 180-day
exclusivity based on a paragraph IV certification to that patent or
after the 180-day exclusivity period of a first applicant based on that
patent has expired or has been extinguished.
V.B.2. When and Where To Submit Patent Information (Sec. 314.53(d))
V.B.2.a. Submission of patent information for NDA supplements
(Sec. 314.53(d)(2)). We proposed to revise Sec. 314.53(d)(2) to
create two broad categories of supplements for purposes of required
submission of patent information. For supplements that seek approval
for a change that would result in a new entry in the Orange Book (e.g.,
a change to the dosage form, route of administration, strength, or
prescription drug status), we proposed that an applicant would continue
to submit the complete patent information required under Sec.
314.53(c) with submission of the supplement and following approval,
respectively. For supplements that seek approval for another type of
change (e.g., 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 that would not
result in a new entry in the Orange Book), we proposed that the patent
information submission requirements would depend on whether the
existing patent information submitted to FDA for the product approved
in the original NDA continued to claim the changed 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 proposed that we would permit an applicant to submit a
statement declaring that the patent(s) currently listed for a specific
NDA (identified by NDA number and product number as listed in the
Orange Book) continue to 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. If,
however, a listed patent no longer claims the product as changed by the
supplement, then we proposed that the applicant must submit a request
to correct or remove the patent information from the list at the time
of approval of the supplement (see proposed Sec. 314.53(f)(2)).
Correspondingly, if one or more existing patents claim the product as
changed by the supplement and this patent information has not been
submitted to FDA, we proposed that the applicant must submit the patent
information with the supplement and following approval of the
supplement. We proposed a conforming revision to Sec. 314.70(f) to
clarify that an applicant that submits a supplement to an NDA also must
comply with the patent information requirements under Sec. 314.53.
One comment supports the proposal because it would reduce
duplicative submissions of patent information for supplements. We are
finalizing proposed Sec. 314.53(d)(2)(i) with an editorial change to
clarify that Sec. 314.53(d)(2)(i)(A) and (B) also apply to a
supplement that seeks to add (rather than change) a dosage form, route
of administration, or strength. To facilitate implementation of this
provision, we are revising Sec. 314.53(c)(2)(i)(F) and (c)(2)(ii)(F)
to require that the NDA applicant or holder, respectively, identify the
dosage form(s), route(s) of administration and whether the drug is
proposed or approved for prescription use or over-the-counter (OTC) use
in its submission of patent information. We are making conforming
revisions to Forms FDA 3542a and 3542.
We are making several clarifying revisions to proposed Sec.
314.53(d)(2)(ii). The proposed rule explained that we would permit an
NDA holder to submit a statement declaring that the patent(s) currently
listed for a specific NDA continue to claim the drug or method of using
the drug for which approval is sought in the NDA supplement (instead of
resubmitting the patent information with the NDA supplement), if this
statement is accompanied by a signed patent declaration verification
(see 80 FR 6802 at 6823). Consistent with the intent of the proposed
rule to reduce duplicative submissions of patent information and
enhance efficiency, we are not requiring an NDA holder to submit a
statement with an NDA supplement if the NDA holder is not required to
resubmit patent information pursuant to Sec. 314.53(d)(2)(ii)(A).
Accordingly, if an NDA supplement is approved for a change other than
one of the changes listed in Sec. 314.53(d)(2)(i) and the NDA holder
does not submit Form FDA 3542 or submit a request to withdraw the
patent or patent information from the list under Sec. 314.53(f)(2)(iv)
(see Sec. 314.53(d)(2)(ii)(B) and (C)), FDA will consider the NDA
holder to have affirmed that any currently listed patent(s) continues
to claim the drug product as changed by the supplement. We are revising
Sec. 314.53(d)(2)(ii)(A) to clarify that patent information already
submitted to FDA refers to information required by Sec. 314.53(c). We
also are revising Sec. 314.53(d)(2)(ii)(A) to clarify that the
requirement to resubmit patent information with a supplement if the
description of the patented method of use would change upon approval of
the supplement refers to the published description of the patented
method of use (i.e., the use code).
We are making a conforming revision to Sec. 314.53(c) to clarify
that if the applicant submits a supplement for a change other than one
of the changes listed under Sec. 314.53(d)(2)(i), then the patent
information submission requirements of Sec. 314.53(d)(2)(ii) apply
(see Sec. 314.53(c)(2)(i)(S)(3) and (c)(2)(ii)(T)(3)).
V.B.2.b. Untimely filing of patent information (Sec. Sec.
314.53(d)(3), 314.50(i)(4), and 314.94(a)(12)(vi)). We proposed to
revise our regulations regarding the submission of information on
patents issued after the approval of an NDA or supplement to expressly
describe our longstanding practice with respect to listing patent
information that is not timely filed (see proposed Sec. 314.53(d)(3)).
Proposed Sec. 314.53(d)(3) stated that if a patent is issued after
approval and 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
[[Page 69602]]
patents in Sec. Sec. 314.50(i)(4) and (6) and 314.94(a)(12)(vi) and
(viii). We also proposed 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 (``use code'') 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.
Two comments agreed with this proposal. In the following
paragraphs, we discuss two other comments on the proposal for certain
amendments to the description of the approved method of use claimed by
the patent to be considered untimely filing of patent information.
After considering these comments, we are making clarifying revisions to
the regulations and describing an additional set of circumstances in
which an NDA holder's amendment to the description of the approved
method(s) of use claimed by the patent will not be considered untimely
filing of patent information.
(Comment 18) One comment recommends that FDA withdraw its proposal,
given that changes in patent law or interpretation, developments in
patent-specific litigation, and/or proceedings before the USPTO may
affect the scope of a patent claim's coverage and necessitate revisions
to the use code. The comment notes that these events typically occur
more than 30 days after patent issuance and do not involve a
corresponding change in product labeling. Another comment recommends
that FDA reevaluate its proposal to consider certain changes to the use
code as untimely filed patent information in light of the lack of
clarity on setting use codes.
(Response 18) We decline to withdraw our proposal given the
important role of use codes in enabling a 505(b)(2) or an ANDA
applicant to state that it is not seeking approval for the method of
use claimed by the patent (see section 505(b)(2)(B) and (j)(2)(D)(viii)
of the FD&C Act). However, we agree that revisions to the use code may
be appropriate in other limited circumstances, as reflected in our
revisions to Sec. Sec. 314.50(i)(4) and 314.94(a)(12)(vi). Our
approach is intended to enhance the accuracy of use codes and ensure
that 505(b)(2) and ANDA applicants have timely notice of changes to the
asserted patent coverage for a listed drug, while reducing
opportunities for manipulation of patent use codes.
As a preliminary matter, we are revising the regulations to more
clearly describe the circumstances in which an NDA holder's amendment
to the description of the approved method(s) of use claimed by the
patent will not be considered untimely filing of patent information
(see Sec. Sec. 314.50(i)(4)(i)(A) and (B) and 314.94(a)(12)(vi)(A)(1)
and (2)). As revised, an NDA holder's amendment to the description of
the approved method(s) of use claimed by the patent will be considered
timely filed if it is submitted within 30 days of patent issuance or
within 30 days of approval of a corresponding change to product
labeling. We also are revising the regulations to provide that an NDA
holder's amendment to the description of the approved method(s) of use
claimed by the patent will be considered timely filed patent
information if it is submitted within 30 days of a decision by the
USPTO or a Federal court that is specific to the patent and alters the
construction of a method-of-use claim(s) of the patent (see Sec. Sec.
314.50(i)(4)(i)(C) and 314.94(a)(12)(vi)(A)(3)). The amendment must
contain a copy of the USPTO or court decision, and the accompanying
Form FDA 3542 must identify the decision as a change related to the
patent in section 1.h of the form (see the following discussion
regarding revisions to Sec. 314.53(c)(2)(i)(K) and (c)(2)(ii)(L)).
Our addition of Sec. Sec. 314.50(i)(4)(i)(C) and
314.94(a)(12)(vi)(A)(3) permits NDA holders to make timely revisions to
the use code based on a patent-specific decision by the USPTO (e.g.,
inter partes review, post-grant review, and reexamination) or by a
Federal court (e.g., Markman hearing) that construes the terms of the
patent claim(s). An NDA holder may submit a revised use code based on a
patent-specific decision by either a Federal district court, the Court
of Appeals for the Federal Circuit, or the U.S. Supreme Court. We
decline to broaden the scope of this provision to allow for use code
changes to be considered timely filed based solely on changes in patent
law or interpretation that are not specific to the patent for which the
use code was submitted because we are not experts in patent law and
would be unable to evaluate arguments that could effectively remove the
limitation for untimely filing of method-of-use patent information.
Our clarifying revisions to the regulations are expected to address
concerns about how to set use codes, and there is no need to reevaluate
our proposal on this basis.
To facilitate implementation of this provision, FDA is revising
Sec. 314.53(c)(2)(i)(K) and (c)(2)(ii)(L) to require that if the
patent has been submitted previously for listing, the NDA holder must
identify all change(s) from the previously submitted patent information
and specify whether the change is related to the patent (e.g., patent
term extension or patent-specific decision by the USPTO or a Federal
court) or related to an FDA action or procedure (e.g., FDA approval of
a supplement that changes the approved conditions of use of the drug).
This information will assist the Orange Book staff in updating listed
patent information where appropriate and replaces the current
requirement that an applicant only identify whether the expiration date
is a new expiration date.
We also are making technical amendments in Sec. Sec. 314.50(i)(4)
and 314.94(a)(12)(vi) to explain that a 505(b)(2) or ANDA applicant
generally is not required to submit a patent certification or statement
to address the patent or patent information that is late-listed with
respect to the pending 505(b)(2) application or ANDA. Although a patent
certification or statement generally would not be required in this
circumstance, 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, an ANDA applicant may wish to submit
a paragraph IV certification to challenge the method-of-use patent with
the revised use code if the applicant may be eligible for 180-day
exclusivity based on that certification.
V.B.2.c. Where to send submissions of Forms FDA 3542a and 3542
(Sec. 314.53(d)(4)). We proposed to clarify that patent information
submitted on Form FDA 3542a with the filing of an NDA, amendment, or
supplement must be submitted to the CDER Central Document Room, and
should not be submitted to the Orange Book staff (see proposed Sec.
314.53(d)(4)(i); see also Sec. Sec. 314.50(h) and 314.70(f)). We also
proposed to require that patent information submitted 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. Our proposal to
designate the OGD Document Room as the official repository for
submission of Form FDA 3542 was intended to facilitate prompt listing
of patent information in the Orange Book after Form FDA 3542 has been
officially
[[Page 69603]]
received by the Agency (see proposed Sec. 314.53(d)(4)(ii) and
(d)(5)).
In the following paragraphs, we discuss a comment on these proposed
revisions. After considering this comment, we are finalizing Sec.
314.53(d)(4)(ii) with revisions to maintain the CDER Central Document
Room as the official repository for submission of Form FDA 3542 and we
are finalizing Sec. 314.53(d)(4)(i) and (ii) to clarify that Forms FDA
3542a and 3542 can be submitted electronically. We also are finalizing
Sec. 314.53(d)(4)(i) and (ii) with an editorial correction to the
title of Forms FDA 3542a and 3542, and we are making the same
correction in Sec. 314.53(f)(2)(ii) through (iv).
(Comment 19) One comment requests confirmation that NDA holders may
submit Form FDA 3542 to the OGD Document Room through the Electronic
Submissions Gateway (ESG). The comment also recommends that FDA clarify
that Form FDA 3542a must be submitted to the NDA via CDER's Central
Document Room.
(Response 19) FDA is revising Sec. 314.53(d) to expressly provide
that Form FDA 3542 can be submitted in an electronic format submission
that complies with Sec. 314.50(l)(5), which permits submission through
the ESG. This revision and the corresponding revision to Sec.
314.53(d)(5) are intended to clarify how submission dates are
determined for Form FDA 3542, given the implications of untimely filing
of patent information on the patent certification obligations of
505(b)(2) and ANDA applicants that rely upon the listed drug (see
Sec. Sec. 314.50(i)(4) and 314.94(a)(12)(vi)). Beginning in May 2017,
Form FDA 3542 and other submissions under section 505(b), (i), and (j)
of the FD&C Act must be submitted in the electronic format specified by
FDA (see section 745A(a) of the FD&C Act (21 U.S.C. 379k-1(a)) and
guidance for industry entitled ``Providing Regulatory Submissions in
Electronic Form--Certain Human Pharmaceutical Product Applications and
Related Submissions Using the eCTD Specifications'' (May 2015),
available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
Accordingly, we only have specified the method of submission where it
is important to describe how receipt dates or submission dates are
determined for a particular type of submission.
Based on the transition to electronic submission of Form FDA 3542
and related changes in FDA's administrative processes, we are not
finalizing our proposal to change the official repository for
submission of Form FDA 3542. Thus, Form FDA 3542 must continue to be
submitted to the NDA via the CDER Central Document Room or the ESG. The
CDER Central Document Room and the ESG promptly direct submissions of
Form FDA 3542 to the Orange Book staff for listing in the Orange Book.
To ensure that patents and patent information are listed in the Orange
Book only after Form FDA 3542 has been officially received by FDA, the
Orange Book staff intends to rely only on submissions of Form FDA 3542
that are received from the Central Document Room and disregard any
duplicate copies or courtesy copies of Form FDA 3542 that are submitted
through other channels. We are revising Sec. 314.53(d)(4)(ii) to
emphasize that Form FDA 3542 should not be submitted to the Orange Book
staff.
V.B.2.d. Submission date of patent information (Sec.
314.53(d)(5)). We proposed to revise Sec. 314.53(d)(5) to establish
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 through the ESG (i.e., at the
completion of electronic transmission). We proposed that patent
information sent to another location at FDA would not be 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 (6) or Sec. 314.94(a)(12)(vi) and
(viii), respectively, unless it is sent to the official repository
identified in the regulation. In the following paragraphs, we discuss
two comments on this provision. After considering these comments, we
are finalizing Sec. 314.53(d)(5) with revisions unrelated to the
comments to conform to the changes made to Sec. 314.53(d)(4)(ii).
(Comment 20) One comment suggests that FDA provide a list of
untimely filed patent information to facilitate evaluation of patent
certification obligations by 505(b)(2) and ANDA applicants. Another
comment recommends that FDA include in the Orange Book the date on
which the patent information was submitted to FDA.
(Response 20) FDA agrees that modifying the Orange Book to list the
date on which patent information was submitted to FDA as described in
Sec. 314.53(d)(5) would enable applicants to determine whether a
patent is late-listed as to a pending 505(b)(2) application or ANDA and
avoid the need for applicants to contact the Orange Book staff for this
information. FDA intends to list the date of submission of patents and
patent information in the Orange Book on a prospective basis beginning
as soon as practicable after the effective date of this rule. This
addition to the Orange Book does not require any modification to the
regulations. FDA does not intend to separately publish a list of
untimely filed patent information.
V.B.3. Public Disclosure of Patent Information (Sec. 314.53(e))
We proposed technical corrections to Sec. 314.53(e) to delete the
reference to monthly supplements to the Orange Book and clarify that
copies of the ``submitted patent information'' (rather than copies of
the ``file'') may be requested from FDA's Freedom of Information Staff.
We also proposed to expressly state that the submitted patent
information, and requests for delisting patents, will be subject to
public disclosure (see proposed Sec. 314.53(e)). In the preamble to
the proposed rule, we explained that FDA may elect to proactively post
on FDA's Web site a copy of the submitted patent information (Form FDA
3542) for listed patents in advance of a request under the Freedom of
Information Act (FOIA) based on our anticipation of requests for this
information. In the following paragraphs, we discuss a comment on the
potential for proactive posting of Form FDA 3542 on FDA's Web site.
After considering this comment, we are making an editorial correction
to clarify the information that may be subject to public disclosure.
(Comment 21) One comment urges FDA not to proactively post Form FDA
3542 on the FDA Web site based on concerns that the patent information
could be misused or lead to misinterpretation of the scope of relevant
patent rights in litigation or commercial contexts.
(Response 21) FDA is not persuaded by the comment, given that Form
FDA 3542 must contain the verification required by Sec.
314.53(c)(2)(ii)(R) and may be subject to disclosure under FOIA and
applicable disclosure regulations. Moreover, FDA has advised
prospective 505(b)(2) and ANDA applicants that the use code and other
information provided on Form FDA 3542 is not meant to substitute for
the applicant's review of the patent. However, at this time, FDA does
not intend to proactively post Form FDA 3542 for patent information
submitted for listing in the Orange Book because there is an adequate
mechanism to obtain a Form FDA 3542 on an individual basis through a
FOIA request. We are revising Sec. 314.53(e) to clarify that the
submitted
[[Page 69604]]
patent information and requests to remove a patent or patent
information from the list may be subject to public disclosure.
V.B.4. Correction or Change of Patent Information (Sec. 314.53(f))
V.B.4.a. Requests by persons other than the NDA holder (Sec.
314.53(f)(1)). We proposed to revise Sec. 314.53(f) to clarify and
improve the mechanism for challenging the accuracy or relevance of
patent information submitted to the Agency under Sec. 314.53 and
listed in the Orange Book (see proposed Sec. 314.53(f)(1)). First, we
proposed to establish a 30-day timeframe in which the NDA holder would
be required to respond to FDA's request to confirm the correctness or
omission of patent information to facilitate timely resolution of the
patent listing dispute. Second, we proposed enhanced procedures to
govern challenges to the accuracy or relevance of an NDA holder's
submission of method-of-use patent information so that the Agency has
additional information to implement section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act in cases where the accuracy or
relevance of the use code is disputed (see proposed Sec.
314.53(f)(1)).
For a patent listing dispute regarding method-of-use patent
information, we proposed to ask the NDA holder to 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 would enable the Agency to make a determination in accordance with
section 505(b)(2)(B) or (j)(2)(A)(viii) of the FD&C Act (see proposed
Sec. 314.53(f)(1)). We proposed that if the NDA holder confirms the
accuracy of its submitted patent information in response to FDA's
request, fails to timely respond to the request, 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,
FDA would 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 such a case, we explained
that FDA would 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.
Two comments support FDA's proposed revisions to the patent listing
dispute procedure. In the following paragraphs, we discuss several
other comments on this proposal. After considering these comments, we
are revising Sec. 314.53(f)(1) to describe the rules that will apply
to patent listing disputes involving drug substance, drug product, and
method-of-use claims. We also are revising Sec. 314.53(c)(2)(ii)(R) to
expressly state that the requirement to verify the accuracy and
completeness of the submission of patent information applies to a
response to a patent listing dispute under Sec. 314.53(f)(1). We
intend to take a stepwise approach and evaluate whether FDA's revisions
to the regulations on submission of method-of-use patent information
(see Sec. 314.53(b)(1) and (c)(2)) and patent listing dispute
procedures adequately address the problem of overbroad and ambiguous
use codes before we establish a process to review a proposed labeling
carve-out with deference to the 505(b)(2) and/or ANDA applicant(s)'
interpretation of the scope of the patent. Therefore, at this time, we
are not finalizing our proposal to review a proposed labeling carve-out
with deference to the applicant(s)' interpretation of the scope of the
patent in certain circumstances. We will continue to consider whether
there is a need to finalize this proposal in the future.
(Comment 22) Three comments indicate that there are inconsistencies
between the text of proposed Sec. 314.53(f) and the process described
in the corresponding preamble, and request that FDA clarify the
circumstances in which the Agency proposes to review a proposed
labeling carve-out for a 505(b)(2) application or ANDA with deference
to the 505(b)(2) or ANDA applicant's interpretation of the scope of the
patent. Several comments contend that it is inappropriate to defer to
the 505(b)(2) or ANDA applicant's interpretation of the scope of the
patent where the NDA holder has confirmed the accuracy of the use code.
One comment asserts that this approach will encourage 505(b)(2) and
ANDA applicants to routinely dispute method-of-use patent information
in an attempt to receive deference on a narrow interpretation of the
method-of-use patent and submit a statement under section 505(b)(2)(B)
or (j)(2)(A)(viii) of the FD&C Act instead of a patent certification.
One comment also contends that the Agency's standard for determining
that an NDA holder's revision to the use code ``does not provide
adequate clarity'' or determining that there is ``insufficient
information'' to evaluate a proposed labeling carve-out is
impermissibly vague.
(Response 22) FDA has made multiple changes to address the issue of
overbroad and ambiguous use codes, including revisions to the
regulations on submission of patent information and revisions to the
patent listing dispute procedures (see sections V.B.1.c and V.B.2.b).
We initially intend to evaluate whether these revisions to the
regulations adequately address the problem of overbroad and ambiguous
use codes. If these revisions to our regulations do not adequately
address the problem, we will further consider whether to finalize the
proposal to review a proposed labeling carve-out for a 505(b)(2)
application or ANDA with deference to the 505(b)(2) and/or ANDA
applicant(s)' interpretation of the scope of the patent. If FDA decides
to finalize the proposal, FDA would clarify the process and the
circumstances in which such deference may be given.
We are revising the regulation to provide a more detailed
description of the procedure for patent listing disputes directed to
the accuracy or relevance of submitted patent information regarding an
approved method of using the drug product (see Sec. 314.53(f)(1) and
(f)(1)(i)(B); see also Sec. 314.53(f)(1)(i)(A) (describing patent
listing dispute procedures directed to drug substance or drug product
claims)). We also are revising Sec. 314.53(c)(2)(ii)(R) to expressly
state that the requirement that an NDA holder verify the accuracy and
completeness of the submission of patent information applies to a
response to a request under Sec. 314.53(f)(1). This regulatory
approach is intended to provide the Agency with additional information
to facilitate implementation of section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act (see section 701(a) of the FD&C Act).
For all patent listing disputes, we are requiring that the patent
listing dispute communication contain a statement of dispute that
describes the specific grounds for disagreement regarding the accuracy
or relevance of patent information for FDA to send to the applicable
NDA holder. If a person disputes the accuracy or relevance of submitted
patent information regarding an approved method of using the drug
product, this statement of dispute must be only a narrative description
(no more than 250 words) of the person's
[[Page 69605]]
interpretation of the scope of the patent with respect to the method of
use.
FDA intends to forward the statement of dispute (without review or
redaction) to the applicable NDA holder using the electronic mail
(email) address or facsimile (fax) number provided by the NDA holder on
the most recent Form FDA 356h submitted to the NDA. Therefore, the
person submitting the patent listing dispute communication should
clearly identify the statement of dispute that he or she intends for
FDA to send to the applicable NDA holder, and only include information
for which the person consents to disclosure.
For patent listing disputes directed to drug substance or
drug product claims, the NDA holder must confirm the correctness of the
patent information and include the signed verification required by
Sec. 314.53(c)(2)(ii)(R) or withdraw or amend the patent information
in accordance with Sec. 314.53(f)(2) within 30 days of the date on
which the Agency sends the statement of dispute. Although proposed
Sec. 314.53(f)(1) would have permitted disputes over the omission of
patent information, it is unnecessary for FDA to request the NDA holder
to confirm the omission of patent information for a listed patent
because we no longer require an NDA holder to identify whether a patent
claims both the drug substance and the drug product (see Sec.
314.53(c)(2)(ii)(T)). Accordingly, we are making a conforming amendment
to remove the phrase ``or omission of patent information'' from Sec.
314.53(f)(1)(i)(A). Unless the NDA holder withdraws or amends its
patent information in response to the patent listing dispute, the
Agency will not change the patent information in the Orange Book (see
Sec. 314.53(f)(1)(i)(A)).
For patent listing disputes directed to method-of-use
claims, the NDA holder must confirm the correctness of the NDA holder's
description of the approved method of use claimed by the patent that
has been included as the ``use code'' in the Orange Book or withdraw or
amend the patent information in accordance with Sec. 314.53(f)(2). In
either case, the NDA holder must provide a narrative description (no
more than 250 words) of the NDA holder's interpretation of the scope of
the patent that explains why the existing or amended ``use code''
describes only the specific approved method of use claimed by the
patent for 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 NDA holder must
also include the signed verification required by Sec.
314.53(c)(2)(ii)(R) and submit its response within 30 days of the date
on which the Agency sends the statement of dispute (see Sec.
314.53(f)(1)(i)(B)). Any response from the NDA holder that is submitted
after 30 days will be considered untimely. The narrative description
must only contain information for which the NDA holder consents to
disclosure because FDA will send the text of the statement to the
person who submitted the patent listing dispute without review or
redaction to further assist the person (generally a 505(b)(2) or ANDA
applicant, a prospective applicant, or its representative) in
determining whether a use for which an applicant may seek approval is a
protected use.
We are revising the regulation to clarify that if the NDA holder
timely responds to the patent listing dispute with a confirmation of
the correctness of the patent information, the narrative description
required by Sec. 314.53(f)(1)(i)(B), and the signed verification
required by Sec. 314.53(c)(2)(ii)(R), the Agency will not change the
patent information in the Orange Book (see Sec.
314.53(f)(1)(i)(B)(1)). We are also revising the regulation to more
clearly state that if the NDA holder timely responds to FDA's request
with revised patent information, the narrative description required by
Sec. 314.53(f)(1)(i)(B), and the signed verification required by Sec.
314.53(c)(2)(ii)(R), FDA will update the Orange Book to reflect the
revised patent information (see Sec. 314.53(f)(1)(i)(B)(2) and
Response 26). This approach provides additional clarity, and
establishes a mechanism for a person (including a 505(b)(2) or ANDA
applicant) to request that an NDA holder confirm compliance with the
updated requirements for submission of patent information described in
Sec. 314.53(b) and (c).
A 505(b)(2) application or ANDA must contain an appropriate
certification or statement for each listed patent, including the
disputed patent, during and after the patent listing dispute (see Sec.
314.53(f)(1)(ii)). A disputed method-of-use patent may continue to be
the subject of a paragraph IV certification. We do not believe that an
ongoing patent listing dispute process will have an impact on the
timing of approval of a 505(b)(2) application or ANDA that is otherwise
eligible for approval and relies on the listed drug for which the
disputed patent is listed in the Orange Book. FDA may consider the
narrative description from the NDA holder required by Sec.
314.53(f)(1)(i)(B), as appropriate, to assist FDA in exercising its
scientific judgment to implement section 505(b)(2)(B) and
(j)(2)(A)(viii) of the FD&C Act.
To advise prospective and pending 505(b)(2) or ANDA applicants of a
patent listing dispute involving a method-of-use patent, FDA will
promptly post information about the patent listing dispute on a Web
page linked to the Orange Book. FDA intends to provide information such
as the relevant drug product, NDA number, NDA holder, U.S. Patent
Number, relevant use code(s), and whether the NDA holder has timely
responded to the patent listing dispute (see Sec. 314.53(f)(1)(iii)).
(Comment 23) Three comments recommend that FDA withdraw or revise
the proposal to review, in certain circumstances, a proposed labeling
carve-out for a 505(b)(2) application or ANDA with deference to the
505(b)(2) or ANDA applicant's interpretation of the scope of the
patent. One comment contends that there is no basis for FDA's proposed
approach because the statutory scheme contemplates that disputes over
the scope of a method-of-use patent will be resolved by Federal courts
in patent infringement litigation, especially given that the MMA
established a counterclaim procedure in which a 505(b)(2) or ANDA
applicant may seek an order requiring the NDA holder to correct or
delete the submitted patent information. Another comment maintains that
it would be legally inappropriate for FDA to defer to the 505(b)(2) or
ANDA applicant's view of the scope of a patent that the applicant does
not own, especially if the NDA holder has confirmed the accuracy of the
use code. Two comments suggest that when patent listing disputes arise,
FDA should seek clarification or correction of patent information
through other means.
(Response 23) We believe that FDA has the authority to establish a
regulation describing the limited circumstances in which the Agency
would defer to the 505(b)(2) or ANDA applicant's interpretation of the
scope of a patent that it does not own. However, in light of the
incremental approach that we are taking to this issue, we are not
finalizing this aspect of our proposal at this time. We will continue
to consider whether there is a need to finalize this proposal in the
future.
The statutory provisions that permit a 505(b)(2) or ANDA applicant
to submit a statement that a listed patent does not claim a use for
which the applicant is seeking approval complement the patent
certification requirements (see section 505(b)(2)(A) and (B) and
(j)(2)(A)(vii)
[[Page 69606]]
and (viii) of the FD&C Act). FDA's revised regulations are intended to
preserve FDA's ministerial role in listing patents (see 59 FR 50338 at
50349 and 68 FR 36676 at 36683 and 36687) and to also address ambiguous
or overbroad use codes that could be a barrier to approval of a
505(b)(2) application or ANDA for uses that are not claimed by the
listed patent (see Sec. 314.53(b)(1), (c)(2)(ii)(P)(3), and (f)(1)).
If an NDA holder provides a timely response to a patent listing dispute
and a 505(b)(2) or ANDA applicant disagrees with the NDA holder's
response to the patent listing dispute (or disagrees with the use
code), the 505(b)(2) or ANDA applicant may submit a paragraph IV
certification to challenge the method-of-use patent and assert a
counterclaim in the context of an infringement action or pursue a
declaratory judgment action, as appropriate, to obtain patent certainty
(see section 505(c)(3)(D)(i) and (ii) and (j)(5)(C)(i) and (ii) of the
FD&C Act).
