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CFR 314.94(a)(12)(i)(A)(4)

[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.