[Code of Federal Regulations]
[Title 21, Volume 5, Parts 300 to 499]
[Revised as of April 1, 1999]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR314.94]
[Page 130-136]
TITLE 21--FOOD AND DRUGS
DEPARTMENT OF HEALTH AND HUMAN SERVICES--Continued
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG--Table of Contents
Subpart C--Abbreviated Applications
Sec. 314.94 Content and format of an abbreviated application.
Abbreviated applications are required to be submitted in the form
and contain the information required under this section. Three copies of
the application are required, an archival copy, a review copy, and a
field copy. FDA will maintain guidelines on the format and content of
applications to assist applicants in their preparation.
(a) Abbreviated new drug applications. Except as provided in
paragraph (b) of this section, the applicant shall submit a complete
archival copy of the abbreviated new drug application that includes the
following:
(1) Application form. The applicant shall submit a completed and
signed application form that contains the information described under
Sec. 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant shall state
whether the submission is an abbreviated application under this section
or a supplement to an abbreviated application under Sec. 314.97.
(2) Table of contents. the archival copy of the abbreviated new drug
application 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 abbreviated new drug application submission. An
abbreviated new drug application must refer to a listed drug.
Ordinarily, that listed drug will be the drug product selected by the
agency as the reference standard for conducting bioequivalence testing.
The application shall contain:
(i) The name of the reference listed drug, including its dosage form
and strength. For an abbreviated new drug application based on an
approverd petition under Sec. 10.30 of this chapter or Sec. 314.93, the
reference listed drug must be the same as the listed drug approved in
the petition.
(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)(4)(D) of the act.
(iii) For an abbreviated new drug application based on an approved
petition under Sec. 10.30 of this chapter or Sec. 314.93, a reference to
FDA-assigned docket number for the petition and a copy of FDA's
correspondence approving the petition.
(4) Conditions of use. (i) A statement that the conditions of use
prescribed, recommended, or suggested in the labeling proposed for the
drug product have been previously approved for the reference listed
drug.
(ii) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(5) Active ingredients. (i) For a single-active-ingredient drug
product, information to show that the active ingredient is the same as
that of the reference single-active-ingredient listed drug, as follows:
(A) A statement that the active ingredient of the proposed drug
product is the same as that of the reference listed drug.
(B) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(ii) For a combination drug product, information to show that the
active ingredients are the same as those of the reference listed drug
except for any different active ingredient that has been the subject of
an approved petition, as follows:
(A) A statement that the active ingredients of the proposed drug
product are the same as those of the reference listed drug, or if one of
the active ingredients differs from one of the active ingredients of the
reference listed drug and the abbreviated application is submitted under
the approval of a petition under Sec. 314.93 to vary such active
ingredient, information to show that the other active ingredients of the
drug product are the same as the other active ingredients of the
reference listed
[[Page 131]]
drug, information to show that the different active ingredient is an
active ingredient of another listed drug or of a drug that does not meet
the definition of ``new drug'' in section 201(p) of the act, and such
other information about the different active ingredient that FDA may
require.
(B) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(6) Route of administration, dosage form, and strength. (i)
Information to show that the route of administration, dosage form, and
strength of the drug product are the same as those of the reference
listed drug except for any differences that have been the subject of an
approved petition, as follows:
(A) A statement that the route of administration, dosage form, and
strength of the proposed drug product are the same as those of the
reference listed drug.
(B) A reference to the applicant's annotated proposed labeling and
to the currently approved labeling for the reference listed drug
provided under paragraph (a)(8) of this section.
(ii) If the route of administration, dosage form, or strength of the
drug product differs from the reference listed drug and the abbreviated
application is submitted under an approved petition under Sec. 314.93,
such information about the different route of administration, dosage
form, or strength that FDA may require.