We disagree, however, that the counterclaim procedure in section
505(c)(3)(D)(ii) and (j)(5)(C)(ii) of the FD&C Act obviates the need
for an enhanced patent listing dispute procedure. Nothing in the FD&C
Act precludes FDA from developing a procedure for patent listing
disputes in light of our broad authority to issue regulations for the
efficient enforcement of the FD&C Act. As the U.S. Supreme Court
observed in Caraco Pharm. Labs., ``the counterclaim cannot restore the
smooth working of a statutory scheme thrown off kilter by an overly
broad use code. At best, it permits the generic manufacturer to do what
the scheme contemplates it should do--file an ANDA with a section viii
statement--but only after expensive and time-consuming litigation. A
fix is in order, but it must come from Congress or FDA'' (132 S.Ct.
1670 at 1689).
Finally, we note that comments recommending that FDA seek
clarification or correction of patent information through other means
do not describe an alternative to the approach we proposed. We believe
that the modifications that we have made to the patent listing dispute
procedure, discussed in Response 22, and our stepwise approach to
evaluating whether FDA's revisions to this procedure and the
regulations on submission of method-of-use patent information address
the problem of overbroad and ambiguous use codes, adequately address
the comments received on our proposal.
(Comment 24) Three comments assert that FDA's proposed deference to
the 505(b)(2) or ANDA applicant's interpretation of the scope of the
patent would be inconsistent with the Agency's longstanding ministerial
role in patent-related matters. These comments suggest that FDA lacks
the expertise to assess the adequacy of use codes and determine whether
deference to the 505(b)(2) or ANDA applicant's interpretation of the
scope of the patent is justified. A fourth comment suggests that FDA
provide an administrative appeals process and Administrative Law Judge
review where FDA reviews a proposed labeling carve-out for a 505(b)(2)
application or ANDA with deference to the 505(b)(2) or ANDA applicant's
interpretation of the scope of the patent. This comment also suggests
that FDA avoid a ``mere ministerial approach.''
(Response 24) As noted in Response 23, we are not finalizing this
proposal at this time. Accordingly, we do not need to address comments
regarding specific aspects of implementation of this proposal in this
final rule.
(Comment 25) One comment recommends that FDA require an NDA holder
to respond to a request to confirm the accuracy or relevance of patent
information in 15 days, rather than 30 days. The comment maintains that
a 15-day timeframe is consistent with the regulatory timeframe to make
corrections to an incomplete or otherwise inadequate submission of
patent information (see Sec. 314.53(c)(2)(ii)).
(Response 25) We decline to modify the regulation as requested. We
believe that a period of 30 days from the date on which FDA sends the
statement of dispute to the NDA holder provides an appropriate
opportunity for the NDA holder to consider the statement of dispute and
submit a response that addresses the requirements of Sec.
314.53(f)(1)(i).
(Comment 26) Two comments recommend that FDA clarify that an NDA
holder's amendment to the use code in response to a patent listing
dispute will not be considered untimely filed patent information under
Sec. Sec. 314.50(i)(4) and 314.94(a)(12)(vi). One comment expresses
concern that whether and how an NDA holder responds to a method-of-use
patent listing dispute may affect the availability of a 30-month stay
should the NDA holder subsequently file a patent infringement action in
response to notice of a paragraph IV certification to the patent.
(Response 26) We agree that an NDA holder's amendment to its use
code or related information on Form FDA 3542 in response to a patent
listing dispute should not be considered untimely filed patent
information if it is submitted within 30 days of FDA's request under
Sec. 314.53(f)(1)(i)(B) and contains the information required under
Sec. 314.53(f)(1)(i)(B)(1) or (2) (see Sec. Sec. 314.50(i)(4)(i) and
314.94(a)(12)(vi)(A) (describing untimely filing of patent information
``except as provided in Sec. 314.53(f)(1)'')). We note, however, that
if an NDA holder responds to the patent listing dispute with an
amendment to its use code more than 30 days after the date on which FDA
sends the statement of dispute to the NDA holder, FDA will consider the
amendment to be untimely filing of patent information because the
submission does not comply with the requirements of Sec. 314.53(f)(1).
The patent listing dispute procedure would not have an impact on
the availability of a 30-month stay if other statutory and regulatory
criteria are met (see section 505(c)(3)(C) and (j)(5)(B)(iii) of the
FD&C Act and Sec. 314.107).
V.B.4.b. Requests by NDA holder (Sec. 314.53(f)(2)). We proposed
to expressly require that if an 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 must promptly notify
FDA to withdraw the patent or patent information and request that the
patent or patent information be removed from the list (see proposed
Sec. 314.53(f)(2)(i) and section 505(b)(1) and (c)(2) of the FD&C
Act). If an NDA holder is required by court order to amend patent
information or withdraw a patent from the list, we proposed to require
the NDA holder to submit a copy of the court order to the Orange Book
Staff within 14 calendar days of the date on which the order was
entered. We also proposed to codify our current practice of removing a
patent or patent information 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 (see proposed Sec. 314.53(f)(2)(i)). In addition, we proposed
that if the term of the patent is extended under the patent term
restoration provisions of 35 U.S.C. 156, the NDA holder must submit a
correction to the patent expiration date on Form FDA 3542 within 30
calendar days of receipt of a certificate of extension or documentation
of an extension of the term of the patent (see proposed Sec.
314.53(f)(2)(ii) and 35 U.S.C. 156(e)(1) and (2)).
We proposed to require that corrections or changes to previously
submitted patent information must be submitted on Form FDA 3542a or
3542,
[[Page 69607]]
as appropriate (see proposed Sec. 314.53(f)(2)(iii)). However, we
proposed to clarify that an NDA holder's withdrawal of a patent and
request to remove a patent from the list is not required to be
submitted on Form FDA 3542, but the request must specify the patent
number, the application number, and each product(s) approved in the
application to which the request applies (see proposed Sec.
314.53(f)(2)(iv)).
In the following paragraphs, we discuss two comments on these
proposed provisions. After considering these comments, we are making
clarifying revisions to the description of the required amendment or
supplement and the address to which the amendment or supplement must be
submitted, and technical amendments described in sections V.B.2.c and
V.P.3 We are also revising proposed Sec. 314.53(f)(2)(i) to more
precisely describe our practice of removing a patent or patent
information from the list in response to an NDA holder's request if
there is no first applicant eligible for 180-day exclusivity based on a
paragraph IV certification to that patent or after the 180-day
exclusivity period of a first applicant based on that patent has
expired or has been extinguished.
(Comment 27) Two comments request that FDA clarify the implications
of failing to timely amend patent information or withdraw a patent. One
of the comments requests that FDA clarify the meaning of ``promptly
notify FDA'' in proposed Sec. 314.53(f)(2)(i), and explain whether the
timeframe may differ based on the circumstances (e.g., delay withdrawal
of an original patent held invalid until the reissued patent has
issued). The other comment suggests that if the NDA holder fails to
timely notify FDA of a patent term extension or of a court order to
amend patent information or withdraw a patent from the list, the patent
should be considered untimely filed.
(Response 27) FDA is establishing regulatory timeframes for
withdrawal or amendment of patent information and withdrawal of a
patent to promote the NDA holder's timely compliance with obligations
under the FD&C Act and applicable regulations. 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 or patent information or amend the patent
information to ensure that pending 505(b)(2) applications or ANDAs that
contain a patent certification to the amended or withdrawn patent or
patent information are not inappropriately delayed if they are
otherwise eligible for approval. An NDA holder's withdrawal or
amendment of patent information or withdrawal of the patent within 14
days of the date on which the NDA holder determines that the patent or
patent claim no longer meets the requirements for listing under section
505(b)(1) or (c)(2) of the FD&C Act would be considered ``prompt.'' If
a court enters a final decision from which no appeal has been or can be
taken that a patent is invalid, the NDA holder must promptly notify FDA
to withdraw the patent and request that the patent be removed from the
list irrespective of whether the NDA holder or patent owner is
separately requesting a reissue of the patent.
We decline to modify the regulation to consider a patent untimely
filed if the NDA holder fails to notify FDA of a court order to amend
or withdraw patent information within 14 days because a court can
enforce a failure to comply with its order. We also decline to modify
the regulation to consider a patent untimely filed if the NDA holder
fails to notify FDA of a patent term extension within 30 days because
NDA holders have adequate incentive to inform FDA of any patent term
extension. We require NDA holders to submit on Form FDA 3542 a
correction to the expiration date of the listed patent if the term is
extended under 35 U.S.C. 156(e) to ensure that prospective 505(b)(2)
and ANDA applicants have timely notice of changes to the asserted
patent coverage for a listed drug.
(Comment 28) One comment recommends that FDA clarify where an NDA
holder should send a voluntary request to remove patent information
from the list.
(Response 28) We agree. We are revising Sec. 314.53(f)(2)(iv) to
clarify that the NDA holder must submit an amendment to its NDA to the
same addresses described in Sec. 314.53(d)(4)(ii) to promptly notify
FDA to withdraw a patent and request that FDA remove a patent from the
list. We are also revising Sec. 314.53(f)(2)(i) and (iii) to clarify
that an NDA holder must submit a copy of a court order to amend patent
information or withdraw a patent from the list in an amendment to its
NDA that bears the identification described in Sec. 314.53(d)(6)
(``Time Sensitive Patent Information''). In addition, we are changing
the address for submission of the amendment from the Orange Book Staff
to the CDER Central Document Room, consistent with Sec.
314.53(d)(4)(ii).
V.C. Patent Certification (Sec. Sec. 314.50(i) and 314.94(a)(12))
V.C.1. Method-of-Use Patents (Sec. Sec. 314.50(i)(1)(iii) and
314.94(a)(12)(iii))
We proposed 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 a condition of use other than an indication
(e.g., a dosing regimen) that is covered by a method-of-use patent for
the listed drug(s) relied upon or RLD, respectively, may submit a
statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the FD&C
Act, instead of a patent certification with respect to any such method-
of-use claims.
We received no comments regarding this proposed revision. We are
finalizing proposed Sec. Sec. 314.50(i)(1)(iii) and 314.94(a)(12)(iii)
with technical amendments to reflect the claim-based approach to patent
certification requirements for patents that include a method-of-use
claim (i.e., a 505(b)(2) or ANDA applicant may submit a statement with
respect to one or more method-of-use claims and a paragraph IV
certification with respect to the remaining patent claims). As revised,
a statement under section 505(b)(2)(B) or 505(j)(2)(A)(viii) of the
FD&C Act may be submitted if the applicant is not seeking approval for
``an'' indication or other condition of use claimed by a method-of-use
patent rather than ``any'' indications or other conditions of use
claimed by the method-of-use patent (see Sec. Sec. 314.50(i)(1)(iii)
and 314.94(a)(12)(iii)).
We also are making technical amendments throughout part 314 to
clarify that a 505(b)(2) or ANDA applicant may submit an appropriate
patent certification or statement (see, e.g., Sec. Sec.
314.50(i)(1)(i)(A) through (C), (i)(5), (i)(6), (i)(6)(ii),
(i)(6)(iii)(A)(1) and (2); 314.53(d)(3); and 314.94(a)(12)(i)(A) and
(B), (a)(12)(vii) and (viii), (a)(12)(viii)(B), and
(a)(12)(viii)(C)(1)(i) and (ii)).
V.C.2. Method-of-Manufacturing Patents (Deletion of Sec. Sec.
314.50(i)(2) and 314.94(a)(12)(iv))
We proposed to remove Sec. Sec. 314.50(i)(2) and
314.94(a)(12)(iv), which provide that an applicant is not required to
make a certification with respect to any patent that claims only a
method of manufacturing the drug product (method-of-manufacturing
patent or process patent) for which the applicant is seeking approval.
We proposed this deletion for clarity and consistency with the
regulation that
[[Page 69608]]
prohibits an NDA holder from submitting information on a patent that
only claims a method of manufacturing the drug product (see Sec.
314.53(b)).
In the following paragraphs, we discuss a comment on this proposed
deletion. After considering this comment, we are removing (and
reserving) Sec. Sec. 314.50(i)(2) and 314.94(a)(12)(iv).
(Comment 29) One comment recommends that FDA permit the listing of
process patents that claim production of the active pharmaceutical
ingredient in the approved drug product (e.g., synthesis process or
impurity reduction process).
(Response 29) We decline to adopt the suggestion provided in the
comment. The FD&C Act requires an NDA applicant or holder to submit
information on any patent that claims the drug or that 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 (see
section 505(b)(1) and (c)(2) of the FD&C Act). A method-of-
manufacturing patent or process patent does not meet the statutory
requirement for listing because it does not claim an approved drug or
an approved method of using the drug. We note, however, that a product-
by-process patent is eligible for listing in the Orange Book because
the invention claimed by the patent is, for example, the novel drug
product and not the process used to make the product (see 68 FR 36676
at 36679 to 36680).
V.C.3. Licensing Agreement (Sec. Sec. 314.50(i)(3) and
314.94(a)(12)(v))
We proposed 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. We
explained that this proposed revision did not alter the current
requirements for a 505(b)(2) (or ANDA) applicant to submit a paragraph
IV certification to a patent that claims the listed drug relied upon
even though the applicant has a licensing agreement with the patent
owner (see proposed Sec. Sec. 314.50(i)(3) and 314.94(a)(12)(v)). We
further explained that an applicant that has a licensing agreement with
the patent owner would still be required to send notice of the
paragraph IV certification to the NDA holder and each patent owner.
In the following paragraphs, we discuss a comment on this proposed
revision. After considering this comment, we are making a clarifying
revision and editorial corrections to Sec. 314.50(i)(3) and conforming
revisions to Sec. 314.94(a)(12)(v).
(Comment 30) One comment requests that FDA revise Sec.
314.50(i)(3) to apply to an ``agreement'' between a 505(b)(2) applicant
and the patent owner(s), rather than restrict the provision to a
``licensing agreement.'' The comment maintains that other forms of
agreement (e.g., a covenant not to sue) should not be treated
differently for purposes of determining the earliest date agreed upon
by the applicant and relevant patent owner(s) for approving an
application. The comment also recommends that FDA amend Sec.
314.94(a)(12)(v) to expressly describe consent to approval as of a
specific date because the provision also should apply to ANDAs.
(Response 30) We decline to modify Sec. 314.50(i)(3) to broadly
refer to an agreement between a 505(b)(2) applicant and the patent
owner. Licensing agreements are described in section 505(b)(1) and
(c)(2) of the FD&C Act, which refer to a patent 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. It accords with the statute for a 505(b)(2) applicant to
submit a paragraph IV certification based on a licensing agreement with
the patent owner, and for the patent owner to consent to approval of
the 505(b)(2) application as of a specific date (if the 505(b)(2)
application is otherwise eligible for approval). However, it is unclear
whether other types of agreements (e.g., a covenant not to sue) would
necessarily be consistent with a paragraph IV certification that the
patent is invalid, unenforceable, or will not be infringed by the
manufacture, use, or sale of the proposed product for which the
505(b)(2) application (or ANDA) is submitted. The FD&C Act does not
contemplate FDA enforcement of private agreements between a 505(b)(2)
(or ANDA) applicant and a patent owner that are unrelated to the
statutory and regulatory requirements for approval.
As a practical matter, it is unnecessary to broaden this provision
to describe other circumstances in which a patent owner may consent to
approval as of a specific date. If a 505(b)(2) applicant submits a
paragraph IV certification and the patent owner provides a covenant not
to sue, then the patent owner would not initiate patent infringement
litigation within the 45-day period and there would be no 30-month stay
of approval. If a 505(b)(2) applicant changes a previously submitted
certification or statement to a paragraph IV certification, the patent
owner and NDA holder for the listed drug relied upon may waive their
opportunity to file a patent infringement action within the 45-day
period (see Sec. 314.107(f)(3)).
We agree that the regulations should expressly provide that if an
ANDA applicant has a licensing agreement with a patent owner, the
patent owner may consent to approval of the ANDA as of a specific date
(if the ANDA is otherwise eligible for approval). We are revising Sec.
314.94(a)(12)(v) to describe the requirements for a written statement
from the patent owner that has a licensing agreement with the applicant
and consents to approval of the ANDA as of a specific date. Agreements
between an ANDA applicant and a brand name drug company that must be
filed with the Assistant Attorney General and the FTC are described in
section 1112 of the MMA.
We also are revising Sec. Sec. 314.50(i)(3) and 314.94(a)(12)(v)
to clarify that the 505(b)(2) application or ANDA will be approved
based on consent to approval as of a specific date only if the
505(b)(2) application or ANDA is ``otherwise eligible for approval''
rather than ``otherwise justified.''
V.D. Notice of Paragraph IV Certification (Sec. Sec. 314.52 and
314.95)
V.D.1. Timing of Notice
V.D.1.a. Date before which notice may not be given. We proposed to
revise our regulations to clearly delineate the two limitations on the
timeframe within which notice of a paragraph IV certification to a
listed patent must be provided to the NDA holder and each patent owner:
The date before which notice must not be given and, as discussed in
section V.D.1.b, the date by which notice must be given.
We proposed to codify our longstanding policy 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 (see proposed
Sec. Sec. 314.52(b)(1) and 314.95(b)(1)). We proposed that any notice
sent by a 505(b)(2) or ANDA applicant before the receipt of an
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
[[Page 69609]]
infringement action and obtain a 30-month stay or the beginning of any
related 30-month period. We proposed that an applicant that prematurely
sends notice of a paragraph IV certification would be required to
resend notice within the required timeframe after the 505(b)(2)
application or ANDA has been filed or received, respectively, to
satisfy the notice requirement of the FD&C Act and, in the case of a
first applicant, to qualify for 180-day exclusivity (see proposed
Sec. Sec. 314.52(b)(2) and 314.95(b)(2)).
We proposed to clarify that if a 505(b)(2) or ANDA applicant
submits an amendment containing a paragraph IV certification before the
filing or receipt of the 505(b)(2) application or ANDA, respectively,
the applicant would be required to 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 (see proposed Sec. Sec. 314.52(b) and (d)(2) and
314.95(b) and (d)(2)).
With respect to patents that are listed in the Orange Book after
submission of an ANDA, we proposed that any notice of paragraph IV
certification would be invalid and would not be considered to comply
with the notice requirement of the FD&C Act if it is sent before the
first working day after the day the patent is listed in the Orange Book
(see proposed Sec. Sec. 314.94(a)(12)(viii)(C)(1)(ii) and
314.95(b)(2)). We proposed that the term ``working day'' would have the
meaning provided in 21 CFR 1.377 (``any day from Monday through Friday,
excluding Federal holidays''). We explained that this proposal is
intended to discourage ANDA applicants from submitting a paragraph IV
certification and sending notice to the NDA holder and each patent
owner every day during the 30-day period after issuance of a patent
that could be listed for the RLD in an effort to qualify as a first
applicant eligible for 180-day exclusivity if such patent ultimately is
listed for the RLD in the Orange Book. We also noted that this proposed
requirement would ensure that all ANDA applicants (irrespective of time
zone) have a reasonable opportunity to be first to certify to a newly
listed patent.
In the following paragraphs, we discuss several comments on our
proposed regulations regarding the date before which notice of
paragraph IV certification must not be given. After considering these
comments, we are revising Sec. 314.52(b)(2) to provide that a
505(b)(2) applicant must send notice of a paragraph IV certification on
or after the date of filing of the 505(b)(2) application described in
Sec. 314.101(a)(2) or (3), as applicable, rather than on or after the
date it receives a paragraph IV acknowledgment letter. We are revising
proposed Sec. 314.95(b)(2) to delete the reference to an
``acknowledgment letter'' because an ANDA applicant will now receive a
``paragraph IV acknowledgment letter'' if it amends its ANDA to add a
paragraph IV certification before the ANDA is received (see section
V.A.1).
(Comment 31) One comment asserts that the statutory terms
``submits'' and ``files'' in section 505(j)(2)(B)(ii)(I) and (II) of
the FD&C Act, respectively, indicate that an ANDA applicant may send
notice of a paragraph IV certification at the time of submission of an
amendment to an ANDA containing a paragraph IV certification, even if
the ANDA has not yet been ``filed'' (i.e., ``received'' under Sec.
314.101(b)). The comment suggests that ANDA applicants that submit an
amendment containing the first paragraph IV certification to a patent
listed for the RLD are concerned that they may risk eligibility for
180-day exclusivity if they do not send notice at the time of
submission of the amendment, even though the ANDA has not been received
under Sec. 314.101(b). The comment proposes that FDA allow ANDA
applicants to ``change'' rather than ``amend'' their patent
certification in an amendment prior to filing, and consider the date of
the ``change'' for purposes of determining eligibility for 180-day
exclusivity.
(Response 31) We disagree with the comment's interpretation of
section 505(j)(2)(B)(ii)(II) of the FD&C Act, and decline to adopt the
comment's proposed revision to the regulations governing submission of
a paragraph IV certification prior to receipt of the ANDA.
As a preliminary matter, we note that the requirement that an ANDA
applicant must wait until its ANDA has been received before sending
notice of a paragraph IV certification ensures that the NDA holder and
patent owner do not needlessly expend resources to initiate litigation
with respect to an ANDA that is incomplete and therefore may not be
reviewed by the Agency (see ``Abbreviated New Drug Application
Regulations,'' 54 FR 28872 at 28887, July 10, 1989; see also 59 FR
50338 at 50349 to 50350). This reflects the Agency's view that Congress
did not intend for incomplete ANDA submissions to have the potential to
trigger legal action by an NDA holder or patent owner (see 54 FR 28872
at 28887; see also Allergan, Inc. v. Actavis, Inc., 2014 WL 7336692 at
*12 (E.D. Tex. 2014) (finding that the act of infringement created by
35 U.S.C. 271(e)(2) requires that the ANDA has been received by FDA,
not merely transmitted to FDA). Accordingly, our existing regulations
require that an ANDA applicant's notice of a paragraph IV certification
must include a statement that FDA has received the ANDA (see Sec.
314.95(c)(1)).
The requirement that notice of a paragraph IV certification only be
sent after FDA has received the ANDA was ratified by the MMA, which
established a 20-day period for sending notice of a paragraph IV
certification that runs from the date of the postmark on the notice
with which FDA informs the applicant that the ANDA has been filed
(i.e., received under Sec. 314.101(b)) (see section
505(j)(2)(B)(ii)(I) of the FD&C Act and section V.D.1.b). The MMA also
requires that an ANDA applicant send notice of a paragraph IV
certification submitted in an amendment or supplement to the ANDA at
the time of submission of the amendment or supplement, regardless of
whether the applicant already has given notice with respect to another
paragraph IV certification contained in the ANDA or in an amendment or
supplement to the ANDA (see section 505(j)(2)(B)(ii)(II) of the FD&C
Act). Consistent with the framework established by section
505(j)(2)(B)(ii) of the FD&C Act, FDA interprets section
505(j)(2)(B)(ii)(II) of the FD&C Act to apply only to an amendment to
the ANDA that is submitted after the Agency has received the ANDA (see
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) (upholding FDA's interpretation of section
505(j)(2)(B)(ii)(II) of the FD&C Act and finding that notice of a
paragraph IV certification sent at the time of submission of an
amendment to an ANDA that had not yet been received ``was not valid or
timely''). Thus, we disagree with the comment's suggestion that an ANDA
applicant can submit an amendment containing a paragraph IV
certification before the ANDA is received and immediately send notice
of the paragraph IV certification. If an ANDA applicant submits an
amendment containing a paragraph IV certification before it has
received 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 paragraph IV acknowledgment letter.
Based on the Agency's interpretation of the statute, it is
unnecessary to use the terminology suggested in the
[[Page 69610]]
comment to describe an amendment that contains a paragraph IV
certification to a newly listed patent or that changes a previously
submitted patent certification or statement to a paragraph IV
certification and is submitted before receipt of the ANDA.
The relevant date for determining 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.
We are revising Sec. 314.95(d)(2) to clarify that if an ANDA
applicant's notice of paragraph IV certification is timely provided in
accordance with Sec. 314.95(b)(2) and the applicant has not submitted
a previous paragraph IV certification, 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.
(Comment 32) One comment accepts FDA's ``settled administrative
practice'' that a 505(b)(2) or ANDA applicant may not send notice of
paragraph IV certification until the application is accepted for
review, but contends that FDA may not condition a 505(b)(2) applicant's
ability to send notice on its prior receipt of a paragraph IV
acknowledgment letter that would be sent up to 14 days after the
505(b)(2) application is accepted for review (filed). The comment
maintains that the benefits of this approach have not been shown to
outweigh the costs of a potential 2-week delay in approval of a
505(b)(2) application, and that the proposal is inconsistent with the
statute. Another comment recommends that FDA send a paragraph IV
acknowledgment letter to a 505(b)(2) applicant via email on the date on
which the 505(b)(2) application is filed to eliminate the disparity
between the dates on which paragraph IV acknowledgment letters are sent
to 505(b)(2) and ANDA applicants. A third comment requests that FDA
clarify when an ANDA applicant can send notice if the paragraph IV
acknowledgment letter is not received on day 60.
(Response 32) We agree that there should not be a delay of
approximately 2 weeks between the date on which a 505(b)(2) application
is filed and the date on or after which a 505(b)(2) applicant must send
notice of a paragraph IV certification to the NDA holder and each
patent owner. We are revising proposed Sec. 314.52(b)(1) and (2) to
provide that a 505(b)(2) applicant must send notice of a paragraph IV
certification on or after the date of filing of the 505(b)(2)
application described in Sec. 314.101(a)(2) or (3), as applicable,
rather than on or after the date it receives a paragraph IV
acknowledgment letter, and we are making conforming revisions to Sec.
314.52(d)(1) and (2). This revised approach ensures that notice of a
paragraph IV certification will not be sent before the Agency has filed
the relevant 505(b)(2) application, and avoids a delay of up to 2 weeks
in the potential 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.
FDA determines whether a 505(b)(2) application may be filed within
60 days after FDA is in receipt of the 505(b)(2) application (see Sec.
314.101(a)(1)). If the 505(b)(2) applicant does not receive a refusal
to file letter on or before day 60, the 505(b)(2) application is deemed
filed. If FDA refuses to file the 505(b)(2) application and the
505(b)(2) application is filed over protest or resubmitted, then the
date of filing described in Sec. 314.101(a)(3) applies. We are
requiring that a 505(b)(2) applicant send notice of a paragraph IV
certification on or after the date of filing of the 505(b)(2)
application, but not later than 20 days after the date of the postmark
on the paragraph IV acknowledgment letter (see Sec. 314.52(b)(1)). The
``paragraph IV acknowledgment letter'' for a 505(b)(2) application is
the filing communication that generally is sent to the 505(b)(2)
applicant not later than 14 calendar days after the 60-day filing date
(sometimes referred to as the ``74 day letter'') (see section V.A.1).
The ``date of the postmark'' for a paragraph IV acknowledgment letter
for a 505(b)(2) application is considered to be four calendar days
after the date on which the letter is signed by the signatory authority
(generally the Division Director or designee in the OND review
division). Accordingly, this revision to our regulations implements the
statutory requirement that notice be sent within 20 days of the
postmark on the filing communication while preserving the principle
that notice must not be sent before a 505(b)(2) application is filed.
We are maintaining the requirement that an ANDA applicant must send
notice of a paragraph IV certification on or after the date it receives
a paragraph IV acknowledgment letter because FDA intends to
electronically transmit the letter to the ANDA applicant on the date on
which the ANDA is received under Sec. 314.101(b). Accordingly, in
contrast to the interval of up to 14 days for 505(b)(2) applications,
there is no interval between the date on which the ANDA is received
under Sec. 314.101(b) and the date on which an ANDA applicant receives
a paragraph IV acknowledgment letter (see section V.A.6). An ANDA
applicant can send notice of a paragraph IV certification submitted in
an original ANDA or submitted in an amendment to an ANDA that has not
yet been received on or after the date the ANDA applicant receives a
paragraph IV acknowledgment letter.
(Comment 33) One comment asserts that the proposed requirement that
a paragraph IV certification must not be submitted earlier than the
first working day after the day the patent or patent claim is listed in
the Orange Book would conflict with the statute and prevent ANDA
applicants from submitting a paragraph IV certification to a newly
listed patent at the first lawful opportunity. Another comment
maintains that the proposed requirement for submission of a paragraph
IV certification to a newly listed patent may result in multiple ANDA
applicants becoming eligible for 180-day exclusivity and thus would
dilute the value of 180-day exclusivity.
(Response 33) We believe that our approach to patent certification
requirements for newly listed patents is consistent with the statute
and provides a reasonable opportunity for ANDA applicants to compete to
have the first substantially complete ANDA that contains a paragraph IV
certification to a listed patent for the RLD.
The requirement that an ANDA applicant must not submit a paragraph
IV certification earlier than the first working day after the day the
patent or patent claim is listed in the Orange Book reflects FDA's
determination that selecting the first working day after the day on
which the patent information is published creates a level playing field
for all ANDA applicants (see Sec. Sec. 314.94(a)(12)(viii)(C)(1)(ii)
and 314.95(b)(2)). One court has determined, in the absence of a
regulation to the contrary, that ``reality matters'' if a patent has
been submitted to FDA, and an ANDA applicant can submit a paragraph IV
certification even if the patent is not yet listed in the Orange Book
(see Teva Pharms., USA, Inc. v. Leavitt, 548 F.3d 103, 105 (D.C. Cir.
2008)). However, FDA has determined that permitting serial submissions
of amendments and multiple notices of paragraph IV certifications is
overly burdensome to FDA and NDA holders. Such a practice makes it
difficult to determine which paragraph IV certification and notice of
paragraph IV certification is valid. Our decision to
[[Page 69611]]
level the playing field for paragraph IV certifications in this manner
is consistent with our authority to establish rules for the efficient
enforcement of the FD&C Act (see section 701(a) of the FD&C Act).
