0A4F4F9BD490A749D5437F821CF06DF1
21 CFR 314
https://www.govinfo.gov/content/pkg/CFR-2012-title21-vol5/pdf/CFR-2012-title21-vol5-part314.pdf
http://leaux.net/URLS/ConvertAPI Text Files/7DBAA1BF7E5B6DC50D11D20062259452.en.txt
Examining the file media/Synopses/7DBAA1BF7E5B6DC50D11D20062259452.html:
This file was generated: 2020-07-14 04:43:36
| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / Illegal Activity
Searching for indicator unlawful:
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p.000166: demonstrate that there is a genuine and substantial issue of fact which justifies a hearing.
p.000166:
p.000166: (4) If review of the data, information, and analyses submitted show that the grounds cited in the notice
p.000166: are not valid, for example, that substantial evidence of effectiveness exists, the Commissioner
p.000166: will enter summary judgment for the person requesting the hearing, and rescind the notice of op- portunity
p.000166: for hearing.
p.000166: (5) If the Commissioner grants a hearing, it will begin within 90 days after the expiration of the
p.000166: time for re- questing the hearing unless the parties otherwise agree in the case of denial of approval, and as
p.000166: soon as practicable in the case of withdrawal of approval.
p.000166: (6) The Commissioner will grant a hearing if there exists a genuine and substantial issue of fact
p.000166: or if the Com- missioner concludes that a hearing would otherwise be in the public inter- est.
p.000166: (7) If the manufacturer or distributor of an identical, related, or similar drug product requests and is granted a
p.000166: hear- ing, the hearing may consider whether the product is in fact identical, related, or similar to the drug
p.000166: product named in the notice of opportunity for a hear- ing.
p.000166: (8) A request for a hearing, and any subsequent grant or denial of a hear- ing, applies only to the
p.000166: drug products named in such documents.
p.000166: (h) FDA will issue a notice with- drawing approval and declaring all products unlawful for
p.000166: drug products subject to a notice of opportunity for a hearing, including any identical, re- lated, or
p.000166: similar drug product under
p.000166: § 310.6, for which an opportunity for a hearing is waived or for which a hear- ing is denied. The
p.000166: Commissioner may defer or stay the action pending a rul- ing on any related request for a hear- ing or
p.000166: pending any related hearing or other administrative or judicial pro- ceeding.
p.000166: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000166: 1985, as amended at 50 FR 21238, May 23, 1985;
p.000166: 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28,
p.000166: 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252,
p.000166: Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 68 FR
p.000166: 24879, May 9, 2003; 69 FR 48775, Aug. 11, 2004;
p.000166: 74 FR 13113, Mar. 26, 2009]
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p.000167:
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p.000167:
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p.000167:
p.000167:
p.000167: § 314.201
p.000167: § 314.201 Procedure for hearings.
p.000167: Parts 10 through 16 apply to hearings relating to new drugs under section 505
p.000167: (d) and (e) of the act.
p.000167: § 314.235 Judicial review.
p.000167: (a) The Commissioner of Food and Drugs will certify the transcript and record. In any case in which
p.000167: the Com- missioner enters an order without a hearing under § 314.200(g), the record certified by
p.000167: the Commissioner is re- quired to include the requests for hear- ing together with the data and infor-
p.000167: mation submitted and the Commis- sioner’s findings and conclusion.
p.000167: (b) A manufacturer or distributor of
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Political / Indigenous
Searching for indicator native:
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p.000096: sections are as follows:
p.000096: (1) Chemistry, manufacturing, and con- trols section. A section describing the composition, manufacture,
p.000096: and speci- fication of the drug substance and the drug product, including the following:
p.000096: (i) Drug substance. A full description of the drug substance including its physical and chemical
p.000096: characteristics and stability; the name and address of its manufacturer; the method of syn- thesis (or
p.000096: isolation) and purification of the drug substance; the process con- trols used during manufacture
p.000096: and packaging; and the specifications nec- essary to ensure the identity, strength, quality, and purity of
p.000096: the drug sub- stance and the bioavailability of the drug products made from the sub- stance,
p.000096: including, for example, tests, analytical procedures, and acceptance criteria relating to stability,
p.000096: sterility, particle size, and crystalline form. The application may provide additionally for the use of
p.000096: alternatives to meet any of these requirements, including alter- native sources, process controls, and
p.000096: analytical procedures. Reference to the current edition of the U.S. Pharma-
p.000097: 97
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p.000097: copeia and the National Formulary may satisfy relevant requirements in this paragraph.