(7) Bioequivalence. (i) Information that shows that the drug product
is bioequivalent to the reference listed drug upon which the applicant
relies; or
(ii) If the abbreviated new drug application is submitted under a
petition approved under Sec. 314.93, the results of any bioavailability
of 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. If the proposed drug product
contains a different active ingredient than the reference listed drug,
FDA will consider the proposed drug product to have the same therapeutic
effect as the reference listed drug if the applicant provides
information demonstrating that:
(A) There is an adequate scientific basis for determining that
substitution of the specific proposed dose of the different active
ingredient for the dose of the member of the same pharmacological or
therapeutic class in the reference listed drug will yield a resulting
drug product whose safety and effectiveness have not been adversely
affected.
(B) The unchanged active ingredients in the proposed drug product
are bioequivalent to those in the reference listed drug.
(C) The different active ingredient in the proposed drug product is
bioequivalent to an approved dosage form containing that ingredient and
approved for the same indication as the proposed drug product or is
bioequivalent to a drug product offered for that indication which does
not meet the definition of ``new drug'' under section 201(p) of the act.
(iii) For each in vivo bioequivalence study contained in the
abbreviated new drug application, a description of the analytical and
statistical methods used in each study and a statement with respect to
each study that it either was conducted in compliance with the
institutional review board regulations in part 56 of this chapter, or
was not subject to the regulations under Sec. 56.104 or Sec. 56.105 of
this chapter and that each study was conducted in compliance with the
informed consent regulations in part 50 of this chapter.
(8) Labeling--(i) Listed drug labeling. A copy of the currently
approved labeling (including, if applicable, any Medication Guide
required under part 208 of this chapter) for the listed drug referred to
in the abbreviated new drug application, if the abbreviated new drug
application relies on a reference listed drug.
(ii) Copies of proposed labeling. Copies of the label and all
labeling for the drug product including, if applicable, any Medication
Guide required under part 208 of this chapter (4 copies of
[[Page 132]]
draft labeling or 12 copies of final printed labeling).
(iii) Statement on proposed labeling. A statement that the
applicant's proposed labeling including, if applicable, any Medication
Guide required under part 208 of this chapter is the same as the
labeling of the reference listed drug except for differences annotated
and explained under paragraph (a)(8)(iv) of this section.
(iv) Comparison of approved and proposed labeling. A side-by-side
comparison of the applicant's proposed labeling including, if
applicable, any Medication Guide required under part 208 of this chapter
with the approved labeling for the reference listed drug with all
differences annotated and explained. Labeling (including the container
label, package insert, and, if applicable, Medication Guide) proposed
for the drug product must be the same as the labeling approved for the
reference listed drug, except for changes required because of
differences approved under a petition filed under Sec. 314.93 or because
the drug product and the reference listed drug are produced or
distributed by different manufacturers. Such differences between the
applicant's proposed labeling and labeling approved for the reference
listed drug may include differences in expiration date, formulation,
bioavailability, or pharmacokinetics, labeling revisions made to comply
with current FDA labeling guidelines or other guidance, or omission of
an indication or other aspect of labeling protected by patent or
accorded exclusivity under section 505(j)(4)(D) of the act.
(9) Chemistry, manufacturing, and controls. (i) The information
required under Sec. 314.50(d)(1), except that Sec. 314.50(d)(1)(ii)(c)
shall 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.
(ii) Inactive ingredients. Unless otherwise stated in paragraphs
(a)(9)(iii) through (a)(9)(v) of this section, an applicant shall
identify and characterize the inactive ingredients in the proposed drug
product and provide information demonstrating that such inactive
ingredients do not affect the safety of the proposed drug product.
(iii) Inactive ingredient changes permitted in drug products
intended for parenteral use. Generally, a drug product intended for
parenteral use shall contain the same inactive ingredients and in the
same concentration as the reference listed drug identified by the
applicant under paragraph (a)(3) of this section. However, an applicant
may seek approval of a drug product that differs from the reference
listed drug in preservative, buffer, or antioxidant provided that the
applicant identifies and characterizes the differences and provides
information demonstrating that the differences do not affect the safety
of the proposed drug product.