We are not persuaded by the comment's assertion that leveling the
playing field for ANDA applicants will dilute the value of 180-day
exclusivity. For example, FDA continues to receive multiple ANDAs on
the day that 4 years of a 5-year exclusivity period under section
505(j)(5)(F)(ii) of the FD&C Act has expired (the first day that ANDAs
containing a paragraph IV certification are permitted to be submitted)
even though many of these ANDAs will likely share eligibility for 180-
day exclusivity.
(Comment 34) One comment supports the proposed requirement that a
paragraph IV certification must not be submitted earlier than the first
working day after the day the patent or patent claim is listed in the
Orange Book, but recommends that FDA establish a time after which
patent information listed in the Orange Book will be deemed to have
been published the next day. Another comment suggests that FDA
instantaneously notify ANDA applicants when a patent is listed for the
RLD after ANDA submission to provide an equal opportunity for timely
submission of an appropriate patent certification or statement to the
pending ANDA and, if applicable, notice of paragraph IV certification.
(Response 34) We decline to adopt the suggestions provided in the
comments. FDA generally posts daily electronic updates to the Orange
Book in the afternoon (Eastern Standard Time); however, we are not
establishing a specific time by which FDA will update the Orange Book
to preserve flexibility in the event of technical difficulties.
Applicants will have an equal opportunity for timely submission of an
appropriate patent certification or statement for a newly listed patent
or patent claim because FDA will make this information publicly
available through the Orange Book. Although we decline to undertake the
burden of notifying individual ANDA applicants when a patent or patent
claim for the RLD is newly listed in the Orange Book, we are committed
to facilitating public access to the Orange Book through efficient
means (see, e.g., the ``Orange Book Express'' mobile application
launched on November 9, 2015).
V.D.1.b. Date by which notice must be given. We proposed to
establish a regulation that would implement section 505(b)(3)(B) and
(j)(2)(B)(ii) of the FD&C Act by providing that an applicant must send
notice of a paragraph IV certification contained in a 505(b)(2)
application or ANDA not later than 20 days after the date of the
``postmark'' on the acknowledgment letter or paragraph IV
acknowledgment letter (see proposed Sec. Sec. 314.52(b)(1) and
314.95(b)(1) and section 505(b)(3)(B)(i) and (j)(2)(B)(ii)(I) of the
FD&C Act). We proposed a definition of the term ``postmark'' and, as
applied to paragraph IV acknowledgment letters for 505(b)(2)
applications, an alternate proposed interpretation of the term
``postmark'' to reflect current practice regarding the mailing of
filing communications (see section V.A.1). We also proposed to specify
the method of calculating the 20-day period for providing notice of a
paragraph IV certification (see proposed Sec. Sec. 314.52(b)(1) and
314.95(b)(1)).
We proposed that an applicant must send notice of a paragraph IV
certification contained in an amendment to a 505(b)(2) application or
ANDA that has been filed or received for substantive review,
respectively, or in a supplement to an approved 505(b)(2) application
or ANDA at the same time that the amendment or supplement is submitted
to FDA (see proposed Sec. Sec. 314.52(d)(1) and 314.95(d)(1) and
section 505(b)(3)(B)(ii) and (j)(2)(B)(ii)(II) of the FD&C Act). We
proposed 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 (see proposed
Sec. Sec. 314.52(d)(1) and 314.95(d)(1) and section 505(b)(3)(B)(ii)
and (j)(2)(B)(ii)(II) of the FD&C Act).
We proposed to require an applicant that submits an amendment or
supplement to a 505(b)(2) application or ANDA that seeks approval for a
different strength of the drug product and contains a paragraph IV
certification adhere to the timing requirements for notice in
Sec. Sec. 314.52(d)(1) or (2) and 314.95(d)(1) or (2), respectively,
based on whether the 505(b)(2) application has been filed or the ANDA
has been received (see proposed Sec. Sec. 314.52(d)(3) and
314.95(d)(3)).
We did not receive any other comments on proposed Sec. Sec.
314.52(b)(1), (d)(1) and (2), and 314.95(b)(1), (d)(1) and (2). We are
finalizing proposed Sec. 314.52(b)(1) and (2) and (d)(1) and (2) with
the revisions discussed in Response 32. We are finalizing proposed
Sec. 314.95(b)(1) and (d)(2) with clarifying revisions to consistently
refer to ``a paragraph IV acknowledgment letter'' because these
provisions refer to an ANDA that contains a paragraph IV certification
before the ANDA is received and thus FDA will send the ANDA applicant a
paragraph IV acknowledgment letter. We also are making the clarifying
revision to proposed Sec. 314.95(d)(2) discussed in Response 31. We
are finalizing proposed Sec. 314.95(d)(1) with a clarifying revision
to add the phrase ``or an acknowledgment letter'' because an applicant
may amend or supplement its ANDA to include a paragraph IV
certification irrespective of whether the ANDA contained a paragraph IV
certification at the time of receipt. We also are making the technical
amendment to Sec. 314.95(d)(1) described in section V.P.1.
V.D.2. Contents of Notice
We proposed that a 505(b)(2) or ANDA applicant's notice of a
paragraph IV certification must include, among other things: (1) A
statement that data from any required bioavailability or bioequivalence
studies have been submitted; (2) a statement that the applicant has
received an acknowledgment letter or a paragraph IV acknowledgment
letter for its 505(b)(2) application or ANDA; (3) the patent number and
expiration date of each patent listed in the Orange Book that is the
subject of the paragraph IV certification; and (4) an offer of
confidential access, 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
(j)(5)(C) of the FD&C Act) (see proposed Sec. Sec. 314.52(c) and
314.95(c)). We also proposed to require the 505(b)(2) or ANDA applicant
to cite section 505(b)(3)(D) and (j)(2)(B)(iv) of the FD&C Act,
respectively, as amended by the MMA, in the notice of paragraph IV
certification (see proposed Sec. Sec. 314.52(c) and 314.95(c)). In the
proposed rule, we explained that the Agency assesses neither 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 the following paragraphs, we discuss two comments on the
proposed requirements for the content of a notice of paragraph IV
certification. After considering these comments, we are not finalizing
proposed Sec. 314.52(c)(3) and we are making conforming editorial
changes to the numbering of subsequent paragraphs in Sec. 314.52(c).
We are
[[Page 69612]]
revising proposed Sec. 314.95(c)(3) to omit the reference to an
``acknowledgment letter'' and require that the ANDA applicant include a
statement that the applicant has received the paragraph IV
acknowledgment letter for the ANDA. We are making a grammatical
correction to the introductory text of Sec. Sec. 314.52(c) and
314.95(c) to provide that the notice must include, but is not limited
to, the information described in Sec. Sec. 314.52(c)(1) through (8)
and 314.95(c)(1) through (9). We are finalizing the remaining
provisions of proposed Sec. Sec. 314.52(c) and 314.95(c) without
change, except for a revision to proposed Sec. Sec. 314.52(c)(8) and
314.95(c)(8) to clarify that an offer of confidential access must be
provided by an applicant that seeks to preserve the option to file a
civil action for declaratory judgment in accordance with section
505(c)(3)(D) or (j)(5)(C) of the FD&C Act.
(Comment 35) One comment asserts that FDA lacks authority to
require a 505(b)(2) or ANDA applicant to include, in any notice of
paragraph IV certification, a statement that the applicant has received
an acknowledgment letter or a paragraph IV acknowledgment letter
because section 505(b)(3)(D) and (j)(2)(B)(iv) of the FD&C Act does not
expressly require such a statement.
(Response 35) We disagree. FDA has the authority to establish
regulations regarding the contents of notice of a paragraph IV
certification to support the efficient enforcement of the FD&C Act (see
section 701(a) of the FD&C Act). The FD&C Act requires that a notice of
paragraph IV certification must state 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 discussed in
Response 31, it is the Agency's longstanding policy that notice of a
paragraph IV certification may not be sent unless and until we have
notified the applicant that its 505(b)(2) application has been filed or
its ANDA has been received because premature notice could result in
lawsuits over applications that FDA refuses to file or receive and thus
no longer are pending. Accordingly, our existing 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)). To help ensure that notices
of paragraph IV certifications are not sent prematurely, we also are
requiring that an ANDA applicant's notice of paragraph IV certification
include a statement that the applicant has received the paragraph IV
acknowledgment letter for the ANDA (see Sec. 314.95(c)(3)). We are
revising proposed Sec. 314.95(c)(3) to delete the reference to an
``acknowledgment letter'' because an ANDA applicant will now receive a
``paragraph IV acknowledgment letter'' if the ANDA contains a paragraph
IV certification at any time before the ANDA is received (see section
V.A.1).
With respect to a 505(b)(2) application, we are maintaining the
requirement that a 505(b)(2) applicant's notice of a paragraph IV
certification must include a statement that FDA has filed the NDA (see
Sec. 314.52(c)(1)). However, we are not requiring the 505(b)(2)
applicant to include a statement that it has received a paragraph IV
acknowledgment letter because we are revising our regulations to
provide that a 505(b)(2) applicant must send notice of a paragraph IV
certification on or after the date of filing of the 505(b)(2)
application described in Sec. 314.101(a)(2) or (3), as applicable,
rather than on or after the date the applicant receives a paragraph IV
acknowledgment letter (see Sec. 314.52(b)(1) and Response 32).
(Comment 36) One comment requests that FDA revise the regulations
to enable any recipient of notice of paragraph IV certification to
request that FDA confirm the adequacy of notice with respect to
statutory and regulatory requirements (other than the factual and legal
basis for the paragraph IV certification). This comment recommends that
FDA provide that inadequate notice is invalid and does not trigger the
45-day period described in section 505(c)(3)(C) or (j)(5)(B)(iii) of
the FD&C Act. Another comment recommends that FDA provide an additional
time period in which a 505(b)(2) or ANDA applicant can correct a
deficient notice of paragraph IV certification that would extend the
time for a patent holder under its duties or obligations.
(Response 36) We decline to revise the regulations to provide for a
ministerial review of notice of a paragraph IV certification to
evaluate compliance with the statutory and regulatory requirements. A
505(b)(2) or ANDA applicant is required to submit an amendment to its
505(b)(2) application or ANDA certifying, among other things, that the
notice of paragraph IV certification met the content requirements under
Sec. Sec. 314.52(c) or 314.95(c), respectively (see Sec. Sec.
314.52(b)(3) or 314.95(b)(3)). The regulations also provide that a copy
of the notice of paragraph IV certification does not need to be
submitted to FDA (see Sec. Sec. 314.52(b)(3) or 314.95(b)(3)). Given
the clarifying revisions to the regulations to enhance compliance with
the requirements for notice of a paragraph IV certification and the
administrative burden that would be associated with a ministerial
review of a notice of paragraph IV certification, we do not believe
that such review is warranted. The second comment does not clearly
describe the requested action or provide adequate support for any
proposed change. We note, however, that an applicant may amend its
505(b)(2) application or ANDA with a written statement that a later
date should be used as the first day of the 45-day period provided in
section 505(c)(3)(C) or (j)(5)(B)(iii) of the FD&C Act (see Sec. Sec.
314.52(f) and 314.95(f)).
V.D.3. Documentation of Timely Sending and Receipt of Notice
V.D.3.a. Acceptable methods of sending notice of paragraph IV
certification. We proposed to expand the list of acceptable delivery
methods that 505(b)(2) and ANDA applicants may use to send notice of
paragraph IV certification to the NDA holder and each patent owner by
permitting a 505(b)(2) or ANDA applicant to use a ``designated delivery
service'' (see proposed Sec. Sec. 314.52(a) and 314.95(a)). We
proposed to define a ``designated delivery service'' to mean a delivery
service provided by a trade or business that FDA 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 the item was given
to the trade or business for delivery; and (3) provides overnight or 2-
day delivery service throughout the United States (see Sec. Sec.
314.52(g)(1) and 314.95(g)(1)). We proposed to periodically issue
guidance describing designated delivery services that meet the
regulatory criteria (see proposed Sec. Sec. 314.52(g)(2) and
314.95(g)(2)). We also proposed 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 (see proposed Sec. Sec. 314.52(a)(4) and (e) and
314.95(a)(4) and (e)).
In the following paragraphs, we discuss a comment on these proposed
provisions. After considering this comment, we are finalizing proposed
[[Page 69613]]
Sec. Sec. 314.52(a) and (g)(1) and 314.95(a) and (g)(1) without
change, except for a technical amendment to add ``505(b)(2)'' before
``applicant'' in Sec. 314.52(a) for clarity. We are revising
Sec. Sec. 314.52(g)(2) and 314.95(g)(2) to clarify that FDA may
periodically issue guidance regarding designated delivery services.
(Comment 37) One comment requests that FDA clarify whether a
505(b)(2) or ANDA applicant may use a delivery service that appears to
satisfy the criteria in Sec. Sec. 314.52(g)(1) and 314.95(g)(1) even
if the delivery service has not been identified by FDA in periodic
guidance.
(Response 37) At this time, FDA does not intend to identify
specific designated delivery services in guidance. A 505(b)(2) or ANDA
applicant that sends notice of a paragraph IV certification may use a
delivery service that satisfies the regulatory criteria in Sec. Sec.
314.52(g)(1) or 314.95(g)(1), as applicable, without FDA's prior
approval. For purposes of the definition of ``designated delivery
service,'' FDA is clarifying that ``United States'' means the 50
States, the District of Columbia, and the Commonwealth of Puerto Rico,
but not the Territories. This approach acknowledges that some delivery
services may not routinely provide overnight or 2-day delivery services
to each of the Territories of the United States. If a 505(b)(2) or ANDA
applicant is required to send notice of a paragraph IV certification to
an NDA holder or patent owner (or its representative) that resides in a
Territory of the United States or outside the United States, the
applicant should ensure that the designated delivery service provides
service to the area or request permission to use an alternate method of
delivery.
We are revising Sec. Sec. 314.52(g)(2) and 314.95(g)(2) to clarify
that FDA may periodically issue guidance regarding designated delivery
services. We note that a 505(b)(2) or ANDA applicant may send notice of
a paragraph IV certification by an alternate method that does not meet
the criteria in Sec. Sec. 314.52(g)(1) or 314.95(g)(1) only if the
applicant has obtained FDA's agreement in advance (see Sec. Sec.
314.52(a)(4) and 314.95(a)(4)).
V.D.3.b. Amendment documenting timely sending and confirmation of
receipt of notice of paragraph IV certification. We proposed 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.
We proposed that an applicant must amend its 505(b)(2) application
or ANDA at the time that it provides notice of a paragraph IV
certification with 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 met the content requirements described in
Sec. Sec. 314.52(c) and 314.95(c) (see proposed Sec. Sec.
314.52(b)(3) and 314.95(b)(3)). We also proposed to clarify that a copy
of the notice of paragraph IV certification itself does not need to be
submitted to FDA in the amendment (see proposed Sec. Sec. 314.52(b)(3)
and 314.95(b)(3)).
We proposed that an applicant must amend its 505(b)(2) application
or ANDA with 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 (see proposed Sec. Sec. 314.52(e) and 314.95(e) and section
505(b)(3)(B) and (j)(2)(B)(ii) of the FD&C Act). For administrative
efficiency, we proposed that a 505(b)(2) or ANDA applicant can submit a
single amendment that contains documentation of timely sending of the
notice(s) of paragraph IV certification and receipt of the notice(s) by
each person provided the notice. We proposed that the amendment must be
submitted 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 (see proposed Sec. Sec. 314.52(e) and 314.95(e)). We also
proposed to clarify the types of documentation of timely sending and
receipt of notice of paragraph IV certification that can satisfy the
regulatory requirements (see proposed Sec. Sec. 314.52(e) and
314.95(e)).
In addition, we proposed 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 proposed requirement would 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 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)).
We did not receive any comments on these proposed revisions.
However, for administrative efficiency, the Agency has revised
Sec. Sec. 314.52(b)(3) and 314.95(b)(3) to remove the requirement for
a 505(b)(2) or ANDA applicant to submit an amendment at the time it
sends notice of paragraph IV certification. Instead, the 505(b)(2) or
ANDA applicant may submit a single amendment that contains the
statements required by Sec. Sec. 314.52(b)(3) and 314.95(b)(3) and
documentation of timely sending and receipt of notice of paragraph IV
certification if the amendment contains all of the information required
by Sec. Sec. 314.52(b)(3) and (e) and 314.95(b)(3) and (e) and is
submitted within 30 days of the date on which the last notice was
received.
V.E. Amended Patent Certifications (Sec. Sec. 314.50(i)(6) and
314.94(a)(12)(viii))
We proposed to revise the introductory text of Sec.
314.94(a)(12)(viii) to remove the provision that restricts an ANDA
applicant from changing a paragraph IV certification to a paragraph III
certification in certain circumstances. We also proposed to revise
Sec. Sec. 314.50(i)(6) 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) and not by letter. We
received no comments, and we are finalizing these proposed revisions to
Sec. Sec. 314.50(i)(6) and 314.94(a)(12)(viii) without change, except
for the technical amendments described in sections V.P.2 and V.P.6.
V.E.1. Amended Patent Certifications After a Finding of Infringement
We proposed 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 to
amend its paragraph IV certification after a judicial finding of patent
infringement (see section 505(c)(3)(C)(ii)(II) and
(j)(5)(B)(iii)(II)(bb) of the FD&C Act). We proposed to require that a
505(b)(2) and ANDA applicant 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
(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 is
valid and has been infringed (see proposed Sec. Sec. 314.50(i)(6)(i)
and 314.94(a)(12)(viii)(A)). We proposed to apply this requirement
irrespective of whether the patent infringement action was brought
within 45 days of receipt of the notice of paragraph IV certification
because a 505(b)(2) or ANDA applicant can no longer lawfully maintain a
paragraph IV certification after the final court decision.
[[Page 69614]]
We also proposed to require a 505(b)(2) or ANDA applicant 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 (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
(see proposed Sec. Sec. 314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)).
We noted, 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.
We received no comments, and we are finalizing these proposed
revisions to Sec. Sec. 314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)
without change, except for a technical amendment to clarify that a
settlement order or consent decree must be signed and entered by the
court as required by section 505(c)(3)(C) and (j)(5)(B)(iii) of the
FD&C Act and the additional technical amendments described in sections
V.P.2 and V.P.6.
V.E.2. Amended Certifications After Request by the NDA Holder To Remove
a Patent or Patent Information From the List
We proposed 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 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 practice
regarding patent delisting as it relates to the eligibility of one or
more first applicants for 180-day exclusivity.
We received one comment supporting our proposal that if an NDA
holder has requested removal of a patent or patent information from the
list and one or more first 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 is eligible
for 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)). We
are finalizing proposed Sec. Sec. 314.50(i)(6)(ii) and
314.94(a)(12)(viii)(B) with revisions to consistently refer to a
request to remove a patent or patent information from the Orange Book
and to clarify that the patent or patent information will remain listed
until any 180-day exclusivity based on that patent has expired or has
been extinguished. We also are making the technical amendments
described in sections V.P.1, V.P.3, and V.P.6 and the revision to Sec.
314.94(a)(12)(viii)(B) described in section V.E.3.
V.E.3. Amended Certifications Upon Patent Reissuance
We proposed to revise our regulations to describe a 505(b)(2) and
ANDA applicant's patent certification obligations with respect to a
reissued patent. Our approach reflected our consideration of 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 section V.B.1.e).
We proposed to require that a 505(b)(2) or ANDA applicant provide
an appropriate patent certification or statement with respect to a
reissued patent, unless the NDA holder did not timely file patent
information with FDA on either the original patent or the reissued
patent. We also proposed that the patent information listed for the
reissued patent would be treated as though it had 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 determining the availability of a 30-
month stay if other criteria were met (see section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act).
For a first applicant eligible for 180-day exclusivity based on a
paragraph IV certification to an original patent that is subsequently
reissued, we proposed that if the applicant opined that the reissued
patent also is invalid, unenforceable, or will not be infringed, the
applicant must submit a paragraph IV certification to the reissued
patent within 30 days of the date on which the reissued patent is
listed 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)). Otherwise, we proposed that we
would consider the first applicant to have amended or withdrawn its
paragraph IV certification to the original patent on which it qualified
for 180-day exclusivity under section 505(j)(5)(D)(i)(III) of the FD&C
Act. We indicated that if a first applicant who qualifies as such based
on a paragraph IV certification to the original patent forfeits 180-day
exclusivity, another applicant would not be eligible for 180-day
exclusivity based on a paragraph IV certification to the reissued
patent (see section 505(j)(5)(D)(iii)(II) of the FD&C Act).
In the following paragraphs, we discuss a comment on this proposal
(see section V.B.1.e for a discussion of comments regarding submission
of additional information on reissued patents). After considering this
comment, we are not finalizing this proposal.
(Comment 38) One comment objects to FDA's proposal that a first
applicant eligible for 180-day exclusivity based on a paragraph IV
certification to a patent that has been reissued 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 180-day exclusivity. The comment asserts that failure to
comply with this proposed requirement does not provide an adequate
basis for FDA to extinguish a first applicant's eligibility for 180-day
exclusivity. In the alternative, the comment requests that FDA
expressly state that the requirement only will be applied
prospectively. The comment also recommends that an amended patent
certification only be required if the original certification becomes
inaccurate.
(Response 38) As discussed in Response 17, FDA has determined that
the ``single bundle of patent rights'' approach reflected in its
proposed regulations on reissued patents is no longer appropriate based
on the recent decision in Mylan Pharms., Inc. v. FDA (594 Fed. Appx.
791). Accordingly, the Agency is not finalizing the proposed revision
to Sec. 314.94(a)(12)(viii)(B) regarding reissued patents because we
now consider reissued patents as separate and distinct from the
original patent for purposes of administering the patent certification
requirements of the FD&C Act and any 30-month stay of approval or 180-
day exclusivity. This determination that the ``single bundle of patent
rights'' approach is no longer appropriate means that FDA assesses
whether a reissued patent is timely filed based solely on whether the
NDA holder has submitted the required patent information within 30 days
of reissuance (provided that the patent is reissued after the date of
approval of the NDA) or otherwise meets the requirements for timely
filing of patent information (see Sec. Sec. 314.50(i)(4) and
314.94(a)(12)(vi)). Similarly, the date on which patent information on
the reissued patent (and not the original patent) is submitted to FDA
determines
[[Page 69615]]
whether a paragraph IV certification to the reissued patent could give
rise to a 30-month stay if other criteria are met (see section
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). This also means that
FDA evaluates eligibility for 180-day exclusivity based on whether the
criteria are met for an original patent (irrespective of whether it
subsequently is reissued) or for a reissued patent. It is unnecessary
to address the comment requesting that FDA prospectively apply the
proposed revision to Sec. 314.94(a)(12)(viii)(B) because we are not
finalizing this proposed change.
With respect to the comment regarding an ``amended'' patent
certification, we note that an appropriate patent certification or
statement is required for timely filed patent information submitted by
an NDA holder for the listed drug relied upon or RLD, including timely
filed patent information on a reissued patent (see Sec. Sec.
314.50(i)(4) and 314.94(a)(12)(vi), and sections V.B.2.b and V.E.4; see
also Sec. Sec. 314.60(f) and 314.96(d) and section V.F).
V.E.4. Other Amended Certifications
We proposed to expressly require a 505(b)(2) or ANDA applicant to
submit an appropriate patent certification or statement if, after
submission of the 505(b)(2) application or ANDA, a new patent is issued
by the USPTO that claims the listed drug or RLD or that claims an
approved use for such drug, except as provided in Sec. Sec.
314.50(i)(4) and 314.94(a)(12)(vi) (see proposed Sec. Sec.
314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(viii)(C)(1)(ii)). We also
explained 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 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. We proposed
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); see also proposed Sec. 314.95(b)(2) and
section V.D.1.a). Finally, we proposed to revise our regulations to
clarify that an applicant is not required to submit a supplement solely
to change a submitted patent certification after approval of the
application (see proposed Sec. Sec. 314.50(i)(6)(iii)(B) and
314.94(a)(12)(viii)(C)(2)).
In section V.D.1.a, we discuss comments on proposed Sec.
314.94(a)(12)(viii)(C)(1)(ii) (see Responses 33 and 34). We received no
other comments and are finalizing these provisions without change,
except for the technical amendments described in section V.P.4.
V.F. Patent Certification Requirements for Amendments and Supplements
to 505(b)(2) Applications and ANDAs (Sec. Sec. 314.60, 314.70, 314.96,
and 314.97)
V.F.1. Types of Amendments for Which Patent Certification Is Required
We proposed to add Sec. Sec. 314.60(f) and 314.96(d) to clarify
and augment the patent certification requirements for amendments
described in Sec. Sec. 314.50(i)(6)(iii) and 314.94(a)(12)(viii)(C).
In these provisions, we proposed to require that an applicant must
submit patent certifications described in Sec. Sec. 314.50(i) or
314.94(a)(12) if approval is sought for any of the following types of
amendments to a 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 the product formulation; or (4) to
change the physical form or crystalline structure of the active
ingredient of the drug product.
We explained that this proposed requirement would not apply to
minor changes in product formulation that FDA would regard as resulting
in essentially the same product (see proposed Sec. Sec. 314.60(f)(3)
and 314.96(d)(3)). We proposed that 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). 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, we proposed that the applicant
would be required to verify that the proposed change described in the
amendment is not the type of change for which a new patent
certification or statement is required (e.g., the proposed formulation
change meets the criteria for a ``minor'' formulation change).
In the following paragraphs, we discuss several comments on this
proposal. After considering these comments, we are finalizing
Sec. Sec. 314.60(f) and 314.96(d) with revisions to clarify that the
specified types of amendments are required to contain an appropriate
patent certification (or recertification) or statement and to describe
the required verification.
(Comment 39) Three comments recommend that an amended patent
certification should not be required if the 505(b)(2) or ANDA applicant
determines that the change described in its amendment does not
materially affect the factual and legal basis for a previous paragraph
IV certification or materially affect the product in a manner that
could be protected by a listed patent. These comments express concern
that requiring a patent certification for the types of amendments
described in Sec. Sec. 314.60(f) and 314.96(d) could give rise to a
second 30-month stay of approval, contrary to the intent of the MMA.
Two other comments opine that the proposal is under-inclusive, and
recommend that FDA require a new patent certification in all
circumstances in which an amendment may alter the proposed product's
relationship to a listed patent and require that the applicant provide
the basis for a claim of noninfringement. These comments recommend
requiring a new patent certification (and corresponding opportunity for
resolution of potential patent infringement claims before approval) if
approval is sought for any of the following types of changes: Any
change in product formulation; a change in the physical form, particle
size, grade, purity, or crystalline structure of the active ingredient;
or a change to a proposed drug-delivery device.
(Response 39) We acknowledge comments suggesting that the patent
certification requirements for amendments to a 505(b)(2) application or
ANDA may be considered either under-inclusive or over-inclusive.
However, we believe that our approach strikes an appropriate balance by
protecting the patent rights of NDA holders without unnecessarily
delaying approval of 505(b)(2) applications and ANDAs. A 505(b)(2) or
ANDA applicant 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)). An applicant that
submits a 505(b)(2) application or ANDA containing a paragraph IV
certification to a listed patent must
[[Page 69616]]
reevaluate whether the patent certification continues to be accurate
after a change to the proposed product submitted in an amendment to the
505(b)(2) application or ANDA. To address concerns that the factual and
legal basis of the applicant's opinion that a patent will not be
infringed may have changed, we are requiring an applicant to submit an
appropriate patent certification (or recertification, for a previously
submitted paragraph IV certification) or statement, for the following
types of amendments to a 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 the product formulation; or (4)
to change the physical form or crystalline structure of the active
ingredient of the drug product (see Sec. Sec. 314.60(f)(1) and
314.96(d)(1) and Response 42). These patent certification requirements
are intended to facilitate ongoing compliance with section 505(b)(2)(A)
and (j)(2)(A)(vii) of the FD&C Act. We do not agree that the need for
an appropriate patent certification (or recertification) or statement
for the types of amendments described in Sec. Sec. 314.60(f) and
314.96(d) should be left entirely to the applicant's discretion because
applicants may be uncertain when it is necessary. To implement the
proposed verification by the 505(b)(2) or ANDA applicant described in
the proposed rule (see 80 FR 6802 at 6823), we are adding Sec. Sec.
314.60(f)(2) and 314.96(d)(2) to require that if the amendment to the
505(b)(2) application or ANDA does not contain a patent certification
or statement, the applicant must verify that the proposed change
described in the amendment is not one of the types of amendments
described in Sec. Sec. 314.60(f)(1)(i) through (iv) and
314.96(d)(1)(i) through (iv).
We also do not agree that it is necessary to expressly require an
appropriate patent certification (or recertification) with the broader
range of changes to a proposed product described in the comments. We
previously have explained that ``[g]iven the range of changes that may
be the subject of a [chemistry, manufacturing, and controls] amendment,
such a requirement would impose a significant burden without clearly
enhancing compliance with the statutory patent certification
requirements. Through our proposal to require 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 that
certain types of amendments are submitted to FDA, we are upholding the
legislative balance of the Hatch-Waxman Amendments that facilitates the
availability of generic drug products while protecting innovator
intellectual property rights'' (see Letter from Janet Woodcock, M.D.,
Director, CDER, to John B. Dubeck and Frederick A. Stearns, dated
February 6, 2015, regarding Docket No. FDA-2003-P-0519, available at
http://www.regulations.gov).