p.000097: (ii)(a) Drug product. A list of all com- ponents used in the manufacture of the drug product (regardless of
p.000097: whether they appear in the drug product) and a statement of the composition of the drug product; the
p.000097: specifications for each component; the name and address of each manufacturer of the drug prod- uct; a description of
p.000097: the manufacturing and packaging procedures and in-proc- ess controls for the drug product; the specifications
p.000097: necessary to ensure the identity, strength, quality, purity, po- tency, and bioavailability of the drug
p.000097: product, including, for example, tests, analytical procedures, and acceptance criteria relating to sterility,
p.000097: dissolu- tion rate, container closure systems; and stability data with proposed expi- ration dating.
p.000097: The application may provide additionally for the use of al- ternatives to meet any of these re-
p.000097: quirements, including alternative com- ponents, manufacturing and packaging procedures, in-process controls, and an-
p.000097: alytical procedures. Reference to the current edition of the U.S. Pharma- copeia and the National
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p.000122: Epidemiology for an acceptable alternative reporting format.
p.000122: (e) Postmarketing studies. (1) An appli-
p.000122: cant is not required to submit a 15-day Alert report under paragraph (c) of this section for an adverse drug
p.000122: experience obtained from a postmarketing study (whether or not conducted under an in- vestigational new drug
p.000122: application) un- less the applicant concludes that there is a reasonable possibility that the drug
p.000122: caused the adverse experience.
p.000122: (2) The applicant shall separate and clearly mark reports of adverse drug experiences that occur during a
p.000122: post- marketing study as being distinct from those experiences that are being re- ported spontaneously to
p.000122: the applicant.
p.000122: (f) Reporting FDA Form 3500A. (1) Ex- cept as provided in paragraph (f)(3) of this section, the
p.000122: applicant shall com- plete FDA Form 3500A for each report of an adverse drug experience (foreign events
p.000122: may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form).
p.000122: (2) Each completed FDA Form 3500A should refer only to an individual pa- tient or a single attached
p.000122: publication.
p.000122: (3) Instead of using FDA Form 3500A, an applicant may use a computer-gen- erated FDA Form 3500A or other
p.000122: alter- native format (e.g., a computer-gen- erated tape or tabular listing) provided that:
p.000122: (i) The content of the alternative for- mat is equivalent in all elements of in- formation to those specified
p.000122: in FDA Form 3500A; and
p.000122:
p.000122: (ii) The format is agreed to in ad- vance by the Office of Surveillance and Epidemiology.
p.000122: (4) FDA Form 3500A and instructions for completing the form are available on the Internet at http://
p.000122: .fda.gov/ med atch/index.html.
p.000122: (g) Multiple reports. An applicant should not include in reports under this section any
p.000122: adverse drug experi- ences that occurred in clinical trials if they were previously submitted as part of the
p.000122: approved application. If a report applies to a drug for which an appli- cant holds more than one approved
p.000122: ap- plication, the applicant should submit the report to the application that was first approved. If a
p.000122: report refers to more than one drug marketed by an ap- plicant, the applicant should submit the report
p.000122: to the application for the drug listed first in the report.
p.000122: (h) Patient privacy. An applicant
p.000122: should not include in reports under this section the names and addresses of individual patients; instead,
p.000122: the appli- cant should assign a unique code num- ber to each report, preferably not more than eight characters
p.000122: in length. The applicant should include the name of the reporter from whom the informa- tion was
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Political / criminal
Searching for indicator criminal:
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p.000163: each study satisfies, on a point- by-point basis, each of the criteria required by § 314.126.
p.000163: B. Combinations of individual active com- ponents.
p.000163: 1. Controlled studies with an analysis showing clearly how each study satisfies on a point-by-point
p.000163: basis, each of the criteria required by § 314.126.
p.000163: 2. An analysis showing clearly how each re- quirement of § 300.50 has been satisfied.
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p.000164: Food and Drug Administration, HHS § 314.200
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p.000164: III. A summary of the data and views set- ting forth the medical rationale and purpose for the drug and its
p.000164: ingredients and the sci- entific basis for the conclusion that the drug and its ingredients have been
p.000164: proven safe and/or effective for the intended use. If there is an absence of controlled studies in the ma- terial
p.000164: submitted or the requirements of any element of § 300.50 or § 314.126 have not been fully met, that fact
p.000164: is required to be stated clearly and a waiver obtained under § 314.126 is required to be submitted.
p.000164: IV. A statement signed by the person re- sponsible for such submission that it in- cludes in full
p.000164: (or incorporates by reference as permitted in § 314.200(c)(2)) all studies and in- formation specified in § 314.200(d).