(iv) Inactive ingredient changes permitted in drug products intended
for ophthalmic or otic use. Generally, a drug product intended for
ophthalmic or otic use shall contain the same inactive ingredients and
in the same concentration as the reference listed drug identified by the
applicant under paragraph (a)(3) of this section. However, an applicant
may seek approval of a drug product that differs from the reference
listed drug in preservative, buffer, substance to adjust tonicity, or
thickening agent provided that the applicant identifies and
characterizes the differences and provides information demonstrating
that the differences do not affect the safety of the proposed drug
product, except that, in a product intended for ophthalmic use, an
applicant may not change a buffer or substance to adjust tonicity for
the purpose of claiming a therapeutic advantage over or difference from
the listed drug, e.g., by using a balanced salt solution as a diluent as
opposed to an isotonic saline solution, or by making a significant
change in the pH or other change that may raise questions of
irritability.
(v) Inactive ingredient changes permitted in drug products intended
for topical use. Generally, a drug product intended for topical use
shall contain the same inactive ingredients as the reference listed drug
identified by the applicant under paragraph (a)(3) of this section.
However, an applicant may seek approval of a drug product that differs
from the reference listed drug
[[Page 133]]
provided that the applicant identifies and characterizes the differences
and provides information demonstrating that the differences do not
affect the safety of the proposed drug product.
(10) Samples. The information required under Sec. 314.50(e)(1) and
(e)(2)(i). Samples need not be submitted until requested by FDA.
(11) Other. The information required under Sec. 314.50(g).
(12) Patent certification--(i) Patents claiming drug, drug product,
or method of use. (A) Except as provided in paragraph (a)(12)(iv) of
this section, a certification with respect to each patent issued by the
United States 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 act and for which
information is required to be filed under section 505(b) and (c) of the
act and Sec. 314.53. For each such patent, the applicant shall 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 shall entitle such a certification ``Paragraph I
Certification'';
(2) That the patent has expired. The applicant shall entitle such a
certification ``Paragraph II Certification'';
(3) The date on which the patent will expire. The applicant shall
entitle such a certification ``Paragraph III Certification''; or
(4) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for which
the abbreviated application is submitted. The applicant shall entitle
such a certification ``Paragraph IV Certification''. This certification
shall be submitted in the following form:
I, (name of applicant), certify that Patent No. ____________ (is
invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of) (name of proposed drug product) for which this
application is submitted.
The certification shall be accompanied by a statement that the applicant
will comply with the requirements under Sec. 314.95(a) with respect to
providing a notice to each owner of the patent or their representatives
and to the holder of the approved application for the listed drug, and
with the requirements under Sec. 314.95(c) with respect to the content
of the notice.
(B) If the abbreviated new drug application refers to a listed drug
that is itself a licensed generic product of a patented drug first
approved under section 505(b) of the act, the appropriate patent
certification under paragraph (a)(12)(i) of this section with respect to
each patent that claims the first-approved patented drug or that claims
a use for such drug.
(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
application 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 act and Sec. 314.53 for a patent
claiming a method of using the listed drug, and the labeling for the
drug product for which the applicant is seeking approval does not
include any indications that are covered by the use patent, a statement
explaining that the method of use patent does not claim any of the
proposed indications.
(B) If the labeling of the drug product for which the applicant is
seeking approval includes an indication that, according to the patent
information submitted under section 505(b) or (c) of the act and
Sec. 314.53 or in the opinion of the applicant, is claimed by a use
patent, an applicable certification under paragraph (a)(12)(i) of this
section.
(iv) Method of manufacturing patent. An applicant is not required to
make a certification with respect to any patent that claims only a
method of manufacturing the listed drug.
(v) Licensing agreements. If the abbreviated new drug application is
for a drug or method of using a drug claimed by a patent and the
applicant has a licensing agreement with the patent owner, a
certification under paragraph
[[Page 134]]
(a)(12)(i)(A)(4) of this section (``Paragraph IV Certification'') as to
that patent and a statement that it has been granted a patent license.