We recognize that a 30-month stay of approval may result from
initiation of a patent infringement action in response to a second
notice of paragraph IV certification that is provided with an amendment
to a 505(b)(2) application or ANDA. This scenario may occur if the
patent at issue in the infringement action was listed before 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 (see, e.g., Letter from Janet Woodcock, M.D.,
Director, CDER, to Gerald F. Masoudi, dated October 19, 2010, regarding
Docket No. FDA-2010-P-0223, available at http://www.regulations.gov
(concluding that a new 30-month stay of approval stems from a timely
lawsuit based on the second notice of paragraph IV certification
submitted in connection with an amendment to the ANDA for reformulated
doxercalciferol injection); Letter from Janet Woodcock, M.D., Director,
CDER, to Christina M. Markus, dated June 7, 2011, regarding Docket No.
FDA-2011-P-0127, available at http://www.regulations.gov (confirming
that a second 30-month stay of approval stems from a timely lawsuit
based on the second notice of paragraph IV certification submitted in
connection with an amendment to the ANDA for desflurane liquid)).
(Comment 40) One comment recommends that an amendment to a
505(b)(2) application or ANDA to add a new indication or other
condition of use should only require submission of a patent
certification to a patent that claims the new use and for which a
patent certification previously was not made.
(Response 40) We agree that if an applicant amends its 505(b)(2)
application or ANDA only to add a new indication or other condition of
use, the applicant need only certify to listed patents that have been
identified as claiming an approved use and relate to the change
described in the amendment (provided that the 505(b)(2) application or
ANDA contained an appropriate patent certification or statement to any
other listed patent(s) prior to submission of the amendment). This
approach preserves the NDA holder's intellectual property rights
without requiring the 505(b)(2) or ANDA applicant to submit a
duplicative certification to a listed patent(s) that has not been
identified by the NDA holder as claiming a method of use and would not
be implicated by the amendment (compare proposed Sec. 314.70(i)(2)).
This approach also is consistent with existing patent certification
requirements under Sec. Sec. 314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C). If any other changes described in paragraphs
(ii) through (iv) of Sec. Sec. 314.60(f)(1) or 314.96(d)(1) are
proposed in the amendment, the applicant would be required to address
all timely filed listed patents for the listed drug relied upon or RLD
with an appropriate patent certification (or recertification) or
statement.
An ANDA applicant would be expected to submit an amendment to add a
new indication or other condition of use if the applicant previously
submitted a statement described in section 505(j)(2)(A)(viii) of the
FD&C Act and now seeks approval for the use or if the RLD was approved
for a new indication or other condition of use after the ANDA was
submitted (see section 505(j)(2)(A)(v) of the FD&C Act and Sec.
314.94(a)(8)(iv)). Most requests for approval of a different indication
or condition of use by a 505(b)(2) applicant should not be made as an
amendment to the 505(b)(2) application (see Sec. 314.60(b)(6) and
guidance for industry entitled ``Submitting Separate Marketing
Applications and Clinical Data for Purposes of Assessing User Fees''
(December 2004) at 4 to 5, available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
Accordingly, we expect that there would be limited circumstances in
which this provision would apply to a 505(b)(2) application (e.g.,
indication changed from prescription status to OTC use).
V.F.2. Types of Supplements for Which Patent Certification Is Required
We proposed 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 the patent certification
requirements for a 505(b)(2) or ANDA supplement. In these provisions,
we proposed to require patent certifications described in Sec.
314.50(i) or Sec. 314.94(a)(12), if the applicant requests approval to
add a new indication or other condition of use or to add a new strength
in a 505(b)(2) or ANDA supplement (see proposed Sec. Sec. 314.70(i)
and 314.97(c)).
[[Page 69617]]
For a 505(b)(2) supplement that seeks approval for a new indication
or other condition of use, the 505(b)(2) applicant currently is
required to submit an appropriate patent certification or statement for
each timely filed patent that claims the listed drug(s) relied upon or
a method of using such drug(s) for which the applicant is seeking
approval (see section 505(b)(2) of the FD&C Act). We proposed to reduce
these patent certification requirements by providing that a 505(b)(2)
supplement that only seeks approval to add a new indication or other
condition of use is required to contain an appropriate patent
certification or statement described in Sec. 314.50(i) only for
patents that are identified as claiming an approved use (see proposed
Sec. 314.70(i)(2)).
We did not propose 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. We explained that it would not be
necessary for FDA 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.
In the following paragraphs, we discuss two comments on proposed
Sec. Sec. 314.70(i) and 314.97(c). We are continuing to consider these
comments, and thus we are not finalizing proposed Sec. Sec. 314.70(i)
and 314.97(c) (or the references to these provisions in proposed
Sec. Sec. 314.50(i)(6)(iii)(B) and 314.94(a)(12)(viii)(C)(2)),
respectively, at this time. Accordingly, FDA will maintain its current
practice of regulating directly from the statute and general patent
certification regulations in requiring an appropriate patent
certification or statement with a 505(b)(2) or ANDA supplement.
(Comment 41) Two comments disagree with FDA's proposal to not
expressly require a new patent certification with a 505(b)(2) or ANDA
supplement in each of the circumstances in which a new patent
certification (or recertification) is required for amendments to a
505(b)(2) application or ANDA. One comment maintains that the Agency's
approach is inconsistent with the statute, which clearly describes
patent certification requirements for 505(b)(2) and ANDA supplements.
This comment also expresses concern that a 505(b)(2) or ANDA applicant
could circumvent the patent certification requirements by seeking
approval of a noninfringing product that the applicant does not intend
to market followed by a supplement for a modified form of the active
ingredient or a different formulation of the drug product that the
applicant intends to market. Both comments contend that monitoring of
postapproval changes by an NDA holder or patent owner is not a
replacement for notice from the 505(b)(2) or ANDA applicant of a
paragraph IV certification and the opportunity to litigate any
potential infringement claims prior to approval of the change requested
in the supplement.
(Response 41) We are continuing to evaluate these comments,
including whether our regulations should expressly require a new patent
certification with a broader range of changes submitted in supplemental
applications than described in the proposed rule. Accordingly, we are
declining to finalize proposed Sec. Sec. 314.70(i) and 314.97(c) at
this time. We will continue to implement the requirement for an
appropriate patent certification or statement with a 505(b)(2) or ANDA
supplement directly from the statute and our general regulations on
patent certifications (see Sec. Sec. 314.50(i)(6)(iii) and
314.94(a)(12)(viii)(C) (requiring a 505(b)(2) or ANDA applicant 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)).
V.F.3. Requirements for Notice of Paragraph IV Certifications and
Implications for 180-Day Exclusivity
We proposed that notice to the NDA holder and each patent owner
would be required for all paragraph IV certifications, irrespective of
whether the 505(b)(2) or ANDA 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 and proposed Sec. Sec. 314.52(d)(1)
and 314.95(d)(1)). We proposed that 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 is accompanied by another paragraph IV certification to the
patent and notice of paragraph IV certification is sent in accordance
with proposed Sec. 314.95(d).
In the following paragraphs, we discuss two comments on this topic.
After considering these comments, we are revising proposed Sec.
314.96(d) regarding amendments to an ANDA to clarify that a paragraph
IV certification to a patent or patent claim for which an ANDA
applicant previously submitted a paragraph IV certification is a
``recertification'' rather than an ``amendment'' of the paragraph IV
certification. We are making conforming revisions to Sec. 314.60(f).
We are finalizing Sec. 314.52(d)(1) with the changes described in
Response 32, and we are finalizing Sec. 314.95(d)(1) with the changes
described in section V.D.1.b and the technical amendments described in
section V.P.1.
(Comment 42) One comment expresses concern that a first applicant
could inadvertently forfeit its eligibility for 180-day exclusivity if,
pursuant to proposed Sec. 314.96(d), the first applicant submits a new
paragraph IV certification to the patent that qualified the applicant
for 180-day exclusivity (see section 505(j)(5)(D)(i)(III) of the FD&C
Act). The comment suggests that FDA require an ANDA applicant to
provide a new notice of its paragraph IV certification to the NDA
holder and each patent owner instead of submitting a new patent
certification to the Agency. Another comment recommends that FDA not
require an ANDA applicant to submit a new patent certification with an
amendment to the ANDA if a patent infringement action already has been
filed against the applicant with respect to the ANDA.
(Response 42) FDA interprets the statute to mean that a first
applicant ``lawfully maintains'' a paragraph IV certification to the
patent or patent claim upon which eligibility for 180-day exclusivity
is based if any subsequent amendment to the ANDA that requires a patent
certification contains a paragraph IV certification to the qualifying
patent or patent claim and notice of the paragraph IV certification is
sent in accordance with Sec. 314.95(d). This interpretation is
supported by our longstanding requirement that an ANDA applicant must
amend a submitted certification if, at any time before approval of the
ANDA, the applicant learns that the submitted certification is no
longer accurate (see Sec. 314.94(a)(12)(viii)(C)(1)(i)). A subsequent
paragraph IV certification to the qualifying patent or patent claim is
not an ``amendment'' of the previously submitted paragraph IV
certification under section 505(j)(5)(D)(i)(III) of the FD&C Act
because the type of certification remains the same; rather, it is a
reaffirmation of the patent challenge
[[Page 69618]]
notwithstanding the amendment to the ANDA. Therefore, we are using the
term ``recertification'' to describe this scenario (see Sec.
314.96(d)(1); see also Sec. 314.60(f)(1)).
We decline to adopt the comment's proposal to require a new notice
of paragraph IV certification--but not a new patent certification--with
an amendment to the ANDA. Notice of a paragraph IV certification is
inextricably linked to the submission of a corresponding paragraph IV
certification. The statute expressly requires that an applicant that
submits a paragraph IV certification in an amendment to the ANDA
provide the required notice at the time of submission of the amendment
regardless of whether the applicant has already given notice with
respect to another such certification contained in the application (see
section 505(j)(2)(B)(ii)(II) of the FD&C Act). Notice of a new
paragraph IV certification submitted with an amendment to the ANDA must
be updated to correspond to the proposed product as changed by the
amendment. However, we believe that the concern described in the
comment is addressed by our explanation that a paragraph IV
certification to a patent or patent claim for which an ANDA applicant
previously submitted a paragraph IV certification is a
``recertification'' rather than an ``amendment'' of the paragraph IV
certification and by the corresponding changes to Sec. 314.96(d)(1).
We also do not agree with the suggestion that a new notice of
paragraph IV certification should not be required if the NDA holder or
owner of the relevant patent(s) already is litigating claims of patent
infringement against the ANDA applicant. As previously discussed, the
statute requires an ANDA applicant to provide notice with all paragraph
IV certifications (see section 505(j)(2)(B)(ii)(II) of the FD&C Act).
Moreover, if the factual and legal bases for the paragraph IV
certification have changed, it would be particularly important to
timely provide this information to the NDA holder and each patent owner
to support the efficient use of judicial resources.
V.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 (Sec. Sec. 314.60, 314.70, 314.96, and 314.97)
V.G.1. Amendments and Supplements to an ANDA (Sec. Sec. 314.96(c) and
314.97(b))
We proposed to establish a regulation that would implement section
505(j)(2)(D)(i) of the FD&C Act by providing that an ANDA applicant may
not amend or supplement an ANDA to seek approval of a drug referring to
a listed drug that is different from the RLD identified in the ANDA
(see proposed Sec. Sec. 314.96(c) and 314.97(b)). For example, we
proposed that if at any time before approval of the ANDA, an NDA is
approved for a drug product that is pharmaceutically equivalent to the
proposed product in the pending ANDA and that NDA is designated as an
RLD, the applicant would not be permitted to amend its pending ANDA to
reference the new RLD (see proposed Sec. 314.96(c)). We proposed that
this restriction also would apply if one or more changes proposed in an
amendment or a supplement to an ANDA would result in the proposed
product being a pharmaceutical equivalent to a different listed drug
than the RLD identified in the ANDA. In these scenarios, we proposed
that the ANDA applicant would be required to submit a new ANDA to
identify the pharmaceutically equivalent product as the new RLD (see
proposed Sec. Sec. 314.96(c) and 314.97(b) and section 505(j)(2)(D)(i)
of the FD&C Act).
In the proposed rule, we confirmed that different strengths of an
approved drug product continue to be regarded as different listed
drugs. However, to implement section 505(j)(2)(D)(ii) of the FD&C Act,
we proposed to codify our practice that permits an applicant to amend
or supplement an ANDA to seek approval of a different strength of the
drug (see proposed Sec. Sec. 314.96(c) and 314.97(b)).
We received no comments on proposed Sec. 314.97(b) regarding
supplements. In the following paragraphs, we discuss three comments on
proposed Sec. 314.96(c) regarding amendments. After considering these
comments, we are finalizing proposed Sec. Sec. 314.96(c) and 314.97(b)
without change.
(Comment 43) One comment requests that FDA modify the proposed
regulation to require that if, at any time before submission (rather
than any time before approval) of the ANDA, an NDA is approved for a
drug product that is pharmaceutically equivalent to the proposed
product and that NDA is designated as an RLD, the ANDA applicant would
be required to submit an ANDA that identifies the pharmaceutically
equivalent product as the RLD. The comment suggests that this proposed
revision (and a similar proposal discussed in comment 49) would
harmonize FDA's proposed requirements for ANDAs and 505(b)(2)
applications by imposing limitations up until the time of ANDA
submission rather than approval. Another comment expresses concern that
requiring an ANDA applicant to submit a new ANDA that identifies the
pharmaceutically equivalent product as the RLD may unnecessarily
require additional data and delay ANDA approval, although the comment
acknowledges that this may be appropriate and efficient in some
circumstances.
(Response 43) We decline to adopt the suggested modification to
proposed Sec. 314.96(c). Under existing practice, FDA will refuse to
receive an ANDA that does not cite an appropriate RLD or rely on an
approved suitability petition as its basis for ANDA submission (see
Sec. 314.94(a)(3)). In addition, there are circumstances in which an
ANDA that has been received, but not approved, may be required to
submit a new ANDA that identifies a pharmaceutically equivalent product
as the RLD. This may occur, for example: (1) If a pharmaceutically
equivalent product is approved after an ANDA is submitted pursuant to
an approved suitability petition (petitioned ANDA) or (2) if changes
are proposed in an amendment or a supplement to the ANDA such that the
proposed product is pharmaceutically equivalent to a different listed
drug than the RLD identified in the original ANDA (modified ANDA).
Before enactment of the MMA, FDA required an applicant to amend its
ANDA in these scenarios to cite the pharmaceutically equivalent product
as its RLD. However, the MMA prohibits an ANDA applicant from amending
its ANDA to change the RLD (see section 505(j)(2)(D)(i) of the FD&C
Act). Accordingly, for the applicant to obtain approval of the proposed
product under section 505(j) of the FD&C Act in these scenarios, we
require the applicant to submit a new ANDA that identifies the
pharmaceutically equivalent product as its RLD and complies with
applicable statutory and regulatory requirements.
We require an ANDA applicant to identify as its RLD a
pharmaceutically equivalent product approved any time before approval,
rather than submission, of the ANDA, because a generic drug product
must demonstrate, among other things, that it is bioequivalent to the
[[Page 69619]]
RLD to obtain approval (see section 505(j)(2)(A)(iv) of the FD&C Act
and Sec. 314.127(a)(6)(i)). We disagree that an ANDA applicant should
only be required to identify a pharmaceutically equivalent product as
its RLD until submission of the ANDA, because this approach would not
ensure that an ANDA applicant cites an appropriate RLD in the context
of a petitioned ANDA or modified ANDA unless the RLD was approved
before submission of the ANDA. Such an approach would foster a
potentially confusing proliferation of pharmaceutically equivalent drug
products that have not demonstrated therapeutic equivalence to the RLD.
The additional data and time that may be needed for an ANDA applicant
to identify a pharmaceutically equivalent drug product as the RLD is
warranted by the need for a clear determination of therapeutic
equivalence. The modification requested in the comment would ``diminish
the utility and accuracy of FDA's therapeutic equivalence
determinations and potentially allow ANDA applicants to circumvent
otherwise applicable patent and exclusivity rights accorded the NDA
holder for the pharmaceutically equivalent RLD'' (see 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, at 11-12, available at http://www.regulations.gov)
(Venlafaxine ER CP Response).
Unlike an ANDA that relies on a single RLD, a 505(b)(2) application
may rely for approval on one or more listed drugs and is not required
to demonstrate bioequivalence or pharmaceutical equivalence to a listed
drug on which it relies for approval. Although the Agency requires a
505(b)(2) applicant to rely upon a drug product approved in an NDA that
is pharmaceutically equivalent to the proposed product, the basis and
timeframe for this requirement for 505(b)(2) applications differs from
that of ANDAs.
(Comment 44) One comment recommends that FDA permit an ANDA
applicant to amend its ANDA if FDA changes the RLD or the ANDA
applicant petitions to change the RLD.
(Response 44) The comment is unclear because the Agency's
designation of an additional RLD or selection of a new reference
standard generally would not require an ANDA applicant to change its
RLD. The RLD is the listed drug identified by FDA as the drug product
upon which an applicant relies in seeking approval of its ANDA (see
Sec. 314.3(b)). An ANDA applicant is prohibited from amending or
supplementing its ANDA to change the RLD after the ANDA has been
submitted (see Sec. Sec. 314.96(c) and 314.97(b) and section
505(j)(2)(D)(i) of the FD&C Act).
We note that if there are two or more approved NDAs for
pharmaceutically equivalent products, a person may submit a citizen
petition requesting that FDA designate an additional RLD, provided that
there is adequate justification (see ``Abbreviated New Drug Application
Regulations; Final Rule,'' 57 FR 17950 at 17958, April 28, 1992, and
section 1.4 of the preface to the Orange Book (36th Edition, 2016, at
ix) (recognizing that a listed drug that is not designated as the RLD
may be shielded from generic competition)). An ANDA would not be
ineligible for approval because it relied on one of two or more RLDs
that were approved under section 505(c) of the FD&C Act based on full
reports of investigations of safety and effectiveness, provided that
other statutory and regulatory requirements are met. Thus, an applicant
is not required to change its RLD upon FDA designation of the
additional RLD.
Generally, the RLD also will be the reference standard, which is
the drug product selected by FDA that an ANDA applicant must use in
conducting an in vivo bioequivalence study required for ANDA approval
(see Sec. Sec. 314.3(b) and 314.94(a)(3)). FDA usually selects as the
reference standard the highest strength available for drug products
with multiple approved strengths. However, a person may petition the
Agency to request that FDA designate a new reference standard for
conducting bioequivalence testing if, for example, the person believes
that another drug product would be a scientifically appropriate
reference standard, or if the drug product selected as the reference
standard has been discontinued and FDA has not selected a new reference
standard. FDA also may select a reference standard in the absence of a
citizen petition (see Letter from Janet Woodcock, M.D., Director, CDER,
to Paul A. Braier, Ph.D., J.D., dated September 5, 2014, regarding
Docket No. FDA-2014-P-0417, at 11, available at http://www.regulations.gov). For example, if the RLD has been withdrawn from
marketing for reasons other than safety or effectiveness, FDA may
select a different drug product (e.g., a different strength of a drug
product that is the RLD) or a therapeutically equivalent drug product
(e.g., an approved ANDA that cited the RLD as its basis of submission)
as the reference standard. Even if FDA selects a reference standard
that is a drug product other than the RLD for use in conducting an in
vivo bioequivalence study, the proposed drug product will be evaluated
against the RLD to determine whether it meets the statutory
requirements for approval under section 505(j) of the FD&C Act. An
applicant also may request, with appropriate scientific justification,
that FDA waive the requirement to use the drug selected by FDA as the
reference standard in an in vivo bioequivalence study required for
approval (see Sec. 314.99(b)).
FDA's selection of a different reference standard or waiver of the
requirement to use the reference standard generally would not result in
a change to the RLD. An ANDA would not be ineligible for approval
because it relied upon an RLD that was not selected as a reference
standard.
We acknowledge that FDA's practice of identifying the reference
standard in the Orange Book by the word ``yes'' in the ``RLD'' column
has resulted in confusion, and we are revising the column heading in
the Orange Book from ``RLD'' to ``RS'' for clarity.
V.G.2. Amendments and Supplements to a 505(b)(2) Application
(Sec. Sec. 314.60(e) and 314.70(h))
We proposed to establish a regulation that would implement section
505(b)(4)(A) of the FD&C Act by providing that an applicant may not
amend or 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 (see proposed Sec. Sec. 314.60(e) and
314.70(h)). We proposed 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, different dosage form, or different excipients that
require either a separate clinical study to establish safety or
effectiveness or, for topical products, that require a separate in vivo
demonstration of bioequivalence (see proposed Sec. Sec. 314.60(e) and
314.70(h)). These proposed modifications would result in a different
drug for which approval must be requested in a new 505(b)(2)
application.
In the proposed rule, we explained 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 before the Agency's decision regarding whether
the 505(b)(2) application can be filed in accordance with Sec.
314.101(a). However, notwithstanding these
[[Page 69620]]
restrictions on amendments to a 505(b)(2) application, we proposed that
an applicant is permitted to amend or supplement a 505(b)(2)
application to identify a new or additional listed drug upon which the
application relies for approval as long as the applicant is not seeking
approval for a different drug from the drug in the original submission
of the 505(b)(2) application. In addition, we proposed that an
applicant is permitted to amend or 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 and proposed Sec. Sec. 314.60(e)
and 314.70(h)).
We received no comments on proposed Sec. 314.70(h) regarding
supplements. In the following paragraphs, we discuss a comment on
proposed Sec. 314.60(e) regarding amendments. After considering this
comment, we are finalizing proposed Sec. Sec. 314.60(e) and 314.70(h)
without change.
(Comment 45) One comment recommends that FDA return to its initial
interpretation of section 505(b)(4)(A) of the FD&C Act and revise Sec.
314.60(e) to prohibit a 505(b)(2) applicant from amending its
application to rely upon a new or different listed drug for approval.
The comment observes that if a new or different listed drug is
identified in an amendment to the 505(b)(2) application, and the
505(b)(2) applicant submits a paragraph IV certification for a patent
that is timely filed after submission of the 505(b)(2) application, a
30-month stay would not be available should the NDA holder or patent
owner initiate patent infringement litigation within the statutory
timeframe.
(Response 45) We decline to revise Sec. 314.60(e) as requested
because the comment does not provide any basis for a different
interpretation of section 505(b)(4)(A) of the FD&C Act that FDA did not
expressly consider in the proposed rule. The preamble to the proposed
rule contains an extensive discussion of the Agency's initial
interpretation of section 505(b)(4)(A) of the FD&C Act and explains why
FDA proposed narrowing that interpretation of section 505(b)(4)(A) of
the FD&C Act as reflected in Sec. Sec. 314.60(e) and 314.70(h) (see 80
FR 6802 at 6850 through 6852). The comment has not persuaded us to
return to that initial interpretation.
V.H. 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 (Sec. 314.54)
We proposed to require that the listed drug(s) 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 (see proposed Sec. Sec.
314.50(i)(1)(i)(C), 314.54(a)(1), and 314.125(b)(19)).
In the following paragraphs, we discuss a comment on these proposed
provisions. After considering this comment, we are finalizing proposed
Sec. 314.54(a)(1) with revisions to clarify that a 505(b)(2) applicant
must identify a pharmaceutically equivalent drug product approved in an
NDA as a listed drug (or an additional listed drug) relied upon if the
pharmaceutically equivalent drug product was approved before the date
of submission of the original 505(b)(2) application, and to codify the
basis for this requirement. If there is more than one drug product that
is pharmaceutically equivalent to the drug product for which the
original 505(b)(2) application is submitted and was approved in one or
more NDAs before the original 505(b)(2) application was submitted, the
505(b)(2) applicant is only required to identify one such
pharmaceutically equivalent drug product as a listed drug relied upon.
We are finalizing proposed Sec. Sec. 314.50(i)(1)(i)(C) and
314.125(b)(19) with conforming revisions.
(Comment 46) One comment suggests that FDA require a 505(b)(2)
applicant to identify any approved pharmaceutically equivalent drug
product as a listed drug relied upon to support approval of the
proposed product irrespective of whether the pharmaceutically
equivalent product was approved before or during the review of the
505(b)(2) application. The comment proposes that if a pharmaceutically
equivalent product is approved after a 505(b)(2) application is
submitted, the 505(b)(2) applicant--like an ANDA applicant--should be
required to file a new 505(b)(2) application to ensure that the NDA
holder for the pharmaceutically equivalent drug product has a
reasonable opportunity for a 30-month stay and that any non-patent
exclusivity is meaningful.
(Response 46) We decline to modify the regulations as suggested. If
a pharmaceutically equivalent drug product is approved before an
original 505(b)(2) application is submitted, we consider the 505(b)(2)
applicant to implicitly rely upon FDA's finding of safety and
effectiveness for one such pharmaceutically equivalent drug product for
approval even if the proposed drug product was developed independently
of that pharmaceutically equivalent drug product. Accordingly, we
require the 505(b)(2) applicant to identify one pharmaceutically
equivalent drug product approved in an NDA as a listed drug (or an
additional listed drug) relied upon and comply with applicable
regulatory requirements. A 505(b)(2) applicant that identifies a listed
drug solely to comply with Sec. 314.54(a)(1)(vi) must provide an
appropriate patent certification or statement for any patents that are
listed in the Orange Book for the pharmaceutically equivalent drug
product, but the 505(b)(2) applicant is not required to submit bridging
data to justify the scientific appropriateness of reliance on the
pharmaceutically equivalent drug product if it is scientifically
unnecessary to support approval. Given that there cannot be any
implicit reliance on FDA's finding of safety and effectiveness for a
drug product that has not yet been approved, this rationale would not
support a requirement for a 505(b)(2) applicant to identify a
pharmaceutically equivalent drug product approved in an NDA after the
505(b)(2) application is submitted. We are revising Sec.
314.54(a)(1)(vi) to clarify the basis for this requirement, which
establishes a bright line requirement for administering the patent
certification requirements of the FD&C Act and is unrelated to our
approach to implementing section 505(b)(4)(A) of the FD&C Act. We are
further revising the regulations to clarify that the requirement to
identify one pharmaceutically equivalent drug product approved in an
NDA as a listed drug (or an additional listed drug) relied upon applies
before the date of submission of an original 505(b)(2) application and
not a resubmission or a supplement (see, e.g., Sec. 314.54(a)(1); see
also Sec. 314.3(b) (definitions of ``original NDA'' and
``resubmission'')). We also are making conforming revisions to Sec.
314.54(a)(1)(iii) and (vi) to clarify that a 505(b)(2) application may
rely on FDA's finding of safety and/or effectiveness for one or more
listed drugs.
We recognize that a 505(b)(2) applicant that does not amend its
pending 505(b)(2) application to rely upon a pharmaceutically
equivalent listed drug would have no occasion to submit a patent
certification or
[[Page 69621]]
statement with respect to any patents listed for the listed drug (and
could be subject to patent infringement litigation after approval).
This illustrates one of many circumstances in which the timing of
submission of an application has certain statutory or regulatory
implications (see, e.g., untimely filing of patent information).
However, to the extent that the 505(b)(2) application is seeking
approval for the exclusivity-protected conditions of approval for the
listed drug, approval of the 505(b)(2) application would be delayed by
any applicable 3-year exclusivity for the listed drug irrespective of
reliance (see Veloxis Pharms. v. FDA, 109 F. Supp. 3d 104, 120 (D.D.C.
2015)).
(Comment 47) One comment suggests that FDA require a 505(b)(2)
applicant to identify any approved drug product that is a
pharmaceutical alternative to the proposed product as a listed drug(s)
relied upon to support approval of the proposed product.
(Response 47) We decline to modify the regulations as suggested.
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 (see Sec.
314.3(b)). Accordingly, there may be numerous pharmaceutical
alternatives to a particular drug product. Given that a proposed drug
product intended for submission in a 505(b)(2) application may differ
in various respects from the listed drug(s) on which it relies for
approval, there is insufficient justification to require a 505(b)(2)
applicant to identify any pharmaceutical alternative (in addition to
one pharmaceutical equivalent) as a listed drug upon which the
505(b)(2) application relies in the absence of explicit reliance (see
Letter from Janet Woodcock, M.D., Director, CDER, to David B. Clissold,
J.D., dated September 18, 2013, regarding Docket Nos. FDA-2011-P-0869
and FDA-2013-P-0995, at 8, available at http://www.regulations.gov)
(``except where a pharmaceutical equivalent already has been approved,
the 505(b)(2) applicant should determine which listed drug(s) is most
appropriate for its development program'').
We consider the 505(b)(2) applicant to implicitly rely for approval
upon FDA's finding of safety and effectiveness for one such
pharmaceutically equivalent listed drug approved in an NDA because the
proposed product shares key characteristics (active ingredient, dosage
form, route of administration, and strength) in common with the listed
drug despite being ineligible for approval under section 505(j) of the
FD&C Act (see Sec. 314.101(d)(9)). As we explained in the proposed
rule, the requirement to identify a pharmaceutically equivalent product
approved in an NDA as a listed drug upon which the 505(b)(2)
application relies ``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'' (80 FR 6802 at 6856).