p.000164: (WARNING: A willfully false statement is a criminal offense, 18 U.S.C. 1001.)
p.000164: (e) Contentions that a drug product is not subject to the ne drug requirements. A notice of opportunity
p.000164: for a hearing encompasses all issues relating to the legal status of each drug product sub- ject to it,
p.000164: including identical, related, and similar drug products as defined in
p.000164: § 310.6. A notice of appearance and re- quest for a hearing under paragraph (c)(1)(i) of this
p.000164: section is required to contain any contention that the prod- uct is not a new drug because it is gen- erally
p.000164: recognized as safe and effective within the meaning of section 201(p) of the act, or because it is
p.000164: exempt from part or all of the new drug provisions of the act under the exemption for products
p.000164: marketed before June 25, 1938, contained in section 201(p) of the act or under section 107(c) of the
p.000164: Drug Amendments of 1962, or for any other reason. Each contention is required to be supported by a
p.000164: submission under paragraph (c)(1)(ii) of this section and the Commissioner of Food and Drugs will make
p.000164: an administrative deter- mination on each contention. The fail- ure of any person subject to a notice of
p.000164: opportunity for a hearing, including any person who manufactures or dis- tributes an identical,
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p.000164: If such discontinu- ance or change has been made, the exact
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p.000165: § 314.200
p.000165: date, nature, and rationale for each dis- continuance or change and a copy of each pertinent
p.000165: document or record to establish each such discontinuance or change should be submitted, including, but
p.000165: not limited to, the labeling which resulted from each such discontinuance or change. If no such
p.000165: dis- continuance or change has been made, a copy of representative documents or records show- ing labeling at
p.000165: representative points in time should be submitted to support the state- ment.
p.000165: III. Marketing.
p.000165: A. A copy of each pertinent document or record to establish the exact date the drug was initially
p.000165: marketed.
p.000165: B. A statement whether such marketing has at any subsequent time been discon- tinued. If such
p.000165: marketing has been discon- tinued, the exact date of each such dis- continuance should be
p.000165: submitted, together with a copy of each pertinent document or record to establish each such date.
p.000165: IV. Verification.
p.000165: A statement signed by the person respon- sible for such submission, that all appro- priate records
p.000165: have been searched and to the best of that person’s knowledge and belief it includes a true and accurate
p.000165: presentation of the facts.
p.000165: (WARNING: A willfully false statement is a criminal offense, 18 U.S.C. 1001.)
p.000165: (3) The Food and Drug Administra- tion will not find a drug product, in- cluding any active ingredient,
p.000165: which is identical, related, or similar, as de- scribed in § 310.6, to a drug product, in- cluding any active
p.000165: ingredient for which an application is or at any time has been effective or deemed approved, or approved
p.000165: under section 505 of the act, to be exempt from part or all of the new drug provisions of the act.
p.000165: (4) A contention that a drug product
p.000165: is not a new drug for any other reason is required to be supported by submis- sion of the factual
p.000165: records, data, and information that are necessary and ap- propriate to support the contention.
p.000165: (5) It is the responsibility of every person who manufactures or distrib- utes a drug product in
p.000165: reliance upon a ‘‘grandfather’’ provision of the act to maintain files that contain the data and
p.000165: information necessary fully to doc- ument and support that status.
p.000165: (f) Separation of functions. Separation of functions commences upon receipt of a request for hearing. The
p.000165: Director of the Center for Drug Evaluation and Re- search, Food and Drug Administration, will prepare an analysis
p.000165: of the request
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Political / political affiliation
Searching for indicator party:
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p.000169: internal reviews of the data
p.000169: 21 CFR Ch. I (4–1–12 Edition)
p.000169: and information, after deletion of the following:
p.000169: (a) Names and any information that would identify patients or test subjects or investigators.
p.000169: (b) Any inappropriate gratuitous comments unnecessary to an objective analysis of the data and
p.000169: information.
p.000169: (ii) For an application approved on or after July 1, 1975, a Summary Basis of Approval (SBA) document that
p.000169: con- tains a summary of the safety and ef- fectiveness data and information eval- uated by FDA during the
p.000169: drug approval process. The SBA is prepared in one of the following ways:
p.000169: (a) Before approval of the applica- tion, the applicant may prepare a draft SBA which the Center for Drug
p.000169: Evalua- tion and Research will review and may revise. The draft may be submitted with the application or
p.000169: as an amend- ment.
p.000169: (b) The Center for Drug Evaluation and Research may prepare the SBA.
