[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: 21CFR314.50]
[Page 99-110]
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 B--Applications
Sec. 314.50 Content and format of an application.
Applications and supplements to approved applications 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 application are required: An archival copy, a review copy, and a
field copy. An application 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 applications will
generally contain only some of those items, and information will be
limited to that needed to support the particular submission. These
include an application of the type described in section 505(b)(2) of the
act, an amendment, and a supplement. The application 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 application that is received or otherwise obtained by
the applicant from any source. FDA will maintain guidelines on the
format and content of applications to assist applicants in their
preparation.
(a) Application form. The applicant shall submit a completed and
signed application form that contains the following:
(1) The name and address of the applicant; the date of the
application; the application number if previously issued
[[Page 100]]
(for example, if the application is a resubmission, an amendment, or a
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
investigational new drug applications that are referenced in the
application; the identification numbers of all drug master files and
other applications under this part that are referenced in the
application; and the drug product's proposed indications for use.
(2) A statement whether the submission is an original submission, a
505(b)(2) application, a resubmission, or a supplement to an application
under Sec. 314.70.
(3) A statement whether the applicant proposes to market the drug
product as a prescription or an over-the-counter product.
(4) A check-list identifying what enclosures required under this
section the applicant is submitting.
(5) The applicant, or the applicant's attorney, agent, or other
authorized official shall sign the application. If the person signing
the application does not reside or have a place of business within the
United States, the application is required to contain the name and
address of, and be countersigned by, an attorney, agent, or other
authorized official who resides or maintains a place of business within
the United States.
(b) Index. The archival copy of the application is required to
contain a comprehensive index by volume number and page number to the
summary under paragraph (c) of this section, the technical sections
under paragraph (d) of this section, and the supporting information
under paragraph (f) of this section.
(c) Summary. (1) An application is required to contain a summary of
the application in enough detail that the reader may gain a good general
understanding of the data and information in the application, including
an understanding of the quantitative aspects of the data. The summary is
not required for supplements under Sec. 314.70. Resubmissions of an
application should contain an updated summary, as appropriate. The
summary should discuss all aspects of the application, and synthesize
the information into a well-structured and unified document. The summary
should be written at approximately the level of detail required for
publication in, and meet the editorial standards generally applied by,
refereed scientific and medical journals. In addition to the agency
personnel reviewing the summary in the context of their review of the
application, FDA may furnish the summary to FDA advisory committee
members and agency officials whose duties require an understanding of
the application. To the extent possible, data in the summary should be
presented in tabular and graphic forms. FDA has prepared a guideline
under Sec. 10.90(b) that provides information about how to prepare a
summary. The summary required under this paragraph may be used by FDA or
the applicant to prepare the Summary Basis of Approval document for
public disclosure (under Sec. 314.430(e)(2)(ii)) when the application is
approved.
(2) The summary is required to contain the following information:
(i) The proposed text of the labeling, including, if applicable, any
Medication Guide required under part 208 of this chapter, for the drug,
with annotations to the information in the summary and technical
sections of the application that support the inclusion of each statement
in the labeling, and, if the application is for a prescription drug,
statements describing the reasons for omitting a section or subsection
of the labeling format in Sec. 201.57 of this chapter.
(ii) A statement identifying the pharmacologic class of the drug and
a discussion of the scientific rationale for the drug, its intended use,
and the potential clinical benefits of the drug product.
(iii) A brief description of the marketing history, if any, of the
drug outside the United States, including a list of the countries in
which the drug has been marketed, a list of any countries in which the
drug has been withdrawn from marketing for any reason related to safety
or effectiveness, and a list of countries in which applications for
[[Page 101]]
marketing are pending. The description is required to describe both
marketing by the applicant and, if known, the marketing history of other
persons.
(iv) A summary of the chemistry, manufacturing, and controls section
of the application.
(v) A summary of the nonclinical pharmacology and toxicology section
of the application.
(vi) A summary of the human pharmacokinetics and bioavailability
section of the application.
(vii) A summary of the microbiology section of the application (for
anti-infective drugs only).
(viii) A summary of the clinical data section of the application,
including the results of statistical analyses of the clinical trials.
(ix) A concluding discussion that presents the benefit and risk
considerations related to the drug, including a discussion of any
proposed additional studies or surveillance the applicant intends to
conduct postmarketing.