(Comment 48) One comment recommends that FDA clarify that the
requirement for a 505(b)(2) applicant to identify an approved
pharmaceutically equivalent product as a listed drug relied upon does
not extend to a complex drug product for which there may be uncertainty
about whether the drug contains the ``identical'' or ``same'' active
drug ingredient.
(Response 48) We acknowledge that a 505(b)(2) applicant may be
uncertain whether to identify a listed drug solely to comply with
Sec. Sec. 314.50(i)(1)(i)(C), 314.54(a)(1), and 314.125(b)(19) due to
the applicant's uncertainty about whether the drug contains the
``identical'' active drug ingredient or meets other criteria for a
pharmaceutical equivalent. FDA intends to consider on a case-by-case
basis any assertions by a prospective 505(b)(2) applicant that there is
uncertainty about whether a previously approved drug product contains
the ``identical'' active drug ingredient as the proposed product.
V.I. Petition To Request a Change From a Listed Drug (Sec. 314.93)
We proposed 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, irrespective of
whether FDA has withdrawn approval of the suitability petition (see
proposed Sec. 314.93(f)). We proposed that an 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 and proposed Sec. 314.96(c)), and
would be required to submit a new ANDA that relies on the
pharmaceutically equivalent RLD if the applicant seeks approval for the
drug product. Accordingly, we proposed 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. We also proposed 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
requested in the petition.
One comment agreed with these proposed revisions to our regulations
on suitability petitions. In the following paragraph, we discuss two
other comments on the proposal. After considering these comments, we
are finalizing proposed Sec. 314.93(e) and (f) with the technical
amendment described in section V.P.1. We are also finalizing proposed
Sec. 314.127(a)(14) with technical amendments to describe an approved
``suitability petition'' as an approved petition under 21 CFR 10.30 and
Sec. 314.93, and we are making conforming revisions to Sec.
314.94(a)(3)(i) and (iii).
(Comment 49) Two comments recommend that FDA revise the proposed
regulation to require that if, at any time before submission (rather
than any time before approval) of an ANDA based on a suitability
petition, an NDA is approved for the change described in the
suitability petition, the ANDA applicant would be required to submit an
ANDA that identifies the drug product approved in the NDA as the RLD.
One comment suggests that this proposed revision would harmonize FDA's
proposed requirements for ANDAs and 505(b)(2) applications with respect
to the timeframe in which an applicant must rely upon a
pharmaceutically equivalent product. The other comment observes that
there still may be multiple versions of a drug product because one or
more ANDAs may have been approved pursuant to the suitability petition
before an NDA is approved for the change described in the petition.
(Response 49) We decline to adopt the suggested modification to
Sec. Sec. 314.93 and 314.127(a)(14). FDA's longstanding practice, as
described in the letter granting a suitability petition, is that once a
drug product is approved in an NDA for the change described in the
petition, that drug product will be the RLD and thereafter the approved
suitability petition may not be used as the basis for submission of an
ANDA. Accordingly, if an NDA is approved for the change described in
the suitability petition before submission of an ANDA pursuant to an
approved suitability petition, FDA would refuse to receive the ANDA. If
an NDA is approved for the change described in the suitability petition
after submission or receipt of an ANDA and is designated as the RLD,
the applicant would be required to submit a new ANDA that cites the RLD
as its basis for submission, and complies with
[[Page 69622]]
applicable statutory and regulatory requirements for approval. As we
explained in the proposed rule, our requirement that an applicant with
a pending ANDA subject to an approved suitability petition change the
RLD upon FDA approval of an NDA for the same drug product described in
the approved suitability petition ``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'' (80
FR 6802 at 6853, quoting Venlafaxine ER CP Response at 9).
V.J. Filing an NDA and Receiving an ANDA (Sec. 314.101)
V.J.1. Notification of Filing of a 505(b)(2) Application or Receipt of
an ANDA
We proposed to clarify that FDA will notify the applicant that the
505(b)(2) application is regarded as filed or the ANDA is regarded as
received by means of a paragraph IV acknowledgment letter if the
505(b)(2) application or ANDA contains a paragraph IV certification
(see proposed Sec. 314.101(a)(2) and (b)(2); see also sections V.A.1
and V.D.1.a). We received no comments regarding these proposed
revisions, and we are finalizing proposed Sec. 314.101(a)(2) without
change, and Sec. 314.101(b)(2) with the clarifying revisions discussed
in section V.J.2.
V.J.2. Refuse-to-Receive Decisions for ANDAs
We proposed to revise Sec. 314.101(b)(1) and (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 V.A.5). We proposed that receipt of an ANDA means
that FDA has made a threshold determination that the ANDA is
substantially complete (see proposed Sec. 314.101(b)(1)). We proposed
to revise 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. We also proposed to amend Sec. 314.101(b)(3) to update the
regulations to reflect our current practice for advising an ANDA
applicant that FDA has refused to receive the ANDA under Sec.
314.101(d) or (e).
In the following paragraphs, we discuss three comments on these
proposed revisions. After considering these comments, we are making
clarifying revisions to proposed Sec. 314.101(b)(2). We are finalizing
proposed Sec. 314.101(b)(3) and (d)(3) with revisions to more
precisely describe the factors that FDA considers in determining
whether an ANDA is incomplete on its face, and the actions that an ANDA
applicant may take following a refuse-to-receive decision.
(Comment 50) Two comments recommend that FDA clarify its
regulations regarding refuse-to-receive standards in light of the
policy described in its guidance for industry entitled ``ANDA
Submissions--Refuse-to-Receive Standards'' (May 2015), available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. One of these comments maintains that the current
regulation permits applicants to amend an ANDA to address deficiencies
irrespective of the number of deficiencies or whether the deficiencies
are major or minor. This comment asserts that FDA would need to reissue
the proposed rule to incorporate the standards described in the
guidance. Another comment suggests that FDA limit the time for a
completeness evaluation to 90 days, and permit applicants to amend an
ANDA to address minor deficiencies that can be corrected within 30
days.
(Response 50) FDA agrees with the recommendations to clarify its
regulations regarding refuse-to-receive standards for ANDAs. To address
these comments, FDA is revising Sec. 314.101(d)(3) to codify its
current practice of considering the nature (e.g., major or minor) of
the deficiencies, including the number of deficiencies in the ANDA, in
determining whether an ANDA is incomplete on its face. This approach
reflects the goal of FDA's filing regulations, which encourage
applicants to submit complete ANDAs and conserve FDA resources by
permitting FDA reviewers to devote their time to examining reviewable
applications (57 FR 17950 at 17965).
To clarify the actions that an ANDA applicant may take following a
refuse-to-receive decision, FDA is revising Sec. 314.101(b)(3)(ii) to
state that if the ANDA is not received, the applicant may correct the
deficiencies and resubmit the ANDA. This amendment reflects the
statutory procedures for ANDAs that FDA considers not to have been
received (see section 744B(a)(3)(E) of the FD&C Act (21 U.S.C. 379j-
42(a)(3)(E) (describing the user fee requirements for resubmission of
an ANDA that FDA considers not to have been received or that has been
withdrawn)). FDA also is revising Sec. 314.101(b)(3)(iii) to clarify
that if the ANDA is not received, the applicant may take no action, in
which case FDA may consider the ANDA withdrawn after 1 year. An ANDA
applicant's failure to take action after a refuse-to-receive decision
on an ANDA may be considered a request by the applicant to withdraw the
ANDA, unless the applicant requests an extension of time in which to
resubmit the ANDA. This revision eliminates the circularity of the
former text, which provided that if the ANDA is refused for receipt and
the applicant takes no action, FDA will refuse to receive the ANDA.
Finally, FDA is revising Sec. 314.101(b)(2) to clarify that if FDA
determines, upon evaluation, that an ANDA was substantially complete as
of the date it was submitted to FDA, FDA will consider the ANDA to have
been received as of the date of submission. We are making a conforming
revision to Sec. 314.101(b)(1) to change ``reviewed'' to ``evaluated''
to clarify that FDA's evaluation does not involve a substantive review
of the data in the ANDA. We disagree with the comment's suggestion that
reissuance of the proposed rule is necessary for these clarifying
revisions to Sec. 314.101 because the revisions are not changing the
standard for refuse-to-receive decisions, but are merely clarifying how
FDA has been implementing the standard.
(Comment 51) One comment recommends that FDA provide a mechanism
for ANDA applicants to challenge a refuse-to-receive decision analogous
to the procedures described in Sec. 314.101(a)(3) for NDA applicants.
(Response 51) FDA declines to adopt the suggestion because a
revision to the regulations is not necessary to provide a mechanism for
ANDA applicants to dispute a refuse-to-receive decision. ANDA
applicants can avail themselves of existing mechanisms to discuss or
dispute a refuse-to-receive action, including the dispute resolution
procedure in Sec. 314.103.
V.J.3. Administrative Consequence for Late Notice
We proposed to establish an administrative consequence for an ANDA
applicant that fails to timely provide notice of a paragraph IV
certification (see section 505(j)(2)(B)(ii) of the FD&C Act). We
proposed that 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
[[Page 69623]]
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 (see proposed Sec. 314.101(b)(4)). This proposal created
the potential for an ANDA applicant to lose its first-applicant status
and thus its eligibility for 180-day exclusivity as a result of
providing late notice, if another applicant were to submit a
substantially complete ANDA containing a paragraph IV certification on
the same first day and were to provide timely notice (see section
505(j)(5)(B)(iv) of the FD&C Act). We noted that this proposed
administrative consequence 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.
Two comments support FDA's proposed administrative consequence for
failure to send notice of paragraph IV certification within the
required timeframe. In the following paragraphs, we discuss two other
comments on this proposal. After considering these comments, we are not
finalizing proposed Sec. 314.101(b)(4).
(Comment 52) One comment asserts that the statutory consequence for
an ANDA applicant's delay in sending notice of paragraph IV
certification is a commensurate delay in the start of any resultant 30-
month stay of approval. The comment contends that the Agency has no
legal authority to impose an additional sanction, and that the proposal
should be withdrawn. Another comment recommends that the administrative
consequence for a first applicant be modified to reduce the 180-day
exclusivity period by the number of days that notice was late and avoid
the potential loss of eligibility for 180-day exclusivity.
(Response 52) Although we believe that the Agency has the authority
to establish an administrative consequence for an ANDA applicant's
failure to comply with the statutory timeframe for sending notice of
paragraph IV certification, we currently do not consider the
administrative consequence to be necessary in light of other incentives
for ANDA applicants to timely provide notice of a paragraph IV
certification. Based on the Agency's implementation of the Generic Drug
User Fee Amendments of 2012 (GDUFA) in Title III of FDASIA and the
GDUFA goals for expeditious review of ANDAs, FDA is approving ANDAs
more quickly and ANDA applicants are unlikely to delay sending notice
of paragraph IV certification because such a delay might result in a
delay in ANDA approval. A 505(b)(2) or ANDA 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) or
ANDA applicant's delay in sending notice. We believe this potential
delay in approval will incentivize 505(b)(2) and ANDA applicants to
comply with the statutory timeframe for sending notice, and provide
adequate opportunity for an NDA holder or patent owner to assert
certain intellectual property rights prior to approval. Accordingly, we
are declining to finalize the proposed administrative consequence as
unnecessary at this time.
V.J.4. Other Proposed Revisions
We proposed several clarifying revisions to Sec. 314.101. First,
we proposed to delete the reference to section 507 of the FD&C Act in
Sec. 314.101(d)(3) to reflect statutory changes made by the Food and
Drug Administration Modernization Act of 1997 (Pub. L. 105-115).
Second, we proposed to replace the term ``application'' in Sec.
314.101(d)(6) and (7) with ``NDA or ANDA'' to clarify that these
provisions apply to ANDAs as well as NDAs. Third, we proposed to
replace the current text of Sec. 314.101(e)(2) with a 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 is not permitted under Sec. 314.108(b)(2).
We received no comments regarding these proposed revisions, and we
are finalizing these revisions to Sec. 314.101(d)(3), (6), and (7)
without change. We are making conforming revisions to Sec.
314.101(d)(5) and the paragraph heading for Sec. 314.101(d). As
discussed in section V.A.7, we are revising Sec. 314.101(e)(2) to
remove the cross-reference to Sec. 314.108(b)(2) because that section
does not address all of the potential exclusivities that would preclude
a 505(b)(2) application or ANDA from being filed or received. We are
also revising Sec. 314.101(e)(2) to expressly state that FDA will
refuse to file an NDA or will consider an ANDA not to have been
received if submission of a 505(b)(2) application or an ANDA is not
permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii),
505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the FD&C Act.
V.K. Approval of an NDA and ANDA (Sec. 314.105)
We proposed to revise Sec. 314.105(a) and (d) regarding approval
of an NDA 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. We explained in the proposed rule that
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 because of unexpired patents, certain circumstances related to
patent litigation, or various types of exclusivity.
In addition, we proposed 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.
We received no comments regarding these proposed revisions. We are
finalizing Sec. 314.105 without change, except for the technical
amendments described in section V.A.3 and V.A.7 to reflect the
enactment of GAIN and IRTNMTA, respectively.
V.L. Refusal To Approve an NDA or ANDA (Sec. Sec. 314.125 and 314.127
and Related Provisions in Sec. Sec. 314.90 and 314.99)
We proposed to revise Sec. Sec. 314.90 and 314.99 to clarify that
if FDA grants 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, 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. We also proposed 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. We
received no comments regarding these proposed revisions, and we are
finalizing these provisions without change.
[[Page 69624]]
V.M. Date of Approval of a 505(b)(2) Application or ANDA (Sec.
314.107)
V.M.1. General (Sec. 314.107(a))
We proposed to revise the general regulation that describes the
``effective date of approval'' of a 505(b)(2) application or ANDA and
the date on which 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'' (see proposed Sec. 314.107(a)). In
the proposed rule, we explained that FDA does not issue approval
letters with delayed effective dates. We received no comments on these
revisions, and we are finalizing proposed Sec. 314.107(a) without
change.
V.M.2. Effect of Patent(s) on the Listed Drug (Sec. 314.107(b))
We proposed to revise the regulation that describes the effect of
one or more patents on the listed drug(s) relied upon or the RLD on the
timing of approval of a 505(b)(2) application or ANDA, respectively
(see proposed Sec. 314.107(b)). We proposed to clarify that an
analysis is required for each relevant patent to determine the first
possible date on which the 505(b)(2) application or ANDA can be
approved based on the patent certification(s) and/or statement(s)
submitted by the applicant (see proposed Sec. 314.107(b)). We proposed
that the 505(b)(2) application or ANDA may be eligible for approval on
the last applicable date for all relevant patents listed in the Orange
Book (see proposed Sec. 314.107(b) and proposed deletion of Sec.
314.107(b)(4)). In the proposed rule, we explained that an analysis of
the effect of one or more 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. We received no comments on
these revisions, and we are finalizing the introductory text of
proposed Sec. 314.107(b) with the IRTNTMA-related revisions described
in section V.A.3.
V.M.2.a. Timing of approval based on patent certification or
statement (Sec. 314.107(b)(1)). We proposed to describe the timing of
approval of a 505(b)(2) application or ANDA based on the patent
certification(s) and/or statement(s) submitted by the applicant for
each relevant patent (see proposed Sec. 314.107(b)(1)). We proposed to
reorganize the regulation and describe the types of patent
certifications or statements that would result in an immediate first
possible date on which a 505(b)(2) application or ANDA may be approved
(see proposed Sec. 314.107(b)(1)(i) and (ii)) or in a delay in the
first possible approval date until the date on which a patent will
expire (see proposed Sec. 314.107(b)(1)(iii)).
We proposed to clarify that, except as provided in Sec.
314.107(b)(3) and (c), a 505(b)(2) application or ANDA containing a
paragraph IV certification may be eligible for immediate approval 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 (see proposed Sec.
314.107(b)(1)(i)(C)). We also proposed to clarify that if a 505(b)(2)
or ANDA applicant submits 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 and submits proposed labeling that
appropriately carves out information related to the patented method of
use, then the 505(b)(2) application or ANDA may be eligible for
immediate approval (see proposed Sec. 314.107(b)(1)(ii)). In the
proposed rule, we explained that a listed patent may claim the drug
substance and/or drug product in addition to one or more methods of
use, and if the 505(b)(2) or ANDA applicant submitted a statement with
respect to one or more methods of use and a paragraph IV certification
with respect to the remaining claims, the first possible date on which
the 505(b)(2) application or ANDA can be approved would be analyzed in
accordance with proposed Sec. 314.107(b)(1)(i)(C) and (b)(1)(ii).
We received no comments on proposed Sec. 314.107(b)(1). However,
we are revising Sec. 314.107(b)(1)(ii) to expressly state that if a
505(b)(2) or ANDA applicant submits a paragraph IV certification for
certain patent claims in addition to a statement under Sec.
314.50(i)(1)(iii) or Sec. 314.94(a)(12)(iii) for other patent claims,
a determination of the first possible date on which the 505(b)(2)
application or ANDA can be approved also would require an analysis
under Sec. 314.107(b)(1)(i)(C). We also are making a minor editorial
revision to proposed Sec. 314.107(b)(1) to clarify that the provision
applies to a 505(b)(2) application or an ANDA.
V.M.2.b. Patent information filed after submission of 505(b)(2)
application or ANDA (Sec. 314.107(b)(2)). We proposed to clarify the
effect of patent information filed after submission of a 505(b)(2)
application or ANDA on the timing of approval of the 505(b)(2)
application or ANDA (see proposed Sec. 314.107(b)(2)). We proposed
that 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. We also proposed that if the 505(b)(2) or
ANDA applicant submits an amendment containing a paragraph IV
certification to a newly listed patent, 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 the paragraph IV certification, if the 505(b)(2)
application or ANDA is otherwise eligible for approval (see proposed
Sec. 314.107(b)(2)). We proposed that there is no need to delay
approval until the expiration of the 45-day period described in section
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act because a 30-month stay
of approval is not available in these circumstances.
We received no comments on these revisions. However, we are
revising Sec. 314.107(b)(2) to clarify that a 505(b)(2) or ANDA
applicant must comply with the regulatory requirements regarding
``submission of an appropriate patent certification or statement'' to a
newly listed patent rather than an ``amendment of its patent
certification or statement'' because the latter phrase may incorrectly
suggest a change to an existing patent certification or statement,
which would not exist in the case of a newly listed patent. We are
making conforming revisions to Sec. Sec. 314.50(i)(4) and
314.94(a)(12)(vi).
V.M.2.c. Disposition of patent litigation: Approval upon expiration
of 30-month stay or 7\1/2\ years from date of listed drug approval
(Sec. 314.107(b)(3)(i)). We proposed that a 30-month stay (or a delay
in approval for a 7\1/2\-year period where applicable) would be
available only when the patent owner or exclusive patent licensee
initiates a patent infringement action within the statutory timeframe
in response to notice of a paragraph IV certification to a patent
submitted to FDA before the date on which the 505(b)(2) application or
ANDA was submitted (see proposed Sec. 314.107(b)(3)(i)(A) and section
505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act). We proposed to
clarify that a 30-month stay (or 7\1/2\ years where applicable) begins
on the later of the date of receipt of the notice of paragraph IV
certification by any owner of the listed patent, the NDA holder who is
an exclusive patent licensee, or its representative(s) (see proposed
Sec. 314.107(b)(3)(i)(A)). In the proposed rule, we noted that a
period of pediatric
[[Page 69625]]
exclusivity under section 505A of the FD&C Act also may affect the
timing of approval of a 505(b)(2) application or ANDA in the
circumstances described in proposed Sec. 314.107(b)(3) (see 80 FR 6802
at 6863).
In the following paragraphs, we discuss a comment on proposed Sec.
314.107(b)(3)(i). After considering this comment, we are finalizing
proposed Sec. 314.107(b)(3)(i) with the IRTNMTA-related revisions
described in section V.A.3 and a revision to conform with Sec.
314.107(f)(1) and clarify that a 30-month stay begins on the later of
the date of receipt of the notice of paragraph IV certification by any
owner of the listed patent, the NDA holder, or its representative(s).
We also are making a technical amendment to the paragraph heading
described in section V.P.3.
(Comment 53) One comment recommended that FDA revise Sec.
314.107(b)(3)(i) to accept any reason a court provides for reducing the
30-month stay, and not solely an extension or reduction of the 30-month
stay because of a failure of the applicant or patent owner to cooperate
reasonably in expediting the action.
(Response 53) We agree that if, before the expiration of the stay,
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 (see Sec. 314.107(b)(3)(vii) and
section V.M.2.i). However, we are not revising the regulation because
Sec. 314.107(b)(3)(vii) adequately addresses the concern described in
the comment by providing for termination of the 30-month stay if the
court enters an order requiring the 30-month stay to be terminated. Our
regulation governing this scenario is consistent with the statutory
purpose of the stay, which allows time for claims of patent
infringement to be litigated prior to approval of the potentially
infringing drug product.
V.M.2.d. Federal district court decision of invalidity,
unenforceability, or non-infringement (Sec. 314.107(b)(3)(ii)). The
MMA amended section 505(c)(3)(C) and (j)(5)(B)(iii) of the FD&C Act to
describe certain types of 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. We proposed to revise our regulations to
implement section 505(c)(3)(C)(i) and (j)(5)(B)(iii)(I) of the FD&C Act
by providing that if, before the expiration of the 30-month stay (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 the date on which the court enters judgment reflecting the
decision pursuant to Federal Rule of Civil Procedure (Fed. R. Civ. P.)
Rule 58, 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 (see proposed Sec.
314.107(b)(3)(ii)). We also proposed that a Federal district court
decision that the applicable patent is unenforceable (for example,
because of inequitable conduct in patent prosecution) would terminate a
30-month stay or 7\1/2\ years where applicable (see proposed Sec.
314.107(b)(3)(ii)).
We received no comments on these proposed revisions. We are
finalizing proposed Sec. 314.107(b)(3)(ii) with a technical amendment
to add the term ``unenforceable'' to Sec. 314.107(b)(3)(ii)(B) for
consistency and completeness.
V.M.2.e. Appeal of Federal district court judgment of infringement
(Sec. 314.107(b)(3)(iii)). We proposed to revise our regulations to
implement section 505(c)(3)(C)(ii)(I) and (j)(5)(B)(iii)(II)(aa) of the
FD&C Act by providing that if, before the expiration of the 30-month
stay (or 7\1/2\ years where applicable), the Federal district court
decides that the patent has been infringed and the judgment is
appealed, the 505(b)(2) application or ANDA may be approved on: (1) 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 (2) 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.
We received no comments on these proposed revisions. We are
finalizing proposed Sec. 314.107(b)(3)(iii) with technical amendments
to add the term ``unenforceable'' to Sec. 314.107(b)(3)(iii)(A) and
(B) for consistency and completeness. We are also deleting the
parenthetical reference to a substantive determination by a Federal
district court that there is no cause of action for patent invalidity
for the reason discussed in section V.M.2.d.
V.M.2.f. Affirmation or non-appeal of Federal district court
judgment of infringement (Sec. 314.107(b)(3)(iv)). We proposed to
establish a regulation that would implement section
505(c)(3)(C)(ii)(II) and (j)(5)(B)(iii)(II)(bb) of the FD&C Act by
providing that if, before the expiration of the 30-month stay (or 7\1/
2\ years where applicable), the Federal district court decides that the
patent that is the subject of the paragraph IV certification 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) (see proposed Sec. 314.107(b)(3)(iv)). We proposed to
clarify that the 505(b)(2) application or ANDA may be approved no
earlier than the date specified by the district court in a 35 U.S.C.
271(e)(4)(A) order because 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 expiration date of the infringed patent (see
proposed Sec. 314.107(b)(3)(iv)). In the following paragraphs, we
discuss a comment related to this provision. After considering this
comment, we are finalizing proposed Sec. 314.107(b)(3)(iv) without
change.
(Comment 54) One comment recommends that FDA revise Sec.
314.107(b)(3) to provide that FDA will not approve a pending 505(b)(2)
application or ANDA if a district court decides after the 30-month stay
or 7\1/2\-year period has expired that the patent that is the subject
of the paragraph IV certification is infringed. The comment expresses
concern that the regulatory focus on court decisions before the
expiration of the 30-month stay or 7\1/2\-year period may be
interpreted to mean that FDA can approve a 505(b)(2) application or
ANDA if a district court decides after the 30-month stay or 7\1/2\-year
period has expired that the proposed product would infringe a listed
patent.
(Response 54) We decline to revise Sec. 314.107(b)(3) as suggested
because other regulations address the concern described in the comment
(see, e.g., Sec. Sec. 314.50(i)(6)(i) and 314.94(a)(12)(viii)(A)
(requiring a 505(b)(2) or ANDA applicant to amend a previously
submitted paragraph IV certification after a finding of patent
infringement)). We are enhancing our regulations to impose a duty on
505(b)(2) and ANDA applicants to notify FDA of any court judgment,
settlement order, or consent decree regarding a patent described in
Sec. 314.107(b)(3) (see Sec. 314.107(e)(1)(i); see also Sec.
314.107(e)(1)(ii)). We are also requiring an applicant to submit a copy
[[Page 69626]]
of any court order under 35 U.S.C. 271(e)(4)(A) providing that the
505(b)(2) application or ANDA may be approved no earlier than the date
specified in the order, irrespective of whether the injunction relates
to a patent described in Sec. 314.107(b)(3), within 14 days of the
court's entry of the order (see Sec. 314.107(e)(1)(vi)). In addition,
the Agency routinely contacts an applicant after the 30-month stay (or
7\1/2\ years where applicable) has expired to confirm the status of any
pending litigation prior to an action on the 505(b)(2) application or
ANDA.
V.M.2.g. Grant of preliminary injunction by Federal district court
(Sec. 314.107(b)(3)(v)). We proposed to revise our regulations to
implement section 505(c)(3)(C)(iii) and (iv) and (j)(5)(B)(iii)(III)
and (IV) of the FD&C Act by providing that if a preliminary injunction
is entered before the expiration of the 30-month stay (or 7\1/2\ years
where applicable), the stay of approval would be extended until the
court decides the issues of patent infringement and validity. In the
proposed rule, we explained that 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 regarding patent validity and
infringement. We proposed that 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 Sec.
314.107(b)(3)(iii) or (iv), whichever is applicable (see proposed Sec.
314.107(b)(3)(v)). In addition, we proposed to clarify that the court
referred to in Sec. 314.107(b)(3)(v) is the Federal district court
hearing the patent infringement action.
In the following paragraphs, we discuss two comments on the timing
of approval of a 505(b)(2) application or ANDA after a preliminary
injunction has been entered. After considering these comments, we are
revising Sec. 314.107(b)(3)(v) to more clearly describe the timing of
approval of a 505(b)(2) application or ANDA when a preliminary
injunction is entered before the expiration of a 30-month stay (or 7\1/
2\ years where applicable) and to cross-reference the applicable
paragraphs of Sec. 314.107(b)(3). We are redesignating a portion of
proposed Sec. 314.107(b)(3)(v) as paragraph (b)(3)(v)(A) and adding
paragraph (b)(3)(v)(B) to implement section 505(c)(3)(C)(iv) and
(j)(5)(B)(iii)(IV) of the FD&C Act. With these revisions, the
regulation provides:
If a preliminary injunction is entered before the
expiration of a 30-month stay (or 7\1/2\ years where applicable) and
the Federal district 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 Sec. 314.107(b)(3)(ii) (see Sec.
314.107(b)(3)(v)(A) and section 505(c)(3)(C)(iii) and
(j)(5)(B)(iii)(III) of the FD&C Act).
If a preliminary injunction is entered before the
expiration of a 30-month stay (or 7\1/2\ years where applicable) and
the Federal district court later decides that the patent is infringed,
the 505(b)(2) application or ANDA may be approved as provided in Sec.
314.107(b)(3)(iii) or (iv), whichever is applicable (see Sec.
314.107(b)(3)(v)(B) and section 505(c)(3)(C)(iv) and (j)(5)(B)(iii)(IV)
of the FD&C Act).
(Comment 55) One comment asserts that if a preliminary injunction
is entered before the expiration of the 30-month stay, the stay should
not be extended until the court decides the issues of patent
infringement and validity because the preliminary injunction serves the
purpose of the stay. The comment recommends that FDA issue a final
approval of the 505(b)(2) application or ANDA (if otherwise eligible
for approval) after the 30-month stay expires so that the product can
be marketed without delay at such time as the injunction is lifted.
(Response 55) We disagree with the comment. If a preliminary
injunction is entered before the expiration of the 30-month stay (or
7\1/2\ years where applicable), FDA interprets section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act to require an extension of the stay
until the court decides the issues of patent infringement and validity
because all of the outcomes described in the statute presume that
approval will not occur until a later date.
(Comment 56) One comment requests that FDA revise the regulation to
clarify the timing of approval if the district court enters a
preliminary injunction after the 30-month stay expires. The comment
recommends that FDA not approve a pending 505(b)(2) application or ANDA
in this scenario unless the court later decides the patent is invalid,
unenforceable, or not infringed. The comment also asserts that FDA's
view that a preliminary injunction entered before the expiration of the
30-month stay would extend the stay until the court decides the issues
of patent infringement and validity suggests that the issuance of a
preliminary injunction after expiry of the 30-month or 7\1/2\-year
period, combined with a district court finding of infringement, stays
approval through at least the appeal.
(Response 56) We decline to adopt the recommendations in the
comment. It is unnecessary for FDA to establish a regulation that
addresses the timing of approval of a 505(b)(2) application or ANDA if
a district court enters a preliminary injunction after the 30-month
stay (or 7\1/2\-year period where applicable) has expired. If a party
to a patent infringement action involving a patent described in Sec.