p.000169: (3) A protocol for a test or study, un- less it is shown to fall within the ex- emption established for
p.000169: trade secrets and confidential commercial informa- tion in § 20.61.
p.000169: (4) Adverse reaction reports, product experience reports, consumer com- plaints, and other similar
p.000169: data and in- formation after deletion of the fol- lowing:
p.000169: (i) Names and any information that would identify the person using the product.
p.000169: (ii) Names and any information that would identify any third party involved with the report, such as a
p.000169: physician or hospital or other institution.
p.000169: (5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as
p.000169: set forth in
p.000169: § 20.81.
p.000169: (6) An assay procedure or other ana- lytical procedure, unless it serves no regulatory or compliance
p.000169: purpose and is shown to fall within the exemption established for trade secrets and con- fidential
p.000169: commercial information in
p.000169: § 20.61.
p.000169: (7) All correspondence and written summaries of oral discussions between FDA and the applicant relating
p.000169: to the application, under the provisions of part 20.
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p.000170: Food and Drug Administration, HHS § 314.440
p.000170:
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p.000170: (f) All safety and effectiveness data and information which have been sub- mitted in an application
p.000170: and which have not previously been disclosed to the public are available to the public, upon request, at
p.000170: the time any one of the following events occurs unless ex- traordinary circumstances are shown:
p.000170: (1) No work is being or will be under- taken to have the application ap- proved.
p.000170: (2) A final determination is made that the application is not approvable and all legal appeals
p.000170: have been ex- hausted.
p.000170: (3) Approval of the application is withdrawn and all legal appeals have been exhausted.
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Political / stateless persons
Searching for indicator nation:
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p.000156: permit ac- cess to, or copying or verification of, its records.
p.000156: (2) That on the basis of new informa- tion before FDA, evaluated together with the evidence available when
p.000156: the application or abbreviated application
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p.000157:
p.000157: § 314.150
p.000157: was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and
p.000157: packing of the drug are inadequate to ensure and preserve its identity, strength, quality, and purity
p.000157: and were not made adequate within a reasonable time after receipt of written notice from the agency.
p.000157: (3) That on the basis of new informa- tion before FDA, evaluated together with the evidence available when
p.000157: the application or abbreviated application was approved, the labeling of the drug, based on a fair
p.000157: evaluation of all mate- rial facts, is false or misleading in any particular, and the labeling was
p.000157: not corrected by the applicant within a reasonable time after receipt of writ- ten notice from the
p.000157: agency.
p.000157: (4) That the applicant has failed to comply with the notice requirements of section 510(j)(2) of the act.
p.000157: (5) That the applicant has failed to submit bioavailability or bioequiva- lence data required under
p.000157: part 320 of this chapter.
p.000157: (6) The application or abbreviated ap- plication does not contain an expla- nation of the omission of a
p.000157: report of any investigation of the drug product sponsored by the applicant, or an ex- planation of the
p.000157: omission of other in- formation about the drug pertinent to an evaluation of the application or ab-
p.000157: breviated application that is received or otherwise obtained by the applicant from any source.
p.000157: (7) That any nonclinical laboratory study that is described in the applica- tion or abbreviated
p.000157: application and that is essential to show that the drug is safe for use under the conditions pre- scribed,
p.000157: recommended, or suggested in its labeling was not conducted in com- pliance with the good laboratory
p.000157: prac- tice regulations in part 58 of this chap- ter and no reason for the noncompli- ance was provided or, if it
p.000157: was, the dif- ferences between the practices used in conducting the study and the good lab- oratory practice
p.000157: regulations do not support the validity of the study.
p.000157: (8) Any clinical investigation involv-
p.000157: ing human subjects described in the ap- plication or abbreviated application, subject to the
p.000157: institutional review board regulations in part 56 of this chapter or informed consent regula-
p.000157: 21 CFR Ch. I (4–1–12 Edition)
p.000157: tions in part 50 of this chapter, was not conducted in compliance with those regulations such that the
p.000157: rights or safety of human subjects were not ade- quately protected.