(vi) Late submission of patent information. If a patent on the
listed drug is issued and the holder of the approved application for the
listed drug does not submit the required information on the patent
within 30 days of issuance of the patent, an applicant who submitted an
abbreviated new drug application for that drug that contained an
appropriate patent certification before the submission of the patent
information is not required to submit an amended certification. An
applicant whose abbreviated new drug application is submitted after a
late submission of patent information, or whose pending abbreviated
application was previously submitted but did not contain an appropriate
patent certification at the time of the patent submission, shall submit
a certification under paragraph (a)(12)(i) of this section or a
statement under paragraph (a)(12)(iii) of this section as to that
patent.
(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 or changed, the applicant
shall submit an appropriate certification for each relevant patent.
(viii) Amended certifications. A certification submitted under
paragraphs (a)(12)(i) through (a)(12)(iii) of this section may be
amended at any time before the effective date of the approval of the
application. However, an applicant who has submitted a paragraph IV
patent certification may not change it to a paragraph III certification
if a patent infringement suit has been filed against another paragraph
IV applicant unless the agency has determined that no applicant is
entitled to 180-day exclusivity or the patent expires before the lawsuit
is resolved or expires after the suit is resolved but before the end of
the 180-day exclusivity period. If an applicant with a pending
application voluntarily makes a patent certification for an untimely
filed patent, the applicant may withdraw the patent certification for
the untimely filed patent. An applicant shall submit an amended
certification by letter or as an amendment to a pending application or
by letter to an approved application. Once an amendment or letter is
submitted, the application will no longer be considered to contain the
prior certification.
(A) After finding of infringement. An applicant who has submitted a
certification under paragraph (a)(12)(i)(A)(4) of this section and is
sued for patent infringement within 45 days of the receipt of notice
sent under Sec. 314.95 shall amend the certification if a final judgment
in the action against the applicant is entered finding the patent to be
infringed. In the amended certification, the applicant shall certify
under paragraph (a)(12)(i)(A)(3) of this section that the patent will
expire on a specific date. Once an amendment or letter for the change
has been submitted, the application will no longer be considered to be
one containing a certification under paragraph (a)(12)(i)(A)(4) of this
section. If a final judgment finds the patent to be invalid and
infringed, an amended certification is not required.
(B) After removal of a patent from the list. If a patent is removed
from the list, any applicant with a pending application (including a
tentatively approved application with a delayed effective date) who has
made a certification with respect to such patent shall amend its
certification. The applicant shall certify under paragraph (a)(12)(ii)
of this section that no patents described in paragraph (a)(12)(i) of
this section claim the drug or, if other relevant patents claim the
drug, shall amend the certification to refer only to those relevant
patents. In the amendment, the applicant shall state the reason for the
change in certification (that the patent is or has been removed from the
list). A patent that is the subject of a lawsuit under Sec. 314.107(c)
shall not be removed from the list until FDA determines either that no
delay in effective dates of approval is required under that section as a
result of the lawsuit, that the patent has expired, or
[[Page 135]]
that any such period of delay in effective dates of approval is ended.
An applicant shall submit an amended certification. Once an amendment or
letter for the change has been submitted, the application will no longer
be considered to be one containing a certification under paragraph
(a)(12)(i)(A)(4) of this section.
(C) Other amendments. (1) Except as provided in paragraphs
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section, an applicant shall
amend a submitted certification if, at any time before the effective
date of the approval of the application, the applicant learns that the
submitted certification is no longer accurate.
(2) An applicant is not required to amend a submitted certification
when information on a patent on the listed drug is submitted after the
effective date of approval of the abbreviated application.
(13) Financial certification or disclosure statement. An abbreviated
application shall contain a financial certification or disclosure
statement as required by part 54 of this chapter.
(b) Drug products subject to the Drug Efficacy Study Implementation
(DESI) review. If the abbreviated new drug application is for a
duplicate of a drug product that is subject to FDA's DESI review (a
review of drug products approved as safe between 1938 and 1962) or other
DESI-like review and the drug product evaluated in the review is a
listed drug, the applicant shall comply with the provisions of paragraph
(a) of this section.