314.107(b)(3) seeks to ensure that a 505(b)(2) application or ANDA is
not approved while the litigation is pending, the party may request a
preliminary injunction before the 30-month stay (or 7\1/2\-year period
where applicable) expires. If a court enters a preliminary injunction
after the 30-month stay (or 7\1/2\-year period where applicable) has
expired, parties should ensure that the court specifies the duration
and effect of the injunction.
(Comment 57) One comment suggests that if a court requests an
applicant to voluntarily agree not to begin marketing the drug product
or to provide pre-launch notice instead of issuing a preliminary
injunction, FDA should treat these agreements as equivalent to a
preliminary injunction and similarly extend the 30-month stay or 7\1/
2\-year period.
(Response 57) We decline to adopt this suggestion. The FD&C Act
provides that if the district court grants a preliminary injunction
before the expiration of the 30-month stay (or 7\1/2\ years where
applicable) to preserve the status quo until the court decides the
issues of patent infringement and validity, the stay must be extended
until the applicable date described in section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act. A voluntary agreement not to begin
marketing the drug product or to provide pre-launch notice does not
fall within this statutory exception to the termination of the stay at
the end of the 30-month period (or 7\1/2\ year-period where
applicable). Accordingly, we do not consider such agreements to be
equivalent to a preliminary injunction for purposes of extending the
stay. Moreover, it is unnecessary for the Agency to address these
circumstances through regulation because the parties to the litigation
can specify the desired terms of the agreement.
V.M.2.h. Written consent to approval by patent owner or exclusive
patent licensee (Sec. 314.107(b)(3)(vi)). We proposed to clarify that
if the patent owner or exclusive patent licensee (or their
representatives) agreed in writing that the 505(b)(2) application or
ANDA may be approved, the 30-month stay (or 7\1/2\ years where
applicable) would be terminated and the approval may be granted on or
after the date of the
[[Page 69627]]
consent (see proposed Sec. 314.107(b)(3)(vi)). In the proposed rule,
we noted that this scenario may arise, for example, if settlement of
the patent litigation results in a license to the 505(b)(2) or ANDA
applicant. One comment agrees with the addition of this provision
because it expressly permits the party that receives the benefit of the
statutory 30-month stay to waive that benefit. We agree with the
comment and we are finalizing proposed Sec. 314.107(b)(3)(vi) without
change.
V.M.2.i. Court order terminating 30-month or 7\1/2\-year period
(Sec. 314.107(b)(3)(vii)). We proposed 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 eligible for approval, may be approved in accordance with the
court order (see proposed Sec. 314.107(b)(3)(vii)). We received no
comments on this provision, and we are finalizing proposed Sec.
314.107(b)(3)(vii) without change.
V.M.2.j. Court order of dismissal without a finding of infringement
(Sec. 314.107(b)(3)(viii)). We proposed to codify FDA's policy that a
Federal district court's entry of an order of dismissal, with or
without prejudice, of patent infringement litigation that was timely
initiated in response to the 505(b)(2) or ANDA applicant's 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 (see proposed Sec. 314.107(b)(3)(viii)).
In the following paragraphs, we discuss two comments on proposed
Sec. 314.107(b)(3)(viii). After considering these comments, we are
revising Sec. 314.107(b)(3)(viii) to clarify that the 30-month period
(or 7\1/2\ years where applicable) will be terminated if the court(s)
enter(s) an order of dismissal without a finding of infringement in
each pending suit for patent infringement brought within 45 days of
receipt of the notice of paragraph IV certification sent by the
505(b)(2) or ANDA applicant.
(Comment 58) One comment opines that proposed Sec.
314.107(b)(3)(viii) should be withdrawn because the statute does not
specify that an order of dismissal without a finding of infringement
will terminate a 30-month stay (see section 505(c)(3)(C) and
(j)(5)(B)(iii) of the FD&C Act).
(Response 58) We decline to withdraw our proposal. The MMA's
amendments to 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
(see section 505(c)(3)(C)(i)(II), (c)(3)(C)(ii)(I)(bb),
(j)(5)(B)(iii)(I)(bb), and (j)(5)(B)(iii)(II)(aa)(BB) of the FD&C Act).
However, the MMA does not address whether a 30-month stay may be
terminated and a 505(b)(2) application or ANDA may be approved if the
court enters an order of dismissal without a finding of patent
infringement. Because this issue was not addressed by Congress, the
Agency is using its authority to establish rules for the efficient
enforcement of the FD&C Act to clarify the effect of a Federal district
court's entry of an order of dismissal without a finding of
infringement on a 30-month stay of approval. The Agency's approach is
consistent with the statutory scheme because it avoids unwarranted
delays in approval of a 505(b)(2) application or ANDA while protecting
innovator intellectual property rights. As we explained in the proposed
rule, it is appropriate that a 30-month stay be terminated 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.
(Comment 59) One comment recommends that FDA revise proposed Sec.
314.107(b)(3)(viii) to exclude dismissals that do not terminate all
timely filed litigation with respect to the patent(s) in suit. The
comment explains that parallel suits for patent infringement may be
filed in different Federal district courts within the 45-day period
described in section 505(j)(5)(B)(iii) of the FD&C Act, and one or more
suits may be dismissed because of lack of jurisdiction or other
reasons. The comment maintains that the 30-month stay should remain in
effect if one of multiple patent infringement actions filed in response
to notice of a paragraph IV certification is dismissed while at least
one of the timely filed lawsuits continues to be litigated.
(Response 59) We agree that the 30-month stay should remain in
effect if a patent infringement action that was timely filed in
response to a paragraph IV certification continues to be litigated
after the dismissal of a parallel action. We are revising Sec.
314.107(b)(3)(viii) to clarify that the 30-month period (or 7\1/2\
years where applicable) will be terminated if the court(s) enter(s) an
order of dismissal without a finding of infringement in each pending
suit for patent infringement brought within 45 days of receipt of the
notice of paragraph IV certification sent by the 505(b)(2) or ANDA
applicant.
(Comment 60) One comment recommends that FDA revise proposed Sec.
314.107(b)(3)(viii) to provide that if the court enters an order of
dismissal without a finding of patent infringement based on an
agreement not to make or sell the drug until a specified future date,
the stay should continue until the date provided in the agreement.
(Response 60) We decline to adopt this suggestion. If the court(s)
enter(s) an order of dismissal without a finding of infringement in
each pending suit for patent infringement brought within 45 days of
receipt of the notice of paragraph IV certification sent by the
505(b)(2) or ANDA applicant, FDA may approve the 505(b)(2) application
or ANDA on or after the date of the order. If a 505(b)(2) or ANDA
applicant has entered into an agreement not to make or sell the drug
until a specified future date and the 505(b)(2) application or ANDA
receives final approval, the applicant can choose not to make or sell
the product until the specified date.
V.M.3. Timing of Approval of Subsequent ANDA (Sec. 314.107(c))
We proposed to revise Sec. 314.107(c) to remove provisions that
have been superseded by the FD&C Act as revised by the MMA and to
generally conform with the FD&C Act. We proposed to revise Sec.
314.107(c)(1) to incorporate the statutory term ``first applicant'' and
to distinguish a ``first applicant'' from a ``subsequent applicant''
(see section 505(j)(5)(B)(iv)(II)(bb) of the FD&C Act and proposed
Sec. 314.3(b)). We proposed that 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 (see proposed Sec. 314.107(c)(1)). We
proposed that 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 any
first applicant (see proposed Sec. 314.107(c)(1) and section
505(j)(5)(B)(iv)(I) of the FD&C Act).
[[Page 69628]]
We proposed to delete the definition of the ``applicant submitting
the first application'' in existing Sec. 314.107(c)(2) because it was
superseded by the statutory definition of ``first applicant'' added by
the MMA. We also proposed 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 (see section 505(j)(5)(D) of the
FD&C Act).
We proposed to revise Sec. 314.107(c)(4) (redesignated as proposed
Sec. 314.107(c)(2)) to conform with the statutory change to the event
that triggers 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). Given that
the 180-day exclusivity period begins on the date of the first
commercial marketing of the drug product (including the commercial
marketing of the listed drug) by any first applicant, we proposed 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 proposed Sec. 314.107(c)(2) and section
505(j)(5)(B)(iv)(I) of the FD&C Act). If the first applicant does not
notify FDA within this timeframe, we proposed to deem the date of first
commercial marketing to be the date of the ANDA's approval. In the
proposed rule, we noted that this may have the effect of shortening the
180-day period of exclusivity in a manner similar to existing Sec.
314.107(c)(4). We also proposed to remove the description of
``commercial marketing'' from Sec. 314.107(c)(4) because we proposed
to define ``commercial marketing'' in proposed Sec. 314.3(b) with
certain modifications to the scope of the exclusion for transfer of the
drug product for reasons other than sale.
In the following paragraphs, we discuss three comments on proposed
Sec. 314.107(c). After considering these comments, we are finalizing
proposed Sec. 314.107(c)(1) without change and we are finalizing
proposed Sec. 314.107(c)(2) with a technical amendment to include a
reference to first commercial marketing of the RLD for consistency with
section 505(j)(5)(B)(iv)(I) of the FD&C Act. We also are making an
editorial correction to remove the introductory phrase in Sec.
314.107(c)(2) referring to Sec. 314.107(c)(1). We are not finalizing
our proposal to delete Sec. 314.107(c)(3) because we want to retain
flexibility to ensure that approval of ANDAs of subsequent applicants
is not blocked, for example, by a first applicant that is nonresponsive
to repeated inquiries from the Agency regarding its ANDA. In addition,
we are making clarifying revisions to this provision. As revised, Sec.
314.107(c)(3) explains that if FDA concludes that a first applicant is
not actively pursuing approval of its ANDA, FDA may immediately approve
an ANDA(s) of a subsequent applicant(s) if the ANDA(s) is otherwise
eligible for approval.
(Comment 61) One comment asserts that FDA's proposal to deem the
date of first commercial marketing to be the date of the drug product's
approval if a first applicant fails to timely notify FDA is
inconsistent with the statute, FDA's proposed and existing definitions
of ``commercial marketing,'' and the predecessor regulation at Sec.
314.107(c)(3), because the product was not actually marketed on the
deemed date. Another comment maintains that FDA's proposal to deem the
date of first commercial marketing to be the date of the drug product's
approval if a first applicant fails to timely notify FDA is a penalty
that is not warranted by the statutory change in the commercial
marketing trigger of the 180-day exclusivity period.
(Response 61) We do not find these comments persuasive. 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. Based on 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 requiring the first
applicant to notify FDA within 30 days of the date of first commercial
marketing. This requirement is intended to facilitate the efficient
enforcement of the FD&C Act and provide FDA with adequate notice to
inform the timing of approval for ANDAs submitted by subsequent
applicants. If a first applicant does not notify FDA within this
timeframe, we will deem the date of first commercial marketing to be
the date of the ANDA's approval. This consequence of a first
applicant's failure to provide timely notification to FDA is similar to
the consequence described in the predecessor regulation at Sec.
314.107(c)(4), which provided that if an applicant does not promptly
notify FDA of commercial marketing, the effective date of approval
shall be deemed to be the date of the commencement of first commercial
marketing. We expect that the regulation will encourage first
applicants to provide timely notification to FDA. Given that the date
of notification is within a first applicant's control, we expect that
there will be few instances in which there is a need to deem the date
of first commercial marketing to be the date of the ANDA's approval.
(Comment 62) One comment expresses concern that FDA may deem the
date of first commercial marketing to be the date of the drug product's
approval if a first applicant does not launch its drug product within
30 days after ANDA approval. The comment proposes that FDA require a
first applicant to notify FDA if the applicant will not launch the drug
product within 30 days after ANDA approval, but intends to launch the
drug product within 75 days after ANDA approval.
(Response 62) We decline to adopt this suggestion because it is
unnecessary. FDA would only deem the date of first commercial marketing
to be the date of the ANDA's approval if a first applicant began
commercial marketing of the drug product described in the ANDA or of
the reference listed drug and failed to notify FDA within 30 days of
the first commercial marketing (see Sec. 314.107(c)(2)). This
provision would not apply if commercial marketing had not yet
commenced. FDA's requirement for a first applicant to timely notify the
Agency of the date of first commercial marketing is intended to
facilitate implementation of the statutory change in the commercial
marketing trigger of the 180-day exclusivity period (section
505(j)(5)(B)(iv)(I) of the FD&C Act). This notification requirement is
unrelated to the statutory conditions under which a first applicant
would forfeit the 180-day exclusivity period for failure to market the
product (see section 505(j)(5)(D)(i)(I) of the FD&C Act). We will
determine whether additional rulemaking related to 180-day exclusivity
is necessary in the future.
V.M.4. Delay of Approval Due to Exclusivity (Sec. 314.107(d))
We proposed to clarify that approval of a 505(b)(2) application or
ANDA may be delayed by orphan drug exclusivity under 21 CFR 316.31 or
pediatric exclusivity under section 505A of the FD&C Act, in addition
to the exclusivities described in Sec. 314.108 (see proposed Sec.
314.107(d)).
[[Page 69629]]
In section V.A.7, we discuss a comment on proposed Sec. 314.107(d)
(see Comment 8). After considering this comment, we are revising Sec.
314.107(d) to indicate that approval of a 505(b)(2) application or ANDA
also may be delayed by a period of exclusivity for the listed drug
under section 505E of the FD&C Act. We are also making a technical edit
to refer to section 527 of the FD&C Act in the context of a delay in
approval of a 505(b)(2) application or ANDA because of orphan drug
exclusivity.
V.M.5. Notification of Court Actions or Written Consent to Approval
(Sec. 314.107(e))
We proposed 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 that may affect the timing
of approval of a 505(b)(2) application or ANDA. We proposed to require
a 505(b)(2) or ANDA applicant to submit a copy of any judgment by the
court (Federal 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 (see proposed Sec. 314.107(e)(1)(i)). We also proposed to
require a 505(b)(2) or ANDA applicant to submit to FDA a copy of
specified documented agreements and court actions other than judgments
to facilitate FDA's administration of the FD&C Act (see Sec.
314.107(e)(1)(i) through (vi)).
We explained that the proposed requirement to submit a copy of any
documented agreement described in Sec. 314.107(b)(3)(vi) would require
submission of written documentation that the parties have entered into
a settlement that terminated the patent infringement litigation, but
would not require applicants to send copies of the actual settlement
agreement to FDA (see proposed Sec. 314.107(e)(1)(iv)). To ensure
timely notification to FDA, we proposed to require a 505(b)(2) or ANDA
applicant to submit all required information to the appropriate
division in OND or to OGD, within 14 calendar 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 (see proposed Sec.
314.107(e)(2)).
In the following paragraphs, we discuss a comment on proposed Sec.
314.107(e)(1)(iv). After considering this comment, we are revising
Sec. 314.107(e)(1)(iv) to require submission of a copy of any
``written consent to approval'' by the patent owner or exclusive patent
licensee, and we are making a conforming revision to Sec.
314.107(e)(2) and to the paragraph heading for Sec. 314.107(e). We
also are clarifying that a copy of any order entered by the court
terminating the 30-month or 7\1/2\-year period includes an order
described in Sec. 314.107(b)(3)(vii) and (viii). Finally, for
administrative convenience, we are revising Sec. 314.107(e)(2) to
provide that all information required by Sec. 314.107(e)(1) must be
sent to the applicant's NDA or ANDA rather than to OGD or the
appropriate division in OND.
(Comment 63) One comment agrees with FDA's proposal to require
submission of written documentation that the parties have entered into
a settlement that has terminated the patent infringement litigation,
and recommends that FDA revise proposed Sec. 314.107(e)(1)(iv) to
expressly state that a ``documented agreement'' does not refer to the
settlement agreement, and that a copy of the actual settlement
agreement need not be submitted. The comment also requests that FDA
clarify the content of the documentation that should be submitted.
(Response 63) We agree that the proposal to require applicants to
submit a copy of any ``documented agreement'' has been the source of
confusion, notwithstanding the statement in the proposed rule that
applicants are not required to send copies of the actual settlement
agreement to FDA. We are revising Sec. 314.107(e)(1)(iv) to require
submission of a copy of any ``written consent to approval'' by the
patent owner or exclusive patent licensee. This revision is intended to
clarify the requested information and align with the text of Sec.
314.107(b)(3)(vi). A letter to FDA from the patent owner(s) or
exclusive patent licensee that provides consent to approval of the
505(b)(2) application or ANDA any time on or after the date of consent
would be acceptable. Although FDA does not require a copy of the actual
settlement agreement, we note that generic drug applicants are required
to file certain agreements with the FTC (see section 1112 of the MMA).
V.M.6. Computation of the 45-Day Time Clock (Sec. 314.107(f))
We proposed to revise Sec. 314.107(f)(1) and (2) 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 within this timeframe. We proposed to add Sec.
314.107(f)(2)(iii) to clarify 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. We
also proposed to revise Sec. 314.107(f)(3) to expressly 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.
We received no comments regarding these proposed revisions, and we
are finalizing proposed Sec. 314.107(f) without change, except for the
technical amendments described in section V.P.5 regarding the location
to which the notification must be sent.
V.M.7. Conversion of Approval to Tentative Approval (Sec. 314.107(g))
We proposed 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. In the following paragraphs, we discuss a
comment on this proposed provision. After considering this comment, we
are finalizing proposed Sec. 314.107(g) without change.
(Comment 64) One comment recommends that FDA remove the qualifier
``if appropriate'' from proposed Sec. 314.107(g). The comment also
requests that FDA clarify that ``court'' refers to either a district
court or an appellate court for consistency with Mylan Labs., Inc. v.
Thompson, 389 F.3d 1272 (D.C. Cir. 2004).
(Response 64) FDA declines to adopt the suggestion to remove the
qualifier ``if appropriate'' from proposed Sec. 314.107(g) because
there are circumstances in which it may not be appropriate to convert
an approval to a tentative approval (e.g., a stay of the district
court's order pending appeal). Moreover, the qualifier ``if
appropriate'' also modifies FDA's issuance of an approval letter in
error, and the appropriateness of conversion to tentative approval may
depend on a variety of factors. If either a district court or appellate
court enters an order requiring that the date of approval of an already
approved 505(b)(2) application or ANDA be delayed, FDA will convert the
approval to a tentative approval if appropriate.
[[Page 69630]]
V.N. Assessing Bioavailability and Bioequivalence for Drugs Not
Intended To Be Absorbed Into the Bloodstream (Sec. 320.23)
We proposed to revise Sec. 320.23 to reflect the MMA's amendments
to section 505(j)(8) of the FD&C Act, which permit use of
scientifically valid methods for assessing bioavailability and
bioequivalence for drugs that are not intended to be absorbed into the
bloodstream and essentially codify our existing practice. We received
no comments regarding these proposed revisions, and we are finalizing
proposed Sec. 320.23 without change.
V.O. Miscellaneous
We proposed several clarifying revisions and editorial changes
throughout the sections of parts 314 and 320 that were the subject of
the proposed rule. These changes were intended to promote consistency
throughout our regulations, incorporate ``plain language,'' employ
grammatically correct phrasing, and otherwise clarify the text of these
regulations. We also proposed certain revisions to provisions that
contemplated the submission of paper to facilitate the transition to
electronic submissions in the future. We did not receive any comments
on these proposed revisions, and we are finalizing them without change.
V.P. Technical Amendments
We are making several technical amendments in the sections of parts
314 and 320 that are the subject of this rulemaking. These changes are
intended to promote clarity and consistency throughout our regulations
and correct certain outdated or incorrect information. Examples of
revisions that are not otherwise described are provided in sections
V.P.1 through V.P.6.
V.P.1. Consistent Use of Defined Terms
We are replacing the terms ``application'' and ``abbreviated
application'' with the commonly used abbreviations ``NDA'' and/or
``ANDA,'' as appropriate, in the following sections: Sec. Sec.
314.3(b) (definitions of ``original application or original NDA'' and
``tentative approval''); 314.50(h); 314.53(b)(1); 314.93(b);
314.94(a)(3), (a)(12)(i)(A)(4)(i), (a)(12)(ii), (a)(12)(viii)(B), and
introductory text to Sec. 314.94; 314.95(d)(1) and (f); 314.97(a);
314.107(b)(4) and (f)(3); and 314.127(a)(2) and (a)(8)(ii)(B) and (C).
We are replacing the term ``act'' with ``Federal Food, Drug, and
Cosmetic Act'' in the following sections: Sec. Sec. 314.50(d);
314.60(b)(1) and (4), (c)(1)(i), and (c)(2); 314.93(d)(3) and
(e)(1)(iii)(C); 314.94(a)(3)(ii), (a)(5)(ii)(A), (a)(7)(ii)(C), and
(a)(8)(iv); 314.125(a) and (b)(2), (11), and (18); and
314.127(a)(3)(iii)(A)(2) and (a)(12).
We are defining ``Agency'' as an alternate term for ``FDA'' for
clarity (see Sec. 314.3(b)).
We are replacing references to the ``holder of [an or the] approved
application'' with the defined term ``NDA holder'' in the following
sections: Sec. Sec. 314.50(i)(1)(i)(A)(4)(ii); 314.70(a)(2); and
314.94(a)(12)(i)(A)(4)(ii).
We are revising the proposed definition of ``resubmission'' in
Sec. 314.3(b) to clarify that the definition applies only in the
context of a complete response letter (compare Sec. 314.101(b)(3)(ii),
which uses the term ``resubmit'' with a different meaning and in a
different context).
We are replacing the term ``right of reference'' with the defined
term ``right of reference or use'' in Sec. 314.60(c)(1)(iii).
We are making an editorial correction to the proposed definition of
``therapeutic equivalents'' in Sec. 314.3(b) to combine the sentences
into a single-sentence definition to be consistent with the definition
in the Orange Book. As revised, ``therapeutic equivalents'' are
approved drug products that are pharmaceutical equivalents for which
bioequivalence has been demonstrated, and that can be expected to have
the same clinical effect and safety profile when administered to
patients under the conditions specified in the labeling.
We are replacing the reference to a ``use patent'' with the term
``method-of-use patent'' (see Sec. Sec. 314.50(i)(1)(iii)(A) and (B),
314.52(a)(3), 314.53(e), 314.94(a)(12)(iii)(A) and (B), and
314.95(a)(3)).
V.P.2. Alignment of Certain Regulations for 505(b)(2) Applications and
ANDAs
We are making conforming revisions between certain provisions in
Sec. Sec. 314.50 and 314.94 to align the requirements for 505(b)(2)
applications and ANDAs and enhance clarity.
We are expressly providing, with respect to a 505(b)(2) applicant
that amends its paragraph IV certification after a finding of patent
infringement, that once an amendment for the change has been submitted,
the 505(b)(2) application will no longer be considered to contain a
paragraph IV certification to the patent (see Sec. 314.50(i)(6)(i)).
However, we explain that if a final decision finds the patent to be
invalid and infringed, an amended certification is not required. This
revision to Sec. 314.50(i)(6)(i) corresponds to the parallel
regulation for ANDAs in Sec. 314.94(a)(12)(viii)(A) and clarifies the
general statement in the introductory text of Sec. 314.50(i)(6)
regarding amended patent certifications for 505(b)(2) applications.
We are revising Sec. 314.94(a)(12)(viii)(A) to expressly provide
that, after a finding of patent infringement, an ANDA applicant must
submit a paragraph III certification or, with respect to a method-of-
use patent, the applicant may instead provide a statement under Sec.
314.94(a)(12)(iii) if the applicant amends its ANDA such that the
applicant is no longer seeking approval for a method of use claimed by
the patent. This revision to Sec. 314.94(a)(12)(viii)(A) corresponds
to the parallel regulation for 505(b)(2) applications in Sec.
314.50(i)(6)(i) and describes an acceptable approach under the statute
and existing regulations.
We are revising Sec. Sec. 314.50(i)(1)(i)(A)(4)(ii) and
314.94(a)(12)(i)(A)(4)(ii) to conform with Sec. Sec. 314.52(a)(2) and
314.95(a)(2), respectively, and provide that if the NDA holder does not
reside or maintain a place of business in the United States, notice of
a paragraph IV certification must be sent to its attorney, agent, or
other authorized official.
We are revising Sec. 314.94(a)(12)(viii) to clarify that a patent
certification or statement may be amended at any time ``before the
approval of the ANDA,'' rather than ``before the date of approval of
the ANDA'' for consistency with Sec. 314.50(i)(6).
V.P.3. Technical Corrections to Regulatory Concepts
We are revising the definition of ``505(b)(2) application'' to
clarify that it is an NDA for which ``at least some of'' the
investigations relied upon by the applicant for approval were not
conducted by or for the applicant and for which the applicant has not
obtained a right of reference or use (see Sec. 314.3(b)).
We are replacing the term ``filed'' with ``submitted'' in the first
sentence of Sec. 314.50(i)(4)(ii) to use consistent terminology in
this paragraph and to accurately describe FDA's longstanding practice.
As revised, an applicant whose 505(b)(2) application is submitted after
the NDA holder's untimely filing of patent information must submit an
appropriate patent certification or statement as to that patent.
We are deleting the phrase ``or changed'' from Sec. Sec.
314.50(i)(5) and 314.94(a)(12)(vii) because a 505(b)(2) or ANDA
applicant must submit an appropriate patent certification or statement
for changes to patent information that are timely filed. We also are
changing ``each relevant patent''
[[Page 69631]]
to ``each listed patent'' in Sec. Sec. 314.50(i)(5) and
314.94(a)(12)(vii) for clarity.
We are revising the titles of Sec. Sec. 314.52 and 314.95 to
clarify that these sections relate to a notice of certification of
invalidity, unenforceability, or non-infringement of a patent, as
reflected in the text of these sections and FDA's definition of a
paragraph IV certification.
We are revising the paragraph headings of Sec. Sec. 314.52(f) and
314.95(f) to change them from ``Approval'' to ``Forty-five day period
after receipt of notice'' to more clearly describe the content of these
sections. We are also revising Sec. Sec. 314.52(f) and 314.95(f) to
add the NDA holder's attorney, agent, or other authorized official as
potential recipients of the 505(b)(2) or ANDA applicant's notice of
paragraph IV certification for consistency with Sec. Sec. 314.52(a)(2)
and 314.95(a)(2).
We are changing ``a drug product'' to ``the drug product'' in Sec.
314.53(b)(1) to clarify that for patents that claim a drug product, the
applicant must submit information only on those patents that claim the
drug product, as is defined in Sec. 314.3, that is described in the
pending or approved NDA.
We are revising the description of required patent information for
drug substance patents to clarify that information must include whether
the patent claims ``a'' drug substance that is ``an'' active ingredient
in the drug product described in the NDA or supplement to reflect
submission of patent information on drug products that contain more
than one active ingredient (see Sec. 314.53(c)(2)(i)(M)(1) and
(c)(2)(ii)(N)(1)).
We are deleting the phrase ``including a 505(b)(2) application'' in
Sec. 314.53(d)(1) because the provision refers to an original NDA,
which describes ``stand-alone'' applications submitted under section
505(b)(1) of the FD&C Act and 505(b)(2) applications.
We are adding the word ``active'' to a parenthetical reference to
``ingredient'' for clarity and consistency with the regulations
governing submission of patent information on drug substances (see
Sec. 314.53(d)(1)).
We are replacing a reference to the provisions regarding ``untimely
filed patents'' with the phrase ``untimely filed patent information''
for consistency with the paragraph headings of Sec. Sec. 314.50(i)(4)
and 314.94(a)(12)(vi) (see Sec. 314.53(d)(3)).
We are replacing a reference to a request to ``delist a patent''
with the phrase ``remove a patent from the list'' for clarity (see
Sec. 314.53(f)(2)(iv)).
We are replacing a reference to an ``NDA'' in Sec. 314.60(a) with
a reference to an ``NDA, supplement, or resubmission'' for clarity and
consistency with the content of this regulation.
We are replacing the phrase ``the listed drug approved in the
petition'' in Sec. 314.93 with the phrase ``the listed drug referenced
in the approved petition'' for accuracy (see Sec. 314.94(a)(3)(i)).
We are revising the paragraph heading of Sec. 314.94(a)(12)(i) to
describe ``patents claiming drug substance, drug product, or method of
use'' for clarity and consistency with the regulation.
We are deleting the word ``who'' in the phrase ``letter
acknowledging receipt by the person who provided the notice'' because
the letter described in Sec. 314.95(e) must acknowledge receipt by the
person who received the notice, not the person who provided the notice.
We are deleting the phrase ``for the active moiety'' in the phrase
``[s]ubmission of a 505(b)(2) application or an ANDA for the active
moiety'' because applicants submit 505(b)(2) applications and ANDAs for
drug products, not active moieties, and the restriction on submission
is described in the cited statutory references (see Sec.
314.101(e)(2)).
We are revising the paragraph heading of Sec. 314.107(b)(3)(i) to
refer to the date of ``listed drug approval'' rather than the
``reference product approval'' because a 505(b)(2) application or ANDA
may rely on a listed drug approved under the FD&C Act.
We are revising Sec. 314.94(a)(12)(viii)(B) to clarify that 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 relevant
patents,'' rather than ``no listed patents,'' to incorporate the
terminology used in Sec. 314.94(a)(12)(ii).
We are revising the reference to an approval that ``will become
effective'' to an approval that ``will occur'' because the Agency no
longer uses this terminology (see Sec. 314.108(b)(3)).