(d) Technical sections. The application is required to contain the
technical sections described below. Each technical section is required
to contain data and information in sufficient detail to permit the
agency to make a knowledgeable judgment about whether to approve the
application or whether grounds exist under section 505(d) of the act to
refuse to approve the application. The required technical sections are
as follows:
(1) Chemistry, manufacturing, and controls section. A section
describing the composition, manufacture, and specification of the drug
substance and the drug product, including the following:
(i) Drug substance. A full description of the drug substance
including its physical and chemical characteristics and stability; the
name and address of its manufacturer; 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 drug substance and the bioavailability of the
drug products made from the substance, including, for example,
specifications relating to stability, sterility, particle size, and
crystalline form. The application may provide additionally for the use
of alternatives to meet any of these requirements, including alternative
sources, process controls, methods, and specifications. Reference to the
current edition of the U.S. Pharmacopeia and the National Formulary may
satisfy relevant requirements in this paragraph.
(ii)(a) Drug product. A list of all components used in the
manufacture of the drug product (regardless of whether they appear in
the drug product); and a statement of the composition of the drug
product; a statement of the specifications and analytical methods for
each component; the name and address of each manufacturer the drug
product; 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, for
example, specifications relating to sterility, dissolution rate,
containers and closure systems; and stability data with proposed
expiration dating. The application may provide additionally for the use
of alternatives to meet any of these requirements, including alternative
components, manufacturing and packaging procedures, in-process controls,
methods, and specifications. Reference to the current edition of the
U.S. Pharmacopeia and the National Formulary may satisfy relevant
requirements in this paragraph.
(b) Unless provided by paragraph (d)(1)(ii)(a) of this section, for
each batch of the drug product used to conduct a bioavailability or
bioequivalence study described in Sec. 320.38 or Sec. 320.63 of this
chapter or used to conduct a primary stability study: The batch
production record; the specifications and test procedures for each
component and for the drug product; the names and addresses of the
sources of the active and noncompendial inactive components and of the
container and closure system for the drug product; the name and address
of each contract facility involved in the manufacture, processing,
packaging, or testing of the drug product and identification of the
[[Page 102]]
operation performed by each contract facility; and the results of any
test performed on the components used in the manufacture of the drug
product as required by Sec. 211.84(d) of this chapter and on the drug
product as required by Sec. 211.165 of this chapter.
(c) 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 or a comparably detailed description
of the production process for a representative batch of the drug
product.
(iii) Environmental impact. The application is required to contain
either a claim for categorical exclusion under Sec. 25.30 or 25.31 of
this chapter or an environmental assessment under Sec. 25.40 of this
chapter.
(iv) The applicant may, at its option, submit a complete chemistry,
manufacturing, and controls section 90 to 120 days before the
anticipated submission of the remainder of the application. FDA will
review such early submissions as resources permit.
(v) Except for a foreign applicant, the applicant shall include a
statement certifying that the field copy of the application has been
provided to the applicant's home FDA district office.
(2) Nonclinical pharmacology and toxicology section. A section
describing, with the aid of graphs and tables, animal and in vitro
studies with drug, including the following:
(i) Studies of the pharmacological actions of the drug in relation
to its proposed therapeutic indication and studies that otherwise define
the pharmacologic properties of the drug or are pertinent to possible
adverse effects.
(ii) Studies of the toxicological effects of the drug as they relate
to the drug's intended clinical uses, including, as appropriate, studies
assessing the drug's acute, subacute, and chronic toxicity;
carcinogenicity; and studies of toxicities related to the drug's
particular mode of administration or conditions of use.
(iii) Studies, as appropriate, of the effects of the drug on
reproduction and on the developing fetus.
(iv) Any studies of the absorption, distribution, metabolism, and
excretion of the drug in animals.
(v) For each nonclinical laboratory study subject to the good
laboratory practice regulations under part 58 a statement that it was
conducted in compliance with the good laboratory practice regulations in
part 58, or, if the study was not conducted in compliance with those
regulations, a brief statement of the reason for the noncompliance.