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Health / Drug Dependence
Searching for indicator dependence:
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p.000117: assurance that the drug substance or drug product will have the characteristics of identity,
p.000117: strength, quality, purity, or potency that it purports or is represented to possess;
p.000117: (ii) A change in the size and/or shape of a container for a nonsterile drug product, except for solid
p.000117: dosage forms, without a change in the labeled amount of drug product or from one container
p.000117: closure system to another;
p.000117: (iii) Changes in the labeling to reflect newly acquired information, except for changes to the information
p.000117: required in
p.000117: § 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish
p.000117: any of the following:
p.000117: (A) To add or strengthen a contra- indication, warning, precaution, or ad- verse reaction for which the
p.000117: evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c)
p.000117: of this chapter;
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p.000118:
p.000118:
p.000118: Food and Drug Administration, HHS § 314.70
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p.000118: (B) To add or strengthen a statement about drug abuse, dependence, psycho- logical effect, or overdosage;
p.000118: (C) To add or strengthen an instruc- tion about dosage and administration that is intended to increase
p.000118: the safe use of the drug product;
p.000118: (D) To delete false, misleading, or un- supported indications for use or claims for effectiveness; or
p.000118: (E) Any labeling change normally re- quiring a supplement submission and approval prior to distribution of
p.000118: the drug product that FDA specifically re- quests be submitted under this provi- sion.
p.000118: (7) If the agency disapproves the sup- plemental application, it may order the manufacturer to cease
p.000118: distribution of the drug product(s) made with the manufacturing change.
p.000118: (d) Changes to be described in an an- nual report (minor changes). (1) Changes in the drug substance,
p.000118: drug product, production process, quality controls, equipment, or facilities that have a minimal
p.000118: potential to have an adverse effect on the identity, strength, qual- ity, purity, or potency of the
p.000118: drug product as these factors may relate to the safety or effectiveness of the drug product must be
p.000118: documented by the ap- plicant in the next annual report in ac- cordance with § 314.81(b)(2).
p.000118: (2) These changes include, but are not
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Searching for indicator dependency:
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p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
p.000120: includes events that may be symptomatically and pathophysiologically related to an event listed
p.000120: in the labeling, but differ from the event because of greater se-
p.000120:
p.000120: verity or specificity. For example, under this definition, hepatic necrosis would be unexpected
p.000120: (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis.
p.000120: Similarly, cerebral thrombo- embolism and cerebral vasculitis would be unexpected (by virtue of greater
p.000120: specificity) if the labeling only listed cerebral vascular accidents. ‘‘Unex- pected,’’ as used in this
p.000120: definition, re- fers to an adverse drug experience that has not been previously observed (i.e., included in the
p.000120: labeling) rather than from the perspective of such experience not being anticipated from the pharma- cological
p.000120: properties of the pharma- ceutical product.
p.000120: (b) Revie of adverse drug experiences.
p.000120: Each applicant having an approved ap- plication under § 314.50 or, in the case of a 505(b)(2)
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Health / Drug Usage
Searching for indicator drug:
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p.000092:
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p.000092:
p.000092: Pt. 314
p.000092: PART 314—APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
p.000092: Subpart A—General Provisions
p.000092: Sec.
p.000092: 314.1 Scope of this part.
p.000092: 314.2 Purpose.
p.000092: 314.3 Definitions.
p.000092: Subpart B—Applications
p.000092: 314.50 Content and format of an application.
p.000092: 314.52 Notice of certification of invalidity or noninfringement of a patent.
p.000092: 314.53 Submission of patent information.
p.000092: 314.54 Procedure for submission of an appli- cation requiring investigations for ap- proval of a new
p.000092: indication for, or other change from, a listed drug.
p.000092: 314.55 Pediatric use information.
p.000092: 314.60 Amendments to an unapproved appli- cation, supplement, or resubmission.
p.000092: 314.65 Withdrawal by the applicant of an un- approved application.
p.000092: 314.70 Supplements and other changes to an approved application.
p.000092: 314.71 Procedures for submission of a sup- plement to an approved application.
p.000092: 314.72 Change in ownership of an applica- tion.
p.000092: 314.80 Postmarketing reporting of adverse drug experiences.
p.000092: 314.81 Other postmarketing reports.
p.000092: 314.90 Waivers.
p.000092: Subpart C—Abbreviated Applications
p.000092: 314.91 Obtaining a reduction in the dis- continuance notification period.
p.000092: 314.92 Drug products for which abbreviated applications may be submitted.
p.000092: 314.93 Petition to request a change from a listed drug.
p.000092: 314.94 Content and format of an abbreviated application.
p.000092: 314.95 Notice of certification of invalidity or noninfringement of a patent.
p.000092: 314.96 Amendments to an unapproved abbre- viated application.
p.000092: 314.97 Supplements and other changes to an approved abbreviated application.
p.000092: 314.98 Postmarketing reports.
p.000092: 314.99 Other responsibilities of an applicant of an abbreviated application.