(c) Abbreviated antibiotic application. For applications submitted
under section 507 of the act, the applicant shall submit a complete
archival copy of the abbreviated application that contains the
information described under Sec. 314.50 (a)(1), (a)(3), (a)(4), and
(a)(5), (b), (d)(1) and (d)(3), (e), and (g). The applicant shall state
whether the submission is an abbreviated application under this section
or a supplement to an abbreviated application under Sec. 314.97.
(d) Format of an abbreviated application. (1) The applicant shall
submit a complete archival copy of the abbreviated application as
required under paragraphs (a) and (c) of this section. FDA will maintain
the archival copy during the review of the application to permit
individual reviewers to refer to information that is not contained in
their particular technical sections of the application, to give other
agency personnel access to the application for official business, and to
maintain in one place a complete copy of the application. An applicant
may submit all or portions of the archival copy of the abbreviated
application in any form (e.g., microfiche, optical disc, and magnetic
tape) that the applicant and FDA agree is acceptable.
(2) For abbreviated new drug applications, the applicant shall
submit a review copy of the abbreviated application that contains two
separate sections. One section shall contain the information described
under paragraphs (a)(2) through (a)(6), (a)(8), and (a)(9) of this
section 505(j)(2)(A)(vii) of the act and one copy of the analytical
methods 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 methods. The other section shall contain the
information described under paragraphs (a)(3), (a)(7), and (a)(8) of
this section. Each of the sections in the review copy is required to
contain a copy of the application form described under Sec. 314.50(a).
(3) For abbreviated antibiotic applications, the applicant shall
submit a review copy that contains the technical sections described in
Sec. 314.50 (d)(1) and (d)(3). Each of the technical sections in the
review copy is required to be separate with a copy of the application
form required under Sec. 314.50(a).
(4) The applicant may obtain from FDA sufficient folders to bind the
archival, the review, and the field copies of the abbreviated
application.
(5) The applicant shall submit a field copy of the abbreviated
application that contains the technical section described in paragraph
(a)(9) of this section, a copy of the application form required under
paragraph (a)(1) of this section, and a certification that the field
copy is a true copy of the technical section described in paragraph
(a)(9) of this section contained in the
[[Page 136]]
archival and review copies of the abbreviated application.
[57 FR 17983, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58
FR 47352, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. 2,
1998; 63 FR 66399, Dec. 1, 1998]
Effective Date Note: 1. At 63 FR 66399, Dec. 1, 1998, Sec. 314.94
was amended by revising paragraph (a)(8), effective June 1, 1999. For
the convenience of the user, the superseded text follows:
Sec. 314.94 Content and format of an abbreviated application.
* * * * *
(a) * * *
(8) Labeling--(i) Listed drug labeling. A copy of the currently
approved labeling for the listed drug referred to in the abbreviated new
drug application, if the abbreviated new drug application relies on a
reference listed drug.
(ii) Proposed labeling. Copies of the label and all labeling for the
drug product (4 copies of draft labeling or 12 copies of final printed
labeling).
(iii) A statement that the applicant's proposed labeling is the same
as the labeling of the reference listed drug except for differences
annotated and explained under paragraph (a)(8)(iv) of this section.
(iv) A side-by-side comparison of the applicant's proposed labeling
with the approved labeling for the reference listed drug with all
differences annotated and explained. Labeling (including the container
label and package insert) proposed for the drug product must be the same
as the labeling approved for the reference listed drug, except for
changes required because of differences approved under a petition filed
under Sec. 314.93 or because the drug product and the reference listed
drug are produced or distributed by different manufacturers. Such
differences between the applicant's proposed labeling and labeling
approved for the reference listed drug may include differences in
expiration date, formulation, bioavailability, or pharmacokinetics,
labeling revisions made to comply with current FDA labeling guidelines
or other guidance, or omission of an indication or other aspect of
labeling protected by patent or accorded exclusivity under section
505(j)(4)(D) of the act.
* * * * *
Effective Date Note: 2. At 64 FR 401, Jan. 5, 1999, Sec. 314.94 was
amended by removing and reserving paragraphs (c) and paragraph (d)(3),
effective May 20, 1999.