(3) Human pharmacokinetics and bioavailability section. A section
describing the human pharmacokinetic data and human bioavailability
data, or information supporting a waiver of the submission of in vivo
bioavailability data under subpart B of part 320, including the
following:
(i) A description of each of the bioavailability and pharmacokinetic
studies of the drug in humans performed by or on behalf of the applicant
that includes 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, or was not subject to the regulations under
Sec. 56.104 or Sec. 56.105, and that it was conducted in compliance with
the informed consent regulations in part 50.
(ii) If the application describes in the chemistry, manufacturing,
and controls section specifications or analytical methods needed to
assure the bioavailability of the drug product or drug substance, or
both, a statement in this section of the rationale for establishing the
specification or analytical methods, including data and information
supporting the rationale.
(iii) A summarizing discussion and analysis of the pharmacokinetics
and metabolism of the active ingredients and the bioavailability or
bioequivalence, or both, of the drug product.
(4) Microbiology section. If the drug is an anti-infective drug, a
section describing the microbiology data, including the following:
(i) A description of the biochemical basis of the drug's action on
microbial physiology.
[[Page 103]]
(ii) A description of the antimicrobial spectra of the drug,
including results of in vitro preclinical studies to demonstrate
concentrations of the drug required for effective use.
(iii) A description of any known mechanisms of resistance to the
drug, including results of any known epidemiologic studies to
demonstrate prevalence of resistance factors.
(iv) A description of clinical microbiology laboratory methods (for
example, in vitro sensitivity discs) needed for effective use of the
drug.
(5) Clinical data section. A section describing the clinical
investigations of the drug, including the following:
(i) A description and analysis of each clinical pharmacology study
of the drug, including a brief comparison of the results of the human
studies with the animal pharmacology and toxicology data.
(ii) A description and analysis of each controlled clinical study
pertinent to a proposed use of the drug, including the protocol and a
description of the statistical analyses used to evaluate the study. If
the study report is an interim analysis, this is to be noted and a
projected completion date provided. Controlled clinical studies that
have not been analyzed in detail for any reason (e.g., because they have
been discontinued or are incomplete) are to be included in this section,
including a copy of the protocol and a brief description of the results
and status of the study.
(iii) A description of each uncontrolled clinical study, a summary
of the results, and a brief statement explaining why the study is
classified as uncontrolled.
(iv) A description and analysis of any other data or information
relevant to an evaluation of the safety and effectiveness of the drug
product obtained or otherwise received by the applicant from any source,
foreign or domestic, including information derived from clinical
investigations, including controlled and uncontrolled studies of uses of
the drug other than those proposed in the application, commercial
marketing experience, reports in the scientific literature, and
unpublished scientific papers.
(v) An integrated summary of the data demonstrating substantial
evidence of effectiveness for the claimed indications. Evidence is also
required to support the dosage and administration section of the
labeling, including support for the dosage and dose interval
recommended. The effectiveness data shall be presented by gender, age,
and racial subgroups and shall identify any modifications of dose or
dose interval needed for specific subgroups. Effectiveness data from
other subgroups of the population of patients treated, when appropriate,
such as patients with renal failure or patients with different levels of
severity of the disease, also shall be presented.
(vi) A summary and updates of safety information, as follows:
(a) The applicant shall submit an integrated summary of all
available information about the safety of the drug product, including
pertinent animal data, demonstrated or potential adverse effects of the
drug, clinically significant drug/drug interactions, and other safety
considerations, such as data from epidemiological studies of related
drugs. The safety data shall be presented by gender, age, and racial
subgroups. When appropriate, safety data from other subgroups of the
population of patients treated also shall be presented, such as for
patients with renal failure or patients with different levels of
severity of the disease. A description of any statistical analyses
performed in analyzing safety data should also be included, unless
already included under paragraph (d)(5)(ii) of this section.
(b) The applicant shall, under section 505(i) of the act, update
periodically its pending application with new safety information learned
about the drug that may reasonably affect the statement of
contraindications, warnings, precautions, and adverse reactions in the
draft labeling and, if applicable, any Medication Guide required under
part 208 of this chapter. These ``safety update reports'' are required
to include the same kinds of information (from clinical studies, animal
studies, and other sources) and are required to be submitted in the same
format as the integrated summary in paragraph (d)(5)(vi)(a) of this
section. In addition, the reports are required to include the case
report forms for each patient who
[[Page 104]]
died during a clinical study or who did not complete the study because
of an adverse event (unless this requirement is waived). The applicant
shall submit these reports (1) 4 months after the initial submission;
(2) following receipt of an approvable letter; and (3) at other times as
requested by FDA. Prior to the submission of the first such report,
applicants are encouraged to consult with FDA regarding further details
on its form and content.