V.P.4. Technical Corrections to Statutory or Regulatory References
We are correcting statutory and regulatory citations in the
sections of part 314 and 320 that are the subject of this rulemaking,
as illustrated by the following examples:
Delete the reference to ``section 505 of the act'' as
unnecessary in the context of an approved NDA (see Sec. 314.70(a)(2));
Correct the statutory reference to the definition of ``new
drug'' in section 201(p) of the FD&C Act (21 U.S.C. 321(p)) (see Sec.
314.93(d)(3));
Change ``section 505(j)(4)(D)'' to ``section
505(j)(5)(F)'' of the FD&C Act to correctly cite the relevant
exclusivity provision (see Sec. 314.94(a)(3)(ii));
Update the citation for the definition ``same drug product
formulation'' from Sec. 320.1(g) to Sec. 314.3(b) to reflect the
relocation of the definition (see Sec. 314.94(a)(7)(i));
Add a reference to Sec. 314.94(a)(12)(iii) to align with
text regarding an ANDA applicant's submission of an appropriate patent
certification or statement (see Sec. 314.94(a)(12)(i)(B) and
(a)(12)(viii)(C)(1)(ii));
Change ``section 505(j)(4)(B)(iii)'' to ``section
505(j)(5)(B)(iii)'' of the FD&C Act to correctly cite the statutory
provision regarding the 45-day period after receipt of notice of a
paragraph IV certification (see Sec. 314.95(f)); and
Revise Sec. 314.105(a) regarding approval of an NDA to
delete the reference to Sec. 314.107(c), which only applies to ANDAs.
V.P.5. Changes to Location for Sending Information
We are revising Sec. Sec. 314.52(a)(2) and 314.95(a)(2) to clarify
that the name and address of the NDA holder or its attorney, agent, or
authorized official may also be obtained by sending an electronic
communication to the Orange Book staff. As revised, Sec. Sec.
314.52(a)(2) and 314.95(a)(2) provide that this information may be
obtained by sending a written or electronic communication to the Orange
Book Staff, Office of Generic Drugs, 7620 Standish Pl., Rockville, MD
20855, or to the Orange Book Staff at the email address listed on the
Agency's Web site at http://www.fda.gov.
We are revising Sec. 314.53(c)(2)(i)(B) and (c)(2)(ii)(B) to
request the NDA applicant's full address, phone number, and, if
available, fax number and email address in addition to the applicant's
name to facilitate communication.
We are revising Sec. 314.107(f)(2) to clarify that notification of
the filing of any legal action within 45 days of the receipt of notice
of a paragraph IV certification must be sent by a 505(b)(2) applicant
to its NDA (rather than to the appropriate OND Review Division) and
must be sent by an ANDA applicant to its ANDA (rather than to OGD).
V.P.6. Grammatical Corrections
We are making certain revisions to correct or improve grammar or
punctuation in the sections of parts 314 and 320 that are the subject
of this rulemaking, as illustrated by the following examples:
[[Page 69632]]
Change ``which'' to ``that'' (see Sec. Sec.
314.50(i)(1)(i)(A)(4)(ii) and 314.95(a)(1));
Change ``method of use patent'' to ``method-of-use
patent'' (see Sec. Sec. 314.50(i)(1)(iii) and 314.94(a)(12)(iii));
Change ``[o]nce an amendment for the change in
certification has been submitted'' to ``[o]nce an amendment is
submitted to change the certification'' (see Sec. 314.50(i)(6));
Change ``will no longer be considered to be one
containing'' to ``will no longer be considered to contain'' (see
Sec. Sec. 314.50(i)(6) and 314.94(a)(12)(viii)(A) and (B));
Delete the word ``use'' in the phrase ``one or more
methods of using the drug product for which use approval is being
sought'' for clarity (see Sec. 314.53(c)(2)(i)(O)(1));
Change ``United States'' to ``U.S.'' (see Sec.
314.53(c)(2)(ii)(H));
Change ``shall'' to ``must'' as appropriate (see
Sec. Sec. 314.53(d)(1) and 314.94(a), (a)(1), (a)(12)(i)(A)(4)(i) and
(ii), (b), and (d)(2));
Change ``except that Sec. 314.50(d)(1)(ii)(c) must
contain'' to ``except that the [technical] section described in Sec.
314.50(d)(1)(ii)(c) must contain'' or ``except that the information
required under Sec. 314.50(d)(1)(ii)(c) must contain'' for clarity
(see Sec. Sec. 314.54(a)(2) and 314.94(a)(9)(i));
Change ``any bioavailability of bioequivalence testing''
to ``any bioavailability or bioequivalence testing'' to correct a
typographical error (see Sec. 314.94(a)(7)(ii));
Change ``it'' to ``the study'' for clarity (see Sec. Sec.
314.94(a)(7)(iii)(B) and 314.101(d)(6) and (7));
Change ``amendment to Sec. 314.94(a)(9)'' to ``amendment
under Sec. 314.94(a)(9)'' for clarity (see Sec. 314.96(b));
Change ``their representatives'' to ``its representative''
or ``its representative(s)'' (see Sec. Sec. 314.94(a)(12)(i)(A)(4)(ii)
and 314.107(f)(2)(ii) and (iii) and (f)(3));
Delete the words ``is or'' from the phrase ``is or has
been removed'' (see Sec. 314.94(a)(12)(viii)(B)); and
Add appropriate descriptors (e.g., ``section'' and
``paragraph'') to modify statutory and regulatory references (see Sec.
314.94(d)(2)).
VI. Effective Date
This final rule is effective December 5, 2016. The final rule
applies to any new submission (including but not limited to an NDA or
ANDA, an amendment or supplement (including any patent certifications
or statements), submission of patent information and requests by the
NDA holder to amend or withdraw a patent or patent information,
submission of a new patent listing dispute, and notification of court
actions or written consent to approval) received by FDA on or after the
effective date. In addition, a person (including a 505(b)(2) or ANDA
applicant) may submit a request under Sec. 314.53(f)(1) for an NDA
holder to confirm the accuracy or relevance of previously submitted
patent information in light of requirements for submission of patent
information on and after the effective date of this final rule.
VII. Economic Analysis of Impacts
We have examined the impacts of the final 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 us 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). We
have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the final rule. We believe that this final rule
is not a significant regulatory action as defined by Executive Order
12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because average costs per entity are small, and the
regulatory requirement with the highest cost per instance would affect
few if any of the smallest entities, we certify that the final rule
will not have a significant economic impact on a substantial number of
small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``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 $146
million, using the most current (2015) Implicit Price Deflator for the
Gross Domestic Product. This final rule would not result in an
expenditure in any year that meets or exceeds this amount.
Many provisions of this final rule codify current practice, but
some elements will lead to changes that generate additional benefits
and costs. Table 2 summarizes the benefits and costs of this final
rule. The estimated annualized monetized benefits of this final rule
are $215,247 at a 3 percent or 7 percent discount rate, while the
estimated annualized monetized costs are $266,947 at a 3 percent
discount rate and $275,925 at a 7 percent discount rate. We have also
identified, but are unable to quantify, additional impacts from changes
to submitted patent information.
Table 2--Summary of Benefits and Costs
------------------------------------------------------------------------
Benefits Costs
------------------------------------------------------------------------
One-time (Year 1) Cost for Reading the N/A $466,450
Rule...................................
Annually Recurring Compliance Costs or $215,247 213,858
Savings (Years 1-10)...................
Present Value at 3 Percent.............. 1,836,098 2,277,116
Present Value at 7 Percent.............. 1,511,803 1,937,983
Annualized Value at 3 Percent........... 215,247 266,947
Annualized Value at 7 Percent........... 215,247 275,925
------------------------------------------------------------------------
The full analysis of economic impacts is available in the docket
for this final rule (Ref. 2) and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
VIII. Analysis of Environmental Impact
We have 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.
[[Page 69633]]
IX. Paperwork Reduction Act of 1995
The final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520).
The title, description, and respondent description of the information
collection provisions are shown in the following paragraphs with an
estimate of the annual reporting burden. The 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.
Title: Abbreviated New Drug Applications and 505(b)(2)
Applications.
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 final rule implements 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 final rule also amends
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 to 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.
In addition, 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 0910-0191). 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 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.
Under section 505(b), (c), and (j) of the FD&C Act and this final
rule, the following information must be submitted to FDA but is not
currently approved by OMB under the PRA.
Section 314.50(i)(1)(i)(C) requires a 505(b)(2) applicant to submit
an appropriate patent certification or statement for each patent listed
in the Orange Book for one drug product approved in an NDA that is
pharmaceutically equivalent to the proposed drug product for which the
original 505(b)(2) application is submitted and was approved before the
original 505(b)(2) application was submitted. Section 314.54 also
describes this requirement. In general, 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. However,
based on our experience reviewing 505(b)(2) applications, we estimate
that Sec. 314.50(i)(1)(i)(C) may result in two instances per year in
which an applicant is required to identify a pharmaceutically
equivalent drug product as a listed drug relied upon and to comply with
applicable regulatory requirements (including submission of an
appropriate patent certification or statement for each patent listed in
the Orange Book for a pharmaceutically equivalent drug product approved
in an NDA). Based on an average of 3.4 patents submitted by an NDA
holder for listing in the Orange Book, we calculate that the two
instances in which a 505(b)(2) applicant is required to identify a
pharmaceutically equivalent drug product as a listed drug relied upon
will result in 6.8 patent certifications or statements per year. The
burden associated with this requirement in Sec. 314.50(i)(1)(i)(C) is
approximately 2 hours per response. In addition, if the patent
certification submitted pursuant to 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.
The burden estimate for sending notice of a paragraph IV
certification reflects other changes that 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 Sec. 314.52(c)
that increases the estimated burden by 0.33 hours per response. We are
providing an estimate of 15 respondents for Sec. 314.52(a), (b), and
(e) to reflect the additional burden that may arise from the
requirement in Sec. 314.50(i)(1)(i)(C) if the two 505(b)(2)
[[Page 69634]]
applicants submit paragraph IV certifications and to update data
regarding the estimated number of 505(b)(2) applications that contain
one or more paragraph IV certifications, which adds approximately 675
hours (15 hours per response) to the currently approved burden. We
separately describe and estimate the burden of the additional content
requirement in Sec. 314.52(c).
Sections 314.52(a) and 314.95(a) expand the 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 existing Sec. 314.52(a) and (e), a
request to FDA to use common alternate delivery methods. We receive
approximately 390 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. Sections 314.52(a) and
314.95(a) eliminate the requirement to submit a request to use a
designated delivery service, as defined in Sec. Sec. 314.52(g) and
314.95(g). We estimate that approximately 97.5 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 Sec. Sec. 314.52(g) and 314.95(g).
Sections 314.50(i)(6) and 314.94(a)(12)(viii) 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
and enters a settlement order or consent decree with a finding of
infringement (unless the patent also is found invalid). Sections
314.50(i)(6) and 314.94(a)(12)(viii) also 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 receiving submissions of court decisions or
orders with a finding of infringement, and instances in which the
patent or patent information has been removed from the list at the
request of the NDA holder, we estimate that this requirement may result
in approximately 17 and 153 instances per year in which an applicant
amends its 505(b)(2) application or ANDA, respectively, to submit a
revised patent certification. The burden hours associated with this
requirement will be approximately 2 hours per response.
Sections 314.50(i)(6)(iii)(A)(2) and 314.94(a)(12)(viii)(C)(1)(ii)
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 USPTO 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.
Section 314.95(c) requires that the notice of paragraph IV
certification contain a statement that the applicant has received the
paragraph IV acknowledgment letter. In addition, Sec. 314.52(c)
requires 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 20 505(b)(2) applications
filed per year that contain one or more paragraph IV certifications
(plus the additional burden that may arise from the requirement in
Sec. 314.50(i)(1)(i)(C) if the 2 505(b)(2) applicants submit paragraph
IV certifications) and 400 ANDAs received per year that contain one or
more paragraph IV certifications, we estimate that there will be 60 and
1,200 responses per year, respectively, and the burden hours associated
with this requirement will be approximately 20 minutes per response.
Sections 314.52(d)(1) and 314.95(d)(1) 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 in 2003,
FDA has regulated directly from the statute and required notice of
paragraph IV certification in these circumstances, and the burden
associated with this statutory requirement is currently approved under
OMB control number 0910-0001.
Sections 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 existing Sec. Sec. 314.52(b) and (e) and
314.95(b) and (e)). Section 314.95(e) also requires an ANDA applicant
to include in its amendment a dated printout of the Orange Book entry
for the RLD. The burden associated with this statutory requirement is
currently approved under OMB control number 0910-0001.
Section 314.53(c)(2) decreases the patent information that NDA
applicants are currently required to submit for listing in the Orange
Book. Section 314.53(c)(2) requires 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. Section 314.53(c)(2) also provides 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. Section 314.53(c)(2) also modifies requirements for
submission of patent information on method-of-use patents. The
information collection resulting from existing Sec. 314.50(h) (citing
Sec. 314.53) and Form FDA 3542a has been approved by OMB under control
number 0910-0513 for FDA's estimate of 20 hours per response. We
previously estimated that the burden of Form FDA 3542a would fall by 3
hours per response. We now estimate that the burden for Form FDA 3542a
will be reduced by 5 hours from 20 hours to 15 hours per response; we
further estimate that the burden for Form FDA 3542 will increase by 5
hours from 5 to 10 hours per response. We have shifted a portion of the
time spent preparing Form FDA 3542a to the estimated time preparing
Form FDA 3542 to reflect the additional time spent by the NDA holder to
develop the use code in accordance with FDA's revised regulations and
identify the specific section(s) and subsection(s) of labeling that
describe the specific approved method of use claimed by the patent.
Section 314.53(d)(2) avoids duplicative submission of patent
information that would accompany supplements to NDAs and requires such
information only for a supplement to add or change the dosage form or
route of administration, to add or change the strength, to change the
drug product
[[Page 69635]]
from prescription to OTC use, or to revise previously submitted patent
information that differently or no longer claims the changed product.
Section 314.53(f)(1) provides a more detailed description of the
procedure for patent listing disputes directed to the accuracy or
relevance of submitted patent information, and establishes additional
requirements for patent listing disputes directed to method-of-use
claims. Based on our experience, we estimate that there may be
approximately 12 instances per year in which a person submits a patent
listing dispute, and a corresponding 12 instances per year in which the
NDA holder is required to respond to the patent listing dispute. In
light of the additional requirements for patent listing disputes
directed to method-of-use claims, we estimate that the burden
associated with Sec. 314.53(f)(1) will be approximately 10 hours per
response.
Section 314.53(f)(2) expressly requires 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 39
submissions of Form FDA 3542 or other written submission, as provided
in Sec. 314.53(f)(2), by approximately 27 NDA holders. We further
estimate that the burden hours associated with the requirement in 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
prohibits the submission of certain types of changes in an amendment or
a supplement to a 505(b)(2) application or an ANDA, respectively.
Sections 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 than 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 final 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 guidance for industry on ``Submitting Separate
Marketing Applications and Clinical Data for Purposes of Assessing User
Fees'' (December 2004), available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
Accordingly, the burden associated with this statutory requirement is
currently approved under OMB control number 0910-0001.
Sections 314.60(f) and 314.96(d) require an applicant to submit a
patent certification if approval is sought for the following types of
amendments to a 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.
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, the
patent certification requirements would be broadened under this
regulation. We estimate that this broadened requirement may result in
approximately six instances per year in which an applicant is required
to submit a patent certification with an amendment to its 505(b)(2)
application. We further estimate that this requirement may result in
approximately 100 instances per year in which an applicant is required
to submit a patent certification with an amendment to its ANDA. The
burden hours associated with these requirements are estimated to be
approximately 2 hours per response.
Sections 314.96(c) and 314.97(b) 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 300 hours for each
of the estimated two responses per year.
Section 314.107(e) expands the scope of the court actions and
written consent to approval related to a patent described in Sec.
314.107(b)(3) that are required to be submitted to FDA. Section
314.107(e) also requires 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. Based on our
experience, we estimate that 247 505(b)(2) and ANDA applicants will be
required to submit a copy of a court action, written consent to
approval, or written notification of appeal in approximately 494
instances per year. We continue to estimate that the burden associated
with submitting a copy of these documents to FDA (as approved in OMB
control number 0910-0001) is approximately 30 minutes per response.
The estimated burden of this collection of information is described
in Table 3.
Table 3--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
21 CFR section Number of responses per Total annual Average burden per response (in hours) Total hours
respondents respondent responses
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.50(i)(1)................................ 2 3.4 6.8 2......................................... 14
314.50(i)(6)................................ 17 1 17 2......................................... 34
314.52(a), (b), and (e)..................... 15 3 45 15........................................ 675
314.52(c)................................... 22 3 66 0.33 (20 minutes)......................... 22
314.53(f)(1)................................ 24 1 24 10........................................ 240
314.53(f)(2)................................ 27 1.4 39 1......................................... 39
314.60(f)................................... 6 1 6 2......................................... 12
314.94(a)(12)(viii)......................... 153 1 153 2......................................... 306
314.95(c)................................... 400 3 1,200 0.33 (20 minutes)......................... 400
[[Page 69636]]
314.96(c)................................... 1 1 1 300....................................... 300
314.96(d)................................... 100 1 100 2......................................... 200
314.97(b)................................... 1 1 1 300....................................... 300
314.107(e).................................. 247 2 494 0.5 (30 minutes).......................... 247
-----------------------------------------------------------------------------------------------------------
Total Reporting Burden Hours............ .............. .............. .............. .......................................... 2,789
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
The information collection provisions in this final rule have been
submitted to OMB for review as required by section 3507(d) of the
Paperwork Reduction Act of 1995.
Before the effective date of this final rule, FDA will publish a
notice in the Federal Register announcing OMB's decision to approve,
modify, or disapprove the information collection provisions in this
final rule. An Agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.
X. Federalism
We have analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. We have determined that the rule
does not contain policies that 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, we conclude that the 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.
XI. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at http://www.regulations.gov. FDA has
verified the Web site addresses, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.
1. Federal Trade Commission, Report on ``Generic Drug Entry Prior to
Patent Expiration: An FTC Study'' (July 2002), available at http://www.ftc.gov/sites/default/files/documents/reports/generic-drug-entry-prior-patent-expiration-ftc-study/genericdrugstudy_0.pdf.
2. Final Regulatory Impact Analysis, Final Regulatory Flexibility
Analysis, and Unfunded Mandates Reform Act Analysis for Abbreviated
New Drug Applications and 505(b)(2) Applications; Final Rule,
available at http://www.fda.gov/aboutfda/reportsmanualsforms/
reports/economicanalyses/default.htm.
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, 21 CFR parts
314 and 320 are amended as follows:
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
0
1. The authority citation for part 314 is revised to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f,
356, 356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k-1.
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 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.
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 at
least some of 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.
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 an ANDA
is sufficiently complete to permit a substantive review. An
acknowledgment letter indicates that 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.
[[Page 69637]]
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.
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
ANDA, outside the control of the ANDA applicant, except that the term
does not include transfer of the drug product for investigational use
under part 312 of this chapter or transfer of the drug product to
parties identified in the ANDA for reasons other than sale. Commercial
marketing includes the introduction or delivery for introduction into
interstate commerce of the reference listed drug by the ANDA applicant.
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.
Date of approval is the date on the approval letter from FDA
stating that the NDA or ANDA is approved, except that the date of
approval for an NDA described in section 505(x)(1) of the Federal Food,
Drug, and Cosmetic Act is determined as described in section 505(x)(2)
of the Federal Food, Drug, and Cosmetic Act. ``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 this part; or
(8) Incorporate other information based on at least one adequate
and well-controlled clinical study.
[[Page 69638]]
FDA or Agency is the Food and Drug Administration.
First applicant is an ANDA applicant that, on the first day on
which a substantially complete application containing a paragraph IV
certification is submitted for approval of a drug, submits a
substantially complete application 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 (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 approval 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 or 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, in the context of a complete response letter, 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 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
[[Page 69639]]
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. Sufficiently
complete means that the ANDA contains all the information required
under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act
and does not contain a deficiency described in Sec. 314.101(d) and
(e).
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; because there is a
period of exclusivity for the listed drug under section 505E 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 NDA or ANDA 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 for which bioequivalence has been
demonstrated, and that 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. Amend Sec. 314.50 as follows:
0
a. Remove the word ``shall'' and add in its place the word ``must''
wherever it appears in paragraphs (a) introductory text, (a)(5),
(d)(1)(v), (d)(5)(v), (d)(5)(vi)(a) and (b), (e)(2) introductory text,
(f)(3), (g)(2), and (k);
0
b. Remove the word ``application'' and add in its place ``NDA''
wherever it appears in paragraphs (a)(5), (b), (c)(1), (c)(2)(i),
(c)(2)(iv) through (viii), (d) introductory text, (d)(1)(i),
(d)(1)(ii)(a), (d)(1)(iii) through (v), (d)(3)(ii), (d)(5)(iv),
(d)(5)(vi)(b), (e)(1)(i) introductory text, (e)(2) introductory text,
(f) introductory text, (f)(1) through (3), (g)(2), (h), (j)(4)
introductory text, (j)(4)(i) and (ii), (k), (l) heading, (l)(1)
introductory text, and (l)(4);
0
c. Remove the word ``act'' and add in its place ``Federal Food, Drug,
and Cosmetic Act'' in paragraphs (d) introductory text, (d)(5)(vi)(b),
and (j)(3);
0
d. Remove the phrase ``Prior to the submission of'' and add in its
place the words ``Before submitting'' and remove the phrase ``are
required to'' and add in its place the word ``must'' wherever it
appears in paragraph (d)(5)(vi)(b);
0
e. Remove the word ``shall'' and add in its place the word ``must'' and
remove the phrase ``new drug application'' and add in its place ``NDA''
in paragraph (j) introductory text; and
0
f. Revise the section heading, introductory text, and paragraphs
(a)(1), (e)(1) introductory text, (f)(4), (g)(3), (i), the first two
sentences of paragraph (j)(4)(iii), and (l)(2) and (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.
* * * * *
(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) Presentation and format. 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) An appropriate patent certification or statement 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
[[Page 69640]]
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)(i) 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.
(ii) 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 NDA holder (or, if the NDA holder does not
reside or maintain a place of business within the United States, its
attorney, agent, or other authorized official) for the drug product
that 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, an appropriate patent certification or
statement 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 an original 505(b)(2)
application, there is a drug product approved in an NDA that is
pharmaceutically equivalent to the drug product for which the original
505(b)(2) application is submitted, an appropriate patent certification
or statement under this section with respect to each patent that claims
the drug substance or drug product or that claims an approved use for
one such drug product.
(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 an indication or other condition of use that is covered by the
method-of-use patent, a statement explaining that the method-of-use
patent does not claim a proposed indication or other condition 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 method-of-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 submitted
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 paragraph IV certification as to that patent
and a statement that the applicant has been granted a patent license.
If the patent owner consents to approval of the 505(b)(2) application
(if otherwise eligible for approval) 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 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. (i) If a patent
described in paragraph (i)(1)(i)(A) 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 or statement is not required to submit
a patent certification or statement to address the patent or patent
information 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
unless:
(A) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of patent
issuance;
(B) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of approval of a
corresponding change to product labeling; or
(C) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of a decision by
the U.S. Patent and Trademark Office or by a Federal district court,
the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court
that is specific to the patent and alters the construction of a method-
of-use claim(s) of the patent, and the amendment contains a copy of the
decision.
(ii) An applicant whose 505(b)(2) application is submitted 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 or statement at the time of the patent
submission must submit a certification under paragraph (i)(1)(i) of
this section and/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, the applicant must submit
an appropriate certification or statement for each listed patent.
(6) Amended certifications. A patent certification or statement
submitted under paragraphs (i)(1)(i) through (iii) of this section may
be amended at any time before the approval of the 505(b)(2)
application. An applicant must submit
[[Page 69641]]
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 is submitted to change the
certification, the 505(b)(2) application will no longer be considered
to contain 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
and enters 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. Once an amendment for the change
has been submitted, the 505(b)(2) application will no longer be
considered to contain a paragraph IV certification to the patent. If a
final decision finds the patent to be invalid and infringed, an amended
certification is not required.
(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 or patent information 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 or patent information 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 or statement (that the
patent has been removed from the list). If the list reflects that an
NDA holder has requested that a patent or patent information 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 will remain listed until any 180-day exclusivity based on that
patent has expired or has been extinguished. A 505(b)(2) applicant is
not required to provide or maintain a certification to a patent or
patent information 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 contain 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 or statement
if, at any time before the approval of the 505(b)(2) application, the
applicant learns that the submitted certification or statement is no
longer accurate; and
(2) An applicant must submit an appropriate patent 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.
(j) * * *
(4) * * *
(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) * * *
(2) Review copy. The applicant must submit a review copy of the
NDA. Each of the technical sections, described in paragraphs (d)(1)
through (6) of this section, in the review copy is required to be
separately bound with a copy of the application form required under
paragraph (a) of this section and a copy of the summary required under
paragraph (c) of this section.
(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
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, unenforceability,
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 505(b)(2) 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 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 by sending a written or electronic
communication to the Orange Book Staff, Office of Generic Drugs, 7620
Standish Pl., Rockville, MD 20855, or to the Orange Book Staff at the
email
[[Page 69642]]
address listed on the Agency's Web site at http://www.fda.gov.
(3) This paragraph (a) does not apply to a method-of-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 of filing described
in Sec. 314.101(a)(2) or (3), as applicable, 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 (b) 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 date of filing described in Sec.
314.101(a)(2) or, if FDA notifies the applicant that FDA has refused to
file the 505(b)(2) application, before the date described in Sec.
314.101(a)(3) on which the 505(b)(2) application is filed. The
applicant will not have complied with this paragraph (b) until it sends
valid notice.
(3) 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
the notice 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) 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.
(4) The active ingredient, strength, and dosage form of the
proposed drug product.
(5) The patent number and expiration date of each patent on the
list alleged to be invalid, unenforceable, or not infringed.
(6) 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.
(7) If the applicant alleges that the patent will not be infringed
and the applicant seeks to preserve the option to later 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.
(8) 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 the date of filing described in Sec. 314.101(a)(2) or (3), as
applicable, 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 the date of filing described in Sec. 314.101(a)(2)
or (3), as applicable, 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 paragraph (d)(1) or (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 (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
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) Forty-five day period after receipt of notice. 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 or its attorney, agent,
or other authorized official 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
[[Page 69643]]
(iii) Provides overnight or 2-day delivery service throughout the
United States.
(2) FDA may periodically issue guidance regarding designated
delivery services.
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 to its
NDA 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 the drug product, as is
defined in Sec. 314.3, that is described in the pending or approved
NDA. 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 NDA holder's description of the patented method of use required by
paragraph (c)(2)(ii)(P)(3) of this section must describe only the
approved method(s) of use claimed by the patent for 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. If the method(s) of use claimed by the patent
does not cover an indication or other approved condition of use in its
entirety, the applicant must describe only the specific approved method
of use claimed by the patent for 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 approved NDAs, the NDA holder submitting information on
the method-of-use patent must identify with specificity the section(s)
and subsection(s) of the approved labeling that describes the method(s)
of use claimed by the patent submitted. 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;
(B) The NDA applicant's name, full address, phone number and, if
available, fax number and email address;
(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(s) and route(s) of administration of new drug, and
whether the applicant proposes to market the new drug for prescription
use or over-the-counter use;
(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
[[Page 69644]]
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 has been submitted previously
for the NDA or supplement;
(K) If the patent has been submitted previously for listing,
identify all change(s) from the previously submitted patent information
and specify whether the change is related to the patent or related to
an FDA action or procedure;
(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 a drug substance that is an 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 approval is being sought and a description of each
pending method of use and related patent claim of the patent being
submitted;
(2) Identification of the specific section(s) and subsection(s) of
the proposed labeling for the drug product that describes the method of
use claimed by the patent submitted; 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 (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.
(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; and
(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);
(3) If the applicant submits a supplement for a change other than
one of the changes listed under paragraph (d)(2)(i) of this section,
then the patent information submission requirements of paragraph
(d)(2)(ii) of this section apply.
(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 not list or publish
patent information if it is not provided on this form or if the patent
declaration does not contain the required information 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) The NDA holder's name, full address, phone number and, if
available, fax number and email address;
(C) Trade name of new drug;
(D) Active ingredient(s) of new drug;
(E) Strength(s) of new drug;
(F) Dosage form(s) and route(s) of administration of new drug, and
whether the new drug is approved for prescription use or over-the-
counter use;
(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 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);
[[Page 69645]]
(K) Information on whether the patent has been submitted previously
for the NDA or supplement;
(L) If the patent has been submitted previously for listing,
identify all change(s) from the previously submitted patent information
and specify whether the change is related to the patent or related to
an FDA action or procedure;
(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 a drug substance that is an 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 and related patent claim of the patent being submitted;
(2) Identification of the specific section(s) and subsection(s) of
the approved labeling for the drug product that describes the method of
use claimed by the patent submitted;
(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 method(s) of use claimed by
the patent does not cover an indication or other approved condition of
use in its entirety, then the applicant must describe only the specific
approved method of use claimed by the patent for 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); 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 (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 or response to
a request under 21 CFR 314.53(f)(1) 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.
(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; and
(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) If the applicant submits a supplement for a change other than
one of the changes listed under paragraph (d)(2)(i) of this section,
then the patent information submission requirements of paragraph
(d)(2)(ii) of this section apply.