p.000092: Subpart D—FDA Action on Applications and Abbreviated Applications
p.000092: 314.100 Timeframes for reviewing applica- tions and abbreviated applications.
p.000092: 314.101 Filing an application and receiving an abbreviated new drug application.
p.000092: 314.102 Communications between FDA and applicants.
p.000092: 314.103 Dispute resolution.
p.000092:
p.000092: 92
p.000092:
p.000092: 21 CFR Ch. I (4–1–12 Edition)
p.000092: 314.104 Drugs with potential for abuse.
p.000092: 314.105 Approval of an application and an abbreviated application.
p.000092: 314.106 Foreign data.
p.000092: 314.107 Effective date of approval of a 505(b)(2) application or abbreviated new drug
p.000092: application under section 505(j) of the act.
p.000092: 314.108 New drug product exclusivity.
p.000092: 314.110 Complete response letter to the ap- plicant.
p.000092: 314.120 [Reserved]
p.000092: 314.122 Submitting an abbreviated applica- tion for, or a 505(j)(2)(C) petition that re- lies on, a listed
p.000092: drug that is no longer marketed.
p.000092: 314.125 Refusal to approve an application.
p.000092: 314.126 Adequate and well-controlled stud- ies.
p.000092: 314.127 Refusal to approve an abbreviated new drug application.
p.000092: 314.150 Withdrawal of approval of an appli- cation or abbreviated application.
p.000092: 314.151 Withdrawal of approval of an abbre- viated new drug application under sec- tion 505(j)(5) of the
p.000092: act.
p.000092: 314.152 Notice of withdrawal of approval of an application or abbreviated application for a new drug.
p.000092: 314.153 Suspension of approval of an abbre- viated new drug application.
p.000092: 314.160 Approval of an application or abbre- viated application for which approval was previously
p.000092: refused, suspended, or withdrawn.
p.000092: 314.161 Determination of reasons for vol- untary withdrawal of a listed drug.
p.000092: 314.162 Removal of a drug product from the list.
p.000092: 314.170 Adulteration and misbranding of an approved drug.
p.000092:
p.000092: Subpart E—Hearing Procedures for New Drugs
p.000092: 314.200 Notice of opportunity for hearing; notice of participation and request for hearing; grant or
p.000092: denial of hearing.
p.000092: 314.201 Procedure for hearings.
p.000092: 314.235 Judicial review.
p.000092:
p.000092: Subpart F [Reserved]
p.000092: Subpart G—Miscellaneous Provisions
p.000092: 314.410 Imports and exports of new drugs.
p.000092: 314.420 Drug master files.
p.000092: 314.430 Availability for public disclosure of data and information in an application or abbreviated
p.000092: application.
p.000092: 314.440 Addresses for applications and ab- breviated applications.
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092: Food and Drug Administration, HHS § 314.3
p.000092:
p.000092:
p.000092: 314.445 Guidance documents.
p.000092:
p.000092: Subpart H—Accelerated Approval of New Drugs for Serious or Life-Threatening Ill- nesses
p.000092: 314.500 Scope.
p.000092: 314.510 Approval based on a surrogate end- point or on an effect on a clinical end- point other than
p.000092: survival or irreversible morbidity.
p.000092: 314.520 Approval with restrictions to assure safe use.
p.000092: 314.530 Withdrawal procedures.
p.000092: 314.540 Postmarketing safety reporting.
p.000092: 314.550 Promotional materials.
p.000092: 314.560 Termination of requirements.
p.000092:
p.000092: Subpart I—Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible
p.000092: 314.600 Scope.
p.000092: 314.610 Approval based on evidence of effec- tiveness from studies in animals.
p.000092: 314.620 Withdrawal procedures.
p.000092: 314.630 Postmarketing safety reporting. 314.640 Promotional materials.
p.000092: 314.650 Termination of requirements.
p.000092: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000092: 355, 356, 356a, 356b, 356c, 371, 374, 379e.
p.000092: SOURCE: 50 FR 7493, Feb. 22, 1985, unless
p.000092: otherwise noted.
p.000092: EDITORIAL NOTE: Nomenclature changes to part 314 can be found at 69 FR 13717, Mar. 24,
p.000092: 2004.
p.000092:
p.000092: Subpart A—General Provisions
p.000092: § 314.1 Scope of this part.
p.000092: (a) This part sets forth procedures and requirements for the submission to, and the review by,
p.000092: the Food and Drug Administration of applications and abbreviated applications to market a new drug under
p.000092: section 505 of the Federal Food, Drug, and Cosmetic Act, as well as amendments, supplements, and
p.000092: postmarketing reports to them.