(vii) If the drug has a potential for abuse, a description and
analysis of studies or information related to abuse of the drug,
including a proposal for scheduling under the Controlled Substances Act.
A description of any studies related to overdosage is also required,
including information on dialysis, antidotes, or other treatments, if
known.
(viii) An integrated summary of the benefits and risks of the drug,
including a discussion of why the benefits exceed the risks under the
conditions stated in the labeling.
(ix) A statement with respect to each clinical study involving human
subjects that it either was conducted in compliance with the
institutional review board regulations in part 56, or was not subject to
the regulations under Sec. 56.104 or Sec. 56.105, and that it was
conducted in compliance with the informed consent regulations in part
50.
(x) If a sponsor has transferred any obligations for the conduct of
any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have
been transferred, a general statement of this transfer--in lieu of a
listing of the specific obligations transferred--may be submitted.
(xi) If original subject records were audited or reviewed by the
sponsor in the course of monitoring any clinical study to verify the
accuracy of the case reports submitted to the sponsor, a list
identifying each clinical study so audited or reviewed.
(6) Statistical section. A section describing the statistical
evaluation of clinical data, including the following:
(i) A copy of the information submitted under paragraph (d)(5)(ii)
of this section concerning the description and analysis of each
controlled clinical study, and the documentation and supporting
statistical analyses used in evaluating the controlled clinical studies.
(ii) A copy of the information submitted under paragraph
(d)(5)(vi)(a) of this section concerning a summary of information about
the safety of the drug product, and the documentation and supporting
statistical analyses used in evaluating the safety information.
(7) Pediatric use section. A section describing the investigation of
the drug for use in pediatric populations, including an integrated
summary of the information (the clinical pharmacology studies,
controlled clinical studies, or uncontrolled clinical studies, or other
data or information) that is relevant to the safety and effectiveness
and benefits and risks of the drug in pediatric populations for the
claimed indications, a reference to the full descriptions of such
studies provided under paragraphs (d)(3) and (d)(5) of this section, and
information required to be submitted under Sec. 314.55.
(e) Samples and labeling. (1) Upon request from FDA, the applicant
shall submit the samples described below to the places identified in the
agency's request. FDA will generally 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
methods.
(i) Four representative samples of the following, each sample in
sufficient quantity to permit FDA to perform three times each test
described in the application to determine whether the drug substance and
the drug product meet the specifications given in the application:
(a) The drug product proposed for marketing;
(b) The drug substance used in the drug product from which the
samples of the drug product were taken; and
(c) Reference standards and blanks (except that reference standards
recognized in an official compendium need not be submitted).
[[Page 105]]
(ii) Samples of the finished market package, if requested by FDA.
(2) The applicant shall submit the following in the archival copy of
the application:
(i) Three copies of the analytical methods and related descriptive
information contained in the chemistry, manufacturing, and controls
section under paragraph (d)(1) of this section for the drug substance
and the drug product that are necessary for FDA's laboratories to
perform all necessary tests on the samples and to validate the
applicant's analytical methods. The related descriptive information
includes a description of each sample; the proposed regulatory
specifications for the drug; a detailed description of the methods of
analysis; supporting data for accuracy, specificity, precision and
ruggedness; and complete results of the applicant's tests on each
sample.
(ii) Copies of the label and all labeling for the drug product
(including, if applicable, any Medication Guide required under part 208
of this chapter) for the drug product (4 copies of draft labeling or 12
copies of final printed labeling).