(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 form, 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, the information described in paragraph (c) of this section on
each drug substance (active 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 must, 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 add or change the dosage form or route of administration;
(B) To add or change the strength; or
(C) To change the drug product from prescription use to over-the-
counter use.
(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
[[Page 69646]]
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 required by paragraph
(c) of this section 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 pursuant to
paragraph (c) of this section unless the published 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 under paragraph (f)(2)(iv) of this
section 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 or statements will be governed by
the provisions regarding untimely filed patent information at
Sec. Sec. 314.50(i)(4) and (6) and 314.94(a)(12)(vi) and (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, or to FDA in an electronic format submission
that complies with Sec. 314.50(l)(5). 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 Central Document Room, Center for Drug Evaluation and Research,
Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD
20705-1266, or to FDA in an electronic format submission that complies
with Sec. 314.50(l)(5). Form FDA 3542 should not be submitted to the
Orange Book Staff in the Office of Generic Drugs.
(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 Central Document Room, or officially received by
FDA in an electronic format submission that complies with Sec.
314.50(l)(5).
(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
method-of-use patent, the description of the method of use claimed by
the patent as required by Sec. 314.53(c)(2)(ii)(P)(3). 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 Freedom of Information Staff at the address listed on
the Agency's Web site at http://www.fda.gov. The submitted patent
information, and requests to remove a patent or patent information from
the list, may be subject to public disclosure.
(f) Correction of patent information errors--(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.'' The patent listing dispute
communication must include a statement of dispute that describes the
specific grounds for disagreement regarding the accuracy or relevance
of patent information for FDA to send to the applicable NDA holder. For
a dispute regarding the accuracy or relevance of patent information
regarding an approved method of using the drug product, this statement
of dispute must be only a narrative description (no more than 250
words) of the person's interpretation of the scope of the patent. This
statement of dispute must only contain information for which the person
consents to disclosure because FDA will send the text of the statement
to the applicable NDA holder without review or redaction. The patent
listing dispute communication should be directed to the Office of
Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620
Standish Pl., Rockville, MD 20855, or to the Orange Book Staff at the
email address listed on the Agency's Web site at http://www.fda.gov.
(i) Communication with the NDA holder--(A) Drug substance or drug
product claim. For requests submitted under this paragraph (f)(1) that
are directed to the accuracy or relevance of submitted patent
information regarding a drug substance or drug product claim, the
Agency will send the statement of dispute to the applicable NDA holder.
The NDA holder must confirm the correctness of the patent information
and include the signed verification required by paragraph (c)(2)(ii)(R)
of this section or withdraw or amend the patent information in
accordance with paragraph (f)(2) of this section within 30 days of the
date on which the Agency sends the statement of dispute. Unless the NDA
holder withdraws or amends its patent information in response to the
patent listing dispute, the Agency will not change the patent
information in the Orange Book.
(B) Method-of-use claim. For requests submitted under this
paragraph (f)(1) that are directed to the accuracy or relevance of
submitted patent information regarding an approved method of using the
drug product, FDA will send the statement of dispute to the NDA holder.
The NDA holder must confirm the correctness of its description of the
approved method of use claimed by the patent that has been included as
the ``Use Code'' in the Orange Book, or withdraw or amend the patent
information in accordance with paragraph (f)(2) of this section,
provide a narrative description (no more than 250 words) of the NDA
holder's
[[Page 69647]]
interpretation of the scope of the patent that explains why the
existing or amended ``Use Code'' describes only the specific approved
method of use claimed by the patent for 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, and include the signed verification required by paragraph
(c)(2)(ii)(R) of this section within 30 days of the date on which the
Agency sends the statement of dispute. The narrative description must
only contain information for which the NDA holder consents to
disclosure because FDA will send the text of the statement to the
person who submitted the patent listing dispute without review or
redaction.
(1) If the NDA holder confirms the correctness of the patent
information, provides the narrative description required by paragraph
(f)(1)(i)(B) of this section, and includes the signed verification
required by paragraph (c)(2)(ii)(R) of this section within 30 days of
the date on which the Agency sends the statement of dispute, the Agency
will not change the patent information in the Orange Book.
(2) If the NDA holder responds to the patent listing dispute with
amended patent information in accordance with paragraph (f)(2) of this
section, provides the narrative description required by paragraph
(f)(1)(i)(B) of this section, and includes the signed verification
required by paragraph (c)(2)(ii)(R) of this section within 30 days of
the date on which the Agency sends the statement of dispute, FDA will
update the Orange Book to reflect the amended patent information.
(ii) Patent certification or statement during and after patent
listing dispute. A 505(b)(2) application or ANDA must contain an
appropriate certification or statement for each listed patent,
including the disputed patent, during and after the patent listing
dispute.
(iii) Information on patent listing disputes. FDA will promptly
post information on its Web site regarding whether a patent listing
dispute has been submitted for a published description of a patented
method of use for a drug product and whether the NDA holder has timely
responded to the patent listing dispute.
(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 (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 amend the patent information or 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 an amendment to its NDA that includes a copy of the order,
within 14 days of the date the order was entered, to the Central
Document Room, Center for Drug Evaluation and Research, Food and Drug
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. The
amendment to the NDA must bear the identification described in
paragraph (d)(6) of this section. FDA will remove a patent or patent
information from the list if there is no first applicant eligible for
180-day exclusivity based on a paragraph IV certification to that
patent or after the 180-day exclusivity period of a first applicant
based on that patent has expired or has been extinguished.
(ii) Patent term restoration. If the term of a listed patent is
extended pursuant to 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,
in an amendment or supplement to the NDA. The amendment or supplement
to the NDA must bear the identification described in paragraph (d)(6)
of this section. 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)(ii) 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 remove a patent from the list 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.
0
6. AmendSec. 314.54 as follows:
0
a. Remove the word ``shall'' and add in its place the word ``must'' in
paragraph (a)(1) introductory text and paragraphs (a)(1)(i) and (a)(3);
and
0
b. Revise the section heading, paragraph (a) introductory text, and
paragraphs (a)(1)(iii), (v), and (vi), (a)(2) and (4), and (b).
The revisions 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(s) identified as relied
upon must include a drug product approved in an NDA that:
(A) Is pharmaceutically equivalent to the drug product for which
the original 505(b)(2) application is submitted; and
(B) Was approved before the original 505(b)(2) application was
submitted.
* * * * *
(v) Any patent information required under section 505(b)(1) of the
Federal Food, Drug, and Cosmetic Act with respect to any patent which
claims the drug for which approval is sought or a method of using such
drug and to which a claim of patent infringement could
[[Page 69648]]
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.
(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(s) on which
investigations relied on by the applicant for approval of the
application were conducted, or that claim a use for the listed drug(s).
A 505(b)(2) applicant seeking approval of a drug that is
pharmaceutically equivalent to a listed drug approved in an NDA
implicitly relies upon one such pharmaceutically equivalent listed
drug.
* * * * *
(2) The applicant must submit a review copy that contains the
technical sections described in Sec. 314.50(d)(1), except that the
section described in Sec. 314.50(d)(1)(ii)(c) must contain the
proposed or actual master production record, including a description of
the equipment, to be used for the manufacture of a commercial lot of
the drug product, and Sec. 314.50(d)(3), and the technical sections
described in Sec. 314.50(d)(2), (d)(4) through (6), and (f) when
needed to support the modification. Each of the technical sections in
the review copy is required to be separately bound with a copy of the
information required under Sec. 314.50(a), (b), and (c) and a copy of
the proposed labeling.
* * * * *
(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. Amend Sec. 314.60 as follows:
0
a. Remove the word ``application'' and add in its place ``NDA''
wherever it appears;
0
b. Remove the word ``act'' and add in its place ``Federal Food, Drug,
and Cosmetic Act'' wherever it appears in paragraphs (b)(1) and (4),
(c)(1)(i), and (c)(2);
0
c. Remove ``505(c)(3)(D)(ii)'' and add in its place
``505(c)(3)(E)(ii)'' in paragraphs (c)(1)(i) and (c)(2);
0
d. Add paragraph headings in paragraphs (b) and (c);
0
e. Revise the section heading and paragraphs (a), (c)(1)(iii), and (d);
and
0
f. Add paragraphs (e) and (f).
The revisions and additions read as follows:
Sec. 314.60 Amendments to an unapproved NDA, supplement, or
resubmission.
(a) Submission of NDA. FDA generally assumes that when an original
NDA, supplement to an approved NDA, or resubmission of an NDA or
supplement is submitted to the Agency for review, the applicant
believes that the Agency can approve the NDA, supplement, or
resubmission as submitted. However, the applicant may submit an
amendment to an NDA, supplement, or resubmission that has been filed
under Sec. 314.101 but is not yet approved.
(b) Submission of major amendment. * * *
(c) Limitation on certain amendments.
(1) * * *
(iii) The applicant has not obtained a right of reference or use to
the investigation described in paragraph (c)(1)(ii) of this section;
and
* * * * *
(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 paragraph (e), 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 (e), an applicant may amend the
505(b)(2) application to seek approval of a different strength.
(f) Patent certification requirements. (1) An amendment to a
505(b)(2) application is required to contain an appropriate patent
certification or statement described in Sec. 314.50(i) or a
recertification for a previously submitted paragraph IV certification
if approval is sought for any of the following types of amendments:
(i) To add a new indication or other condition of use;
(ii) To add a new strength;
(iii) To make other than minor changes in product formulation; or
(iv) To change the physical form or crystalline structure of the
active ingredient.
(2) If the amendment to the 505(b)(2) application does not contain
a patent certification or statement, the applicant must verify that the
proposed change described in the amendment is not one of the types of
amendments described in paragraph (f)(1) of this section.
0
8. Amend Sec. 314.70 as follows:
0
a. Remove the word ``application'' and add in its place ``NDA''
wherever it appears in the paragraph (a) heading and paragraphs
(a)(1)(i) and (ii), (b)(2)(i) and (viii), (c)(6) introductory text,
(c)(7), (d)(2)(v) through (vii), (d)(3)(i), and (e);
0
b. Remove the words ``cover letter'' and add in their place the word
``submission'' in paragraph (a)(6);
0
c. Remove the words ``and its mailing cover'' in paragraph (b)(4);
0
d. Revise the section heading and paragraphs (a)(2) and (f); and
0
e. Add paragraph (h).
The revisions and addition read as follows:
Sec. 314.70 Supplements and other changes to an approved NDA.
(a) * * *
(2) The NDA holder must assess the effects of the change before
distributing a drug product made with a manufacturing change.
* * * * *
(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
paragraph (h), 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
[[Page 69649]]
demonstration of bioequivalence. However, notwithstanding the
limitation described in this paragraph (h), an applicant may supplement
the 505(b)(2) application to seek approval of a different strength.
0
9. Amend Sec. 314.90 by removing the word ``application'' and adding
in its place ``NDA'' wherever it appears and 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. Amend Sec. 314.93 as follows:
0
a. Remove the words ``abbreviated new drug applications'' and add in
their place ``ANDAs'' in paragraph (a);
0
b. Remove the words ``abbreviated new drug application'' and add in
their place ``ANDA'' wherever they appear in paragraphs (b), (c), and
(e)(3);
0
c. Remove the words ``abbreviated application'' and add in their place
``ANDA'' in paragraph (b);
0
d. Remove ``201(b)'' and add in its place ``201(p)'' in paragraph
(d)(3);
0
e. Remove the word ``act'' and add in its place ``Federal Food, Drug,
and Cosmetic Act'' in paragraphs (d)(3) and (e)(1)(iii)(C);
0
f. Remove the period at the end of paragraph (e)(1)(v) and add in its
place ``; or'';
0
g. Add paragraph (e)(1)(vi);
0
h. Redesignate paragraph (f) as paragraph (f)(1); and
0
i. Add paragraph (f)(2).
The revisions and additions 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. Amend Sec. 314.94 as follows:
0
a. Remove the words ``abbreviated application'' and add in their place
``ANDA'' wherever they appear in paragraphs (a)(1), (a)(5)(ii)(A),
(a)(6)(ii), (a)(9)(v), (a)(12)(i)(A)(4), (a)(13), (d)(1)(i), (d)(4),
and (d)(5);
0
b. Remove the words ``abbreviated new drug application'' and add in
their place ``ANDA'' wherever they appear in paragraph (a) introductory
text and paragraphs (a)(8)(i) and (b);
0
c. Remove the word ``shall'' and add in its place the word ``must''
wherever it appears in paragraph (a) introductory text and paragraphs
(a)(1), (a)(9)(ii) through (iv), (a)(12)(i)(A)(1) through (3), (a)(13),
(b), and (d)(5);
0
d. Remove the word ``act'' and add in its place ``Federal Food, Drug,
and Cosmetic Act'' wherever it appears in paragraphs (a)(5)(ii)(A),
(a)(7)(ii)(C), and (a)(8)(iv);
0
e. Remove ``Sec. 320.1(g) of this chapter'' and add in its place
``Sec. 314.3(b)'' in paragraph (a)(7)(i);
0
f. Remove and reserve paragraph (a)(12)(iv); and
0
g. Revise the section heading and the introductory text, paragraph (a)
heading, paragraph (a)(2), paragraph (a)(3), the first sentence of
paragraph (a)(7)(ii) introductory text, paragraphs (a)(7)(iii) and
(a)(9)(i), paragraph (a)(12)(i) heading, paragraph (a)(12)(i)(A)
introductory text, paragraphs (a)(12)(i)(A)(4), (a)(12)(i)(B),
(a)(12)(ii) and (iii), (a)(12)(iv) through (viii), paragraph (d)
heading, paragraph (d)(1) introductory text, and paragraph (d)(2).
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 ANDA are
required, an archival copy, a review copy, and a field copy. FDA will
maintain guidance documents on the format and content of ANDAs to
assist applicants in their preparation.
(a) ANDAs. * * *
* * * * *
(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 ANDA 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 and Sec. 314.93, the reference listed drug
must be the same as the listed drug referenced in the approved
petition.
(ii) A statement as to whether, according to the information
published in the list, the reference listed drug is entitled to a
period of marketing exclusivity under section 505(j)(5)(F) of the
Federal Food, Drug, and Cosmetic Act.
(iii) For an ANDA based on an approved petition under Sec. 10.30
of this chapter and 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, 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 the study 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.
* * * * *
(9) * * *
(i) The information required under Sec. 314.50(d)(1), except that
the information required under Sec. 314.50(d)(1)(ii)(c) must contain
the proposed or actual master production record, including a
description of the equipment, to be used for the manufacture of a
commercial lot of the drug product.
* * * * *
(12) Patent certification--(i) Patents claiming drug substance,
drug product,
[[Page 69650]]
or method of use. (A) An appropriate patent certification or statement
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)(i) 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 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 ANDA
is submitted.
(ii) 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 its
representative and to the NDA holder (or, if the NDA holder does not
reside or maintain a place of business within the United States, its
attorney, agent, or other authorized official) 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, an appropriate patent
certification or statement under paragraph (a)(12)(i) and/or (iii) of
this section with respect to each patent that claims the first-approved
patented drug or that claims a 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 (a)(12)(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 listed drug referred to in this
ANDA or that claim a use of the listed 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 an indication or other condition of
use that is covered by the method-of-use patent, a statement explaining
that the method-of-use patent does not claim a proposed indication or
other condition 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 method-of-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, the applicant must submit a paragraph
IV certification as to that patent and a statement that the applicant
has been granted a patent license. If the patent owner consents to
approval of the ANDA (if otherwise eligible for approval) as of a
specific date, the ANDA must contain a written statement from the
patent owner that it has a licensing agreement with the applicant and
that it consents to approval of the ANDA as of a specific date.
(vi) Untimely filing of patent information. (A) 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
or statement before the submission of the patent information is not
required to submit a patent certification or statement to address the
patent or patent information 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
unless:
(1) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of patent
issuance;
(2) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of approval of a
corresponding change to product labeling; or
(3) The amendment to the description of the approved method(s) of
use claimed by the patent is submitted within 30 days of a decision by
the U.S. Patent and Trademark Office or by a Federal district court,
the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court
that is specific to the patent and alters the construction of a method-
of-use claim(s) of the patent, and the amendment contains a copy of the
decision.
(B) 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 or statement at the time of the patent submission, must
submit a certification under paragraph (a)(12)(i) of this section and/
or a statement under paragraph (a)(12)(iii) of this section as to that
patent.
(vii) 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, the applicant must submit
an appropriate certification or statement for each listed patent.
(viii) Amended certifications. A patent certification or statement
submitted under paragraphs (a)(12)(i) through (iii) of this section may
be amended at any time before the 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.
(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
and enters 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
[[Page 69651]]
amendment, the applicant must certify under paragraph (a)(12)(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 (a)(12)(iii) of this section if the
applicant amends its ANDA such that the applicant is no longer seeking
approval for a method of use claimed by the patent. Once an amendment
for the change has been submitted, the ANDA will no longer be
considered to contain 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 or patent information 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 or patent information will be
removed and any applicant with a pending ANDA (including a tentatively
approved ANDA) 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 or statement (that the patent has been removed from the
list). If the list reflects that an NDA holder has requested that a
patent or patent information 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 will remain
listed until any 180-day exclusivity based on that patent has expired
or has been extinguished. After any applicable 180-day exclusivity has
expired or has been extinguished, the patent or patent information will
be removed and any applicant with a pending ANDA (including a
tentatively approved ANDA) 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 contain 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 relevant 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 or statement
if, at any time before the date of approval of the ANDA, the applicant
learns that the submitted certification or statement is no longer
accurate; and
(ii) An applicant must submit an appropriate patent certification
or statement under paragraph (a)(12)(i) and/or (iii) 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.
* * * * *
(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 (6) and (8) and
(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), (7), and (8) of this section. Each
of the sections in the review copy is required to contain a copy of the
application form described under paragraph (a) of this section.
* * * * *
0
12. Section 314.95 is revised to read as follows:
Sec. 314.95 Notice of certification of invalidity, unenforceability,
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 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 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
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 by sending a
written or electronic communication to the Orange Book Staff, Office of
Generic Drugs, 7620 Standish Pl., Rockville, MD 20855 or to the Orange
Book Staff at the email address listed on the Agency's Web site at
http://www.fda.gov.
(3) This paragraph (a) does not apply to a method-of-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 (b) 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
[[Page 69652]]
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, 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 (b) until it sends valid notice.
(3) 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 the notice 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 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 seeks to preserve the option to later 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 or 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 ANDA or in an amendment or
supplement to the ANDA.
(2) If, before receipt of 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 and the applicant has not submitted a previous paragraph
IV certification, 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 (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 (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
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) Forty-five day period after receipt of notice. 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 NDA holder or its attorney, agent, or other authorized
official 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.
(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 may periodically issue guidance regarding designated
delivery services.
0
13. Amend Sec. 314.96 as follows:
0
a. Revise the section heading;
0
b. Remove the words ``abbreviated new drug application'' and add in
their place ``ANDA'' in the paragraph (a) heading and the first two
sentences of paragraph (a)(1);
0
c. Remove ``320.1(g) of this chapter'' and add in its place ``314.3''
in paragraph (a)(1);
[[Page 69653]]
0
d. Remove the word ``shall'' and add in its place the word ``must''
wherever it appears and remove ``to Sec. 314.94(a)(9)'' and add in its
place ``under Sec. 314.94(a)(9)'' in paragraph (b);
0
e. Add a heading to paragraph (b); and
0
f. Add paragraphs (c) and (d).
The revisions and additions 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
(c) 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 (c) 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 (c), an applicant may amend the
ANDA to seek approval of a different strength.
(d)(1) Patent certification requirements. An amendment to an ANDA
is required to contain an appropriate patent certification or statement
described in Sec. 314.94(a)(12) or a recertification for a previously
submitted paragraph IV certification if approval is sought for any of
the following types of amendments:
(i) To add a new indication or other condition of use;
(ii) To add a new strength;
(iii) To make other than minor changes in product formulation; or
(iv) To change the physical form or crystalline structure of the
active ingredient.
(2) If the amendment to the ANDA does not contain a patent
certification or statement, the applicant must verify that the proposed
change described in the amendment is not one of the types of amendments
described in paragraph (d)(1) of this section.
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 ANDAs 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 (b) 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 (b), an applicant may supplement the ANDA to seek approval of
a different 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 apply, 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)(1) Receiving an ANDA. An ANDA will be evaluated 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
abbreviated application is substantially complete.
(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 FDA determines, upon
evaluation, that an ANDA was substantially complete as of the date it
was submitted to FDA, FDA will consider the ANDA to have been received
as of the date of submission. 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 of
the refuse-to-receive decision. The applicant may then:
(i) Withdraw the ANDA under Sec. 314.99; or
(ii) Correct the deficiencies and resubmit the ANDA; or
(iii) Take no action, in which case FDA may consider the ANDA
withdrawn after 1 year.
[[Page 69654]]
(c) [Reserved]
(d) NDA or ANDA 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. In determining whether an ANDA is incomplete on its face, FDA
will consider the nature (e.g., major or minor) of the deficiencies,
including the number of deficiencies in the ANDA.
(4) The applicant fails to submit a complete environmental
assessment, which 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 NDA or ANDA that is not in
English.
(6) The NDA or ANDA does not contain a statement for each
nonclinical laboratory study that the study 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 the study 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 is not
permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii),
505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the Federal
Food, Drug, and Cosmetic Act.
(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 (f) 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. 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 of this
chapter, 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) 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 there is a period of exclusivity for the
listed drug under section 505E 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 approval.
(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 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. 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
[[Page 69655]]
Federal Food, Drug, and Cosmetic Act and Sec. 316.31 of this chapter,
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; 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 there is a period of exclusivity for
the listed drug under section 505E 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 approval.
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 (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
on which a 505(b)(2) application or ANDA can be approved. The criteria
in paragraphs (b)(1) and (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 on which the 505(b)(2) application or
ANDA can be approved 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, as
applicable, for refusing to approve the 505(b)(2) application or ANDA
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, except that if the
applicant also submits a paragraph IV certification to the patent, then
the 505(b)(2) application or ANDA may be approved as provided in
paragraph (b)(1)(i)(C) of this section.
(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 (6) and Sec. 314.94(a)(12)(vi)
and (viii) regarding submission of an appropriate 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 listed drug approval.
(A) Except as provided in paragraphs (b)(3)(ii) through (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
(or its representative(s)) 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
of approval of the patented drug 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 the 7\1/2\ years from the date of approval of the NDA for
the patented drug product.
(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, unenforceable, 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
[[Page 69656]]
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, unenforceable, 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, unenforceable, 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:
(A) 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; or
(B) The patent is infringed, the 505(b)(2) application or ANDA may
be approved as provided in paragraph (b)(3)(iii) or (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(s) enter(s) an order of dismissal, with or
without prejudice, without a finding of infringement in each pending
suit for patent infringement brought within 45 days of receipt of the
notice of paragraph IV certification sent by the 505(b)(2) or ANDA
applicant, 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 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 NDA or ANDA
does not constitute ``approval'' of an NDA or ANDA and cannot, absent
an approval letter from the Agency, result in an approval under
paragraph (b)(3) of this section.
(c) Timing of approval of subsequent ANDA. (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) A first applicant must submit correspondence to its ANDA
notifying FDA within 30 days of the date of its first commercial
marketing of its drug product or the reference listed drug. If an
applicant does not notify FDA, as required in this paragraph (c)(2), of
this date, the date of first commercial marketing will be deemed to be
the date of the drug product's approval.
(3) If FDA concludes that a first applicant is not actively
pursuing approval of its ANDA, FDA may immediately approve an ANDA(s)
of a subsequent applicant(s) if the ANDA(s) is otherwise eligible for
approval.
(d) Delay due to exclusivity. The Agency will also delay the
approval of a 505(b)(2) application or ANDA if delay is required by the
exclusivity provisions in Sec. 314.108; section 527 of the Federal
Food, Drug, and Cosmetic Act and Sec. 316.31 of this chapter; section
505A of the Federal Food, Drug, and Cosmetic Act; or section 505E 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; section 527 of the Federal Food, Drug, and Cosmetic Act and
Sec. 316.31 of this chapter; section 505A of the Federal Food, Drug,
and Cosmetic Act; or section 505E 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;
section 527 of the Federal Food, Drug, and Cosmetic Act and Sec.
316.31 of this chapter; section 505A of the Federal Food, Drug, and
Cosmetic Act; or section 505E of the Federal Food, Drug, and Cosmetic
Act, as applicable.
(e) Notification of court actions or written consent to approval.
(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 as described in paragraph (b)(3)(i), (ii),
(vii), or (viii) of this section;
(iv) A copy of any written consent to approval by the patent owner
or exclusive patent licensee 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 applicant's NDA or ANDA, as appropriate, 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 written consent to
approval, as applicable.
[[Page 69657]]
(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 its NDA. An ANDA applicant must send the
notification to its ANDA. 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 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 its representative(s)) 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 its representative(s) does 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 its representative(s)) 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 its representative(s)) 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
NDA or ANDA. FDA will only accept a waiver in the following form:
(Name of patent owner or NDA holder who is an exclusive patent
licensee or its representative(s)) 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 elapse). (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. Amend Sec. 314.108 as follows:
0
a. In paragraph (a):
0
i. Revise the introductory text and the definitions of ``Approved under
section 505(b)'', ``Essential to approval'', and ``New chemical
entity'';
0
ii. Remove the definitions of ``Active moiety'', ``Date of approval'',
and ``FDA''; and
0
iii. Add in alphabetical order the definition of ``Bioavailability
study''; and
0
b. Revise the paragraph (b) heading and paragraphs (b)(2) through (5).
The revisions and addition read as follows:
Sec. 314.108 New drug product exclusivity.
(a) Definitions. The definitions in 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 timing of approval of a 505(b)(2) application
or ANDA. * * *
(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 (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 studies) conducted or sponsored by the
[[Page 69658]]
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 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. Amend Sec. 314.125 as follows:
0
a. Remove the word ``application'' and add in its place ``NDA''
wherever it appears in paragraphs (a) introductory text, (a)(2),
(b)(7), (9), (10), and (12), and (b)(14) through (18);
0
b. Remove the word ``act'' and add in its place ``Federal Food, Drug,
and Cosmetic Act'' in paragraphs (a) introductory text and (b)(2),
(11), and (18);
0
c. Revise the section heading and paragraph (b) introductory text; and
0
d. Add paragraph (b)(19).
The revisions and addition 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 a
drug product approved in an NDA that:
(i) Is pharmaceutically equivalent to the drug product for which
the original 505(b)(2) application is submitted; and
(ii) Was approved before the original 505(b)(2) application was
submitted.
* * * * *
0
21. Amend Sec. 314.127 as follows:
0
a. Remove the words ``abbreviated application'' and ``abbreviated new
drug application'' wherever they appear and add in their place ``ANDA''
in paragraphs (a) introductory text, (a)(3) through (7), (a)(8)(ii)(A)
introductory text, (a)(9) and (10), and (b);
0
b. Remove the word ``act'' wherever it appears and add in its place
``Federal Food, Drug, and Cosmetic Act'' in paragraphs
(a)(3)(iii)(A)(2) and (a)(12);
0
c. Remove ``officer of employee'' and add in its place ``officer or
employee'' in paragraph (b);
0
d. Revise the section heading and paragraphs (a) introductory text,
(a)(2), (a)(8)(i) introductory text, and (a)(8)(ii)(B) and (C); and
0
e. Add paragraph (a)(14).
The revisions and addition 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:
* * * * *
(2) Information submitted with the ANDA is insufficient to show
that each of the proposed conditions of use has been previously
approved for the listed drug referred to in the ANDA.
* * * * *
(8)(i) Information submitted in the ANDA or any other information
available to FDA shows that:
* * * * *
(ii) * * *
(B) FDA will consider an inactive ingredient in, or the composition
of, a drug product intended for parenteral use to be unsafe and will
refuse to approve the ANDA unless it contains the same inactive
ingredients, other than preservatives, buffers, and antioxidants, in
the same concentration as the listed drug, and, if it differs from the
listed drug in a preservative, buffer, or antioxidant, the ANDA
contains sufficient information to demonstrate that the difference does
not affect the safety or efficacy of the drug product.
(C) FDA will consider an inactive ingredient in, or the composition
of, a drug product intended for ophthalmic or otic use unsafe and will
refuse to approve the ANDA unless it contains the same inactive
ingredients, other than preservatives, buffers, substances to adjust
tonicity, or thickening agents, in the same concentration as the listed
drug, and if it differs from the listed drug in a preservative, buffer,
substance to adjust tonicity, or thickening agent, the ANDA contains
sufficient information to demonstrate that the difference does not
affect the safety or efficacy of the drug product and the labeling does
not claim any therapeutic advantage over or difference from the listed
drug.
* * * * *
(14) For an ANDA submitted pursuant to an approved petition under
Sec. 10.30 of this chapter and Sec. 314.93, an NDA subsequently has
been approved for the change described in the approved 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. Amend Sec. 320.23 as follows:
0
a. Revise the last sentence in paragraph (a)(1);
0
b. Remove the word ``shall'' and add in its place the word ``must'' in
paragraph (a)(2);
0
c. Redesignate paragraph (b) as paragraph (b)(1); and
0
d. Add paragraph (b)(2).
The revisions and additions 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: September 15, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-22690 Filed 10-5-16; 8:45 am]
BILLING CODE 4164-01-P