p.000092: (b) This part does not apply to drug products subject to licensing by FDA under the Public Health Service
p.000092: Act (58 Stat. 632 as amended (42 U.S.C. 201 et seq.)) and subchapter F of chapter I of title 21 of the
p.000092: Code of Federal Regula- tions.
p.000092: (c) References in this part to regula- tions in the Code of Federal Regula-
p.000092:
p.000093: 93
p.000093:
p.000093: tions are to chapter I of title 21, unless otherwise noted.
p.000093: [50 FR 7493, Feb. 22, 1985, as amended at 57
p.000093: FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999]
p.000093: § 314.2 Purpose.
p.000093: The purpose of this part is to estab- lish an efficient and thorough drug re- view process in order
p.000093: to: (a) Facilitate the approval of drugs shown to be safe and effective; and (b) ensure the dis-
p.000093: approval of drugs not shown to be safe and effective. These regulations are also intended to
p.000093: establish an effective system for FDA’s surveillance of mar- keted drugs. These regulations shall be construed
p.000093: in light of these objectives.
p.000093: § 314.3 Definitions.
p.000093: (a) The definitions and interpreta- tions contained in section 201 of the act apply to those terms when used in
p.000093: this part.
p.000093: (b) The following definitions of terms apply to this part:
p.000093: Abbreviated application means the ap- plication described under § 314.94, in- cluding all amendments
p.000093: and supple- ments to the application. ‘‘Abbreviated application’’ applies to both an abbre- viated new drug
p.000093: application and an ab- breviated antibiotic application.
p.000093: Act means the Federal Food, Drug, and Cosmetic Act (sections 201–901 (21
p.000093: U.S.C. 301–392)).
p.000093: Applicant means any person who sub- mits an application or abbreviated ap- plication or an amendment or
p.000093: supple- ment to them under this part to obtain FDA approval of a new drug or an anti- biotic drug and any person
p.000093: who owns an approved application or abbreviated application.
p.000093: Application means the application de- scribed under § 314.50, including all amendements and supplements
p.000093: to the application.
p.000093: 505(b)(2) Application means an appli- cation submitted under section 505(b)(1) of the act for a
p.000093: drug for which the investigations described in section 505(b)(1)(A) of the act and relied upon by the
p.000093: applicant for approval of the ap- plication were not conducted by or for the applicant and for which the
p.000093: appli- cant has not obtained a right of ref- erence or use from the person by or for whom the
p.000093: investigations were con- ducted.
p.000093:
p.000093:
p.000093:
p.000093:
p.000093:
p.000093:
p.000093:
p.000093:
p.000093: § 314.3
p.000093: Approval letter means a written com- munication to an applicant from FDA approving an application or an
p.000093: abbre- viated application.
p.000093: Assess the effects of the change means to evaluate the effects of a manufac- turing change on
p.000093: the identity, strength, quality, purity, and potency of a drug product as these factors may relate to
p.000093: the safety or effectiveness of the drug product.
p.000093: Authorized generic drug means a listed drug, as defined in this section, that has been approved under section
p.000093: 505(c) of the act and is marketed, sold, or dis- tributed directly or indirectly to retail class of trade with
p.000093: labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or
p.000093: similar packaging for use in institu- tions), product code, labeler code, trade name, or trademark that
p.000093: differs from that of the listed drug.
p.000093: Class 1 resubmission means the resub- mission of an application or efficacy supplement, following receipt of
p.000093: a com- plete response letter, that contains one or more of the following: Final printed labeling, draft labeling,
p.000093: certain safety updates, stability updates to support provisional or final dating periods,
p.000093: commitments to perform post- marketing studies (including proposals for such studies),
p.000093: assay validation data, final release testing on the last lots used to support approval, minor reanalyses
p.000093: of previously submitted data, and other comparatively minor information.
p.000093: Class 2 resubmission means the resub- mission of an application or efficacy supplement, following receipt of
p.000093: a com- plete response letter, that includes any item not specified in the definition of ‘‘Class 1
p.000093: resubmission,’’ including any item that would require presentation to an advisory committee.
p.000093: Complete response letter means a writ- ten communication to an applicant from FDA usually describing
p.000093: all of the deficiencies that the agency has identi- fied in an application or abbreviated application that
p.000093: must be satisfactorily addressed before it can be approved.
p.000093: Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a
p.000093: drug sub- stance, generally, but not necessarily,
p.000093:
p.000094: 94
p.000094: 21 CFR Ch. I (4–1–12 Edition)
p.000094: in association with one or more other ingredients.