(f) Case report forms and tabulations. The archival copy of the
application is required to contain the following case report tabulations
and case report forms:
(1) Case report tabulations. The application is required to contain
tabulations of the data from each adequate and well-controlled study
under Sec. 314.126 (Phase 2 and Phase 3 studies as described in
Secs. 312.21 (b) and (c) of this chapter), tabulations of the data from
the earliest clinical pharmacology studies (Phase 1 studies as described
in Sec. 312.21(a) of this chapter), and tabulations of the safety data
from other clinical studies. Routine submission of other patient data
from uncontrolled studies is not required. The tabulations are required
to include the data on each patient in each study, except that the
applicant may delete those tabulations which the agency agrees, in
advance, are not pertinent to a review of the drug's safety or
effectiveness. Upon request, FDA will discuss with the applicant in a
``pre-NDA'' conference those tabulations that may be appropriate for
such deletion. Barring unforeseen circumstances, tabulations agreed to
be deleted at such a conference will not be requested during the conduct
of FDA's review of the application. If such unforeseen circumstances do
occur, any request for deleted tabulations will be made by the director
of the FDA division responsible for reviewing the application, in
accordance with paragraph (f)(3) of this section.
(2) Case report forms. The application is required to contain copies
of individual case report forms for each patient who died during a
clinical study or who did not complete the study because of an adverse
event, whether believed to be drug related or not, including patients
receiving reference drugs or placebo. This requirement may be waived by
FDA for specific studies if the case report forms are unnecessary for a
proper review of the study.
(3) Additional data. The applicant shall submit to FDA additional
case report forms and tabulations needed to conduct a proper review of
the application, as requested by the director of the FDA division
responsible for reviewing the application. The applicant's failure to
submit information requested by FDA within 30 days after receipt of the
request may result in the agency viewing any eventual submission as a
major amendment under Sec. 314.60 and extending the review period as
necessary. If desired by the applicant, the FDA division director will
verify in writing any request for additional data that was made orally.
(4) Applicants are invited to meet with FDA before submitting an
application 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 a form other than
hard copy, for example, on microfiche or computer tapes.
(g) Other. The following general requirements apply to the
submission of information within the summary under paragraph (c) of this
section and within the technical sections under paragraph (d) of this
section.
(1) The applicant ordinarily is not required to resubmit information
previously submitted, but may incorporate the information by reference.
A
[[Page 106]]
reference to information submitted previously is required to identify
the file by name, reference number, volume, and page number in the
agency's records where the information can be found. A reference to
information submitted to the agency by a person other than the applicant
is required to contain a written statement that authorizes the reference
and that is signed by the person who submitted the information.
(2) The applicant shall submit an accurate and complete English
translation of each part of the application that is not in English. The
applicant shall submit a copy of each original literature publication
for which an English translation is submitted.
(3) If an applicant who submits a new drug application under section
505(b) of the 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 act, the applicant shall include in its
application 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 application, and provide FDA access to, the underlying
raw data that provide the basis for the report of the investigation
submitted in its application.
(h) Patent information. The application is required to contain the
patent information described under Sec. 314.53.
(i) Patent certification--(1) Contents. A 505(b)(2) application is
required to contain the following:
(i) Patents claiming drug, drug product, or method of use. (A)
Except as provided in paragraph (i)(2) 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 a drug (the drug product or drug substance that
is a component of the drug product) on which investigations that are
relied upon by the applicant for approval of its application were
conducted or that claims an approved use for such drug and for which
information is required to be filed under section 505(b) and (c) of the
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 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. 314.52(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 drug product which
is claimed by the patent or a use of which is claimed by the patent and
with the requirements under Sec. 314.52(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 act, the appropriate
patent certification under this section with respect to each patent that
claims the first-approved patented drug or that claims an approved use
for such a drug.
(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 application
[[Page 107]]
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 act and Sec. 314.53 is for a method
of use patent, and the labeling for the drug product for which the
applicant is seeking approval does not include any indications 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, the applicant shall submit an applicable certification under
paragraph (i)(1)(i) of this section.
(2) 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 drug product for which the applicant is
seeking approval.
(3) Licensing agreements. If a 505(b)(2) application is for a drug
or method of using a drug claimed by a patent and the applicant has a
licensing agreement with the patent owner, the applicant shall submit a
certification under paragraph (i)(1)(i)(A)(4) of this section
(``Paragraph IV Certification'') as to that patent and a statement that
it has been granted a patent license. If the patent owner consents to an
immediate effective date upon approval of the 505(b)(2) application, the
application shall contain a written statement from the patent owner that
it has a licensing agreement with the applicant and that it consents to
an immediate effective date.
(4) Late submission of patent information. If a patent described in
paragraph (i)(1)(i)(A) of this section is issued and the holder of the
approved application for the patented drug does not submit the required
information on the patent within 30 days of issuance of the patent, an
applicant who submitted a 505(b)(2) application that, before the
submission of the patent information, contained an appropriate patent
certification is not required to submit an amended certification. An
applicant whose 505(b)(2) application is filed after a late submission
of patent information or whose 505(b)(2) application was previously
filed but did not contain an appropriate patent certification at the
time of the patent submission shall submit a certification under
paragraph (i)(1)(i) or (i)(1)(ii) of this section or a statement under
paragraph (i)(1)(iii) of this section as to that patent.
(5) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec. 314.53(f).
Unless the patent information is withdrawn or changed, the applicant
must submit an appropriate certification for each relevant patent.
(6) Amended certifications. A certification submitted under
paragraphs (i)(1)(i) through (i)(1)(iii) of this section may be amended
at any time before the effective date of the approval of the
application. An applicant shall submit an amended certification as an
amendment to a pending application or by letter to an approved
application. 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.
Once an amendment or letter for the change in certification has been
submitted, the application will no longer be considered to be one
containing the prior certification.
(i) After finding of infringement. An applicant who has submitted a
certification under paragraph (i)(1)(i)(A)(4) of this section and is
sued for patent infringement within 45 days of the receipt of notice
sent under Sec. 314.52 shall amend the certification if a final judgment
in the action is entered finding the patent to be infringed unless the
final judgment also finds the patent to be invalid. In the amended
certification, the applicant shall certify under paragraph
(i)(1)(i)(A)(3) of this section that the patent will expire on a
specific date.
(ii) After removal of a patent from the list. If a patent is removed
from the
[[Page 108]]
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 (i)(1)(ii) of this section
that no patents described in paragraph (i)(1)(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 that any such period of delay in effective
dates of approval is ended. An applicant shall submit an amended
certification as an amendment to a pending application. Once an
amendment for the change has been submitted, the application will no
longer be considered to be one containing a certification under
paragraph (i)(1)(i)(A)(4) of this section.
(iii) Other amendments. (A) Except as provided in paragraphs (i)(4)
and (i)(6)(iii)(B) 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.
(B) An applicant is not required to amend a submitted certification
when information on an otherwise applicable patent is submitted after
the effective date of approval for the 505(b)(2) application.
(j) Claimed exclusivity. A new drug product, upon approval, may be
entitled to a period of marketing exclusivity under the provisions of
Sec. 314.108. If an applicant believes its drug product is entitled to a
period of exclusivity, it shall submit with the new drug application
prior to approval the following information:
(1) A statement that the applicant is claiming exclusivity.
(2) A reference to the appropriate paragraph under Sec. 314.108 that
supports its claim.
(3) If the applicant claims exclusivity under Sec. 314.108(b)(2),
information to show that, to the best of its knowledge or belief, a drug
has not previously been approved under section 505(b) of the act
containing any active moiety in the drug for which the applicant is
seeking approval.
(4) If the applicant claims exclusivity under Sec. 314.108(b)(4) or
(b)(5), the following information to show that the application contains
``new clinical investigations'' that are ``essential to approval of the
application or supplement'' and were ``conducted or sponsored by the
applicant:''
(i) ``New clinical investigations.'' A certification that to the
best of the applicant's knowledge each of the clinical investigations
included in the application meets the definition of ``new clinical
investigation'' set forth in Sec. 314.108(a).
(ii) ``Essential to approval.'' A list of all published studies or
publicly available reports of clinical investigations known to the
applicant through a literature search that are relevant to the
conditions for which the applicant is seeking approval, a certification
that the applicant has thoroughly searched the scientific literature
and, to the best of the applicant's knowledge, the list is complete and
accurate and, in the applicant's opinion, such published studies or
publicly available reports do not provide a sufficient basis for the
approval of the conditions for which the applicant is seeking approval
without reference to the new clinical investigation(s) in the
application, and an explanation as to why the studies or reports are
insufficient.
(iii) ``Conducted or sponsored by.'' If the applicant was the
sponsor named in the Form FDA-1571 for an investigational new drug
application (IND) under which the new clinical investigation(s) that is
essential to the approval of its application 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
[[Page 109]]
for the clinical investigation(s) that is essential to the approval of
its application, and information supporting the certification. To
demonstrate ``substantial support,'' an applicant must either provide a
certified statement from a certified public accountant that the
applicant provided 50 percent or more of the cost of conducting the
study or provide an explanation of why FDA should consider the applicant
to have conducted or sponsored the study if the applicant's financial
contribution to the study is less than 50 percent or the applicant did
not sponsor the investigational new drug. A predecessor in interest is
an entity, e.g., a corporation, that the applicant has taken over,
merged with, or purchased, or from which the applicant has purchased all
rights to the drug. Purchase of nonexclusive rights to a clinical
investigation after it is completed is not sufficient to satisfy this
definition.
(k) Financial certification or disclosure statement. The application
shall contain a financial certification or disclosure statement or both
as required by part 54 of this chapter.
(l) Format of an original application. (1) The applicant shall
submit a complete archival copy of the application that contains the
information required under paragraphs (a) through (f) 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 on microfiche the portions of the
archival copy of the application described in paragraphs (b) through (d)
of this section. Information relating to samples and labeling
(including, if applicable, any Medication Guide required under part 208
of this chapter), described in paragraph (e) of this section, is
required to be submitted in hard copy. Tabulations of patient data and
case report forms, described in paragraph (f) of this section, may be
submitted on microfiche only if the applicant and FDA agree. If FDA
agrees, the applicant may use another suitable microform system.
(2) The applicant shall submit a review copy of the application.
Each of the technical sections, described in paragraphs (d)(1) through
(d)(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) The applicant shall submit a field copy of the application 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 application.
(4) The applicant may obtain from FDA sufficient folders to bind the
archival, the review, and the field copies of the application.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50
FR 16668, Apr. 26, 1985; 50 FR 21238, May 23, 1985; 52 FR 8847, Mar. 19,
1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17982, Apr. 28, 1992; 58 FR
47351, Sept. 8, 1993; 59 FR 13200, Mar. 21, 1994; 59 FR 50361, Oct. 3,
1994; 59 FR 60051, Nov. 21, 1994; 62 FR 40599, July 29, 1997; 63 FR
5252, Feb. 2, 1998; 63 FR 6862, Feb. 11, 1998; 63 FR 66398, Dec. 1,
1998; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. 5, 1999]
Effective Date Note: 1. At 63 FR 66398, Dec. 1, 1998, Sec. 314.50
was amended by revising the first and third sentences of the
introductory text, paragraph (c)(2)(i), the first sentence of paragraph
(d)(5)(vi)(b), paragraph (e)(2)(ii), and the fourth sentence in
paragraph (l)(1), effective June 1, 1999. For the convenience of the
user, the superseded text is set forth as follows:
Sec. 314.50 Content and format of an application.
Applications and supplements to approved applications are required
to be submitted in the form and contain the information, as appropriate
for the particular submission, required under this section. * * * An
application for a new chemical entity will generally contain an
application form, an index, a summary, five or six technical sections,
case
[[Page 110]]
report tabulations of patient data, case report forms, drug samples, and
labeling.
* * * * *
(c) * * *
(2) * * *
(i) The proposed text of the labeling for the drug, with annotations
to the information in the summary and technical sections of the
application that support the inclusion of each statement in the
labeling, and, if the application is for a prescription drug, statements
describing the reasons for omitting a section or subsection of the
labeling format in Sec. 201.57.
* * * * *
(d) * * *
(5) * * *
(vi) * * *
(b) The applicant shall, under section 505(i) of the act, update
periodically its pending application with new safety information learned
about the drug that may reasonably affect the statement of
contraindications, warnings, precautions, and adverse reactions in the
draft labeling. * * *
(e) * * *
(2) * * *
(ii) Copies of the label and all labeling for the drug product (4
copies of draft labeling or 12 copies of final printed labeling).
* * * * *
(l) * * *
(1) * * * Information relating to samples and labeling, described in
paragraph (e) of this section, is required to be submitted in hard copy.
* * *
* * * * *
Effective Date Note: 2. At 64 FR 401, Jan. 5, 1999, Sec. 314.50 was
amended by removing ``or 507'' from the introductory text of paragraph
(d), effective May 20, 1999.