p.000094: Drug substance means an active ingre- dient that is intended to furnish phar- macological activity or other
p.000094: direct ef- fect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the
p.000094: structure or any function of the human body, but does not in- clude intermediates use in the syn-
p.000094: thesis of such ingredient.
p.000094: Efficacy supplement means a supple- ment to an approved application pro- posing to make one or more
p.000094: related changes from among the following changes to product labeling:
p.000094: (1) Add or modify an indication or claim;
p.000094: (2) Revise the dose or dose regimen;
p.000094: (3) Provide for a new route of admin- istration;
p.000094: (4) Make a comparative efficacy claim naming another drug product;
p.000094: (5) Significantly alter the intended patient population;
p.000094: (6) Change the marketing status from prescription to over-the-counter use;
p.000094: (7) Provide for, or provide evidence of effectiveness necessary for, the tradi- tional approval of a product
p.000094: originally approved under subpart H of part 314; or
p.000094: (8) Incorporate other information based on at least one adequate and well-controlled clinical
p.000094: study.
p.000094: FDA means the Food and Drug Ad- ministration.
p.000094: Listed drug means a new drug product that has an effective approval under section 505(c) of the act for
p.000094: safety and effectiveness or under section 505(j) of the act, which has not been withdrawn or suspended
p.000094: under section 505(e)(1) through (e)(5) or (j)(5) of the act, and which has not been withdrawn from
p.000094: sale for what FDA has determined are reasons of safety or effectiveness. List- ed drug status is evidenced by the
p.000094: drug product’s identification as a drug with an effective approval in the current edition of FDA’s
p.000094: ‘‘Approved Drug Prod- ucts with Therapeutic Equivalence Evaluations’’ (the list) or any current
p.000094: supplement thereto, as a drug with an effective approval. A drug product is deemed to be a listed drug
p.000094: on the date of effective approval of the application or abbreviated application for that drug
p.000094: product.
p.000094:
p.000094:
p.000094:
p.000094:
p.000094:
p.000094:
p.000094:
p.000094: Food and Drug Administration, HHS § 314.50
p.000094:
p.000094:
p.000094: Ne ly acquired information means data, analyses, or other information not previously submitted
p.000094: to the agen- cy, which may include (but are not lim- ited to) data derived from new clinical studies, reports
p.000094: of adverse events, or new analyses of previously submitted data (e.g., meta-analyses) if the stud- ies,
p.000094: events or analyses reveal risks of a different type or greater severity or frequency than previously
p.000094: included in submissions to FDA.
p.000094: Original application means a pending application for which FDA has never issued a complete response letter or
p.000094: ap- proval letter, or an application that was submitted again after FDA had re- fused to file it or
p.000094: after it was with- drawn without being approved.
p.000094: Reference listed drug means the listed drug identified by FDA as the drug product upon which an
p.000094: applicant relies in seeking approval of its abbreviated application.
p.000094: Resubmission means submission by the applicant of all materials needed to fully address all deficiencies
p.000094: identified in the complete response letter. An ap- plication or abbreviated application for which FDA issued a
p.000094: complete response letter, but which was withdrawn before approval and later submitted again, is not a
p.000094: resubmission.
p.000094: Right of reference or use means the au- thority to rely upon, and otherwise use, an investigation for the
p.000094: purpose of obtaining approval of an application, including the ability to make available the underlying raw data
p.000094: from the in- vestigation for FDA audit, if necessary. Specification means the quality stand- ard (i.e., tests,
p.000094: analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of
p.000094: drug substances, drug prod- ucts, intermediates, raw materials, re- agents, components, in-process mate-
p.000094: rials, container closure systems, and other materials used in the production of a drug substance or
p.000094: drug product. For the purpose of this definition, ac- ceptance criteriameans numerical lim- its, ranges,
p.000094: or other criteria for the
p.000094: tests described.
p.000094: The list means the list of drug prod- ucts with effective approvals published in the current edition of
p.000094: FDA’s publi- cation ‘‘Approved Drug Products with Therapeutic Equivalence Evaluations’’
p.000095: 95
p.000095:
p.000095: and any current supplement to the publication.
p.000095: [50 FR 7493, Feb. 22, 1985, as amended at 57
p.000095: FR 17981, Apr. 28, 1992; 69 FR 18763, Apr. 8,
p.000095: 2004; 73 FR 39607, July 10, 2008; 73 FR 49609,
p.000095: Aug. 22, 2008; 74 FR 37167, July 28, 2009]
p.000095:
p.000095: Subpart B—Applications
p.000095: § 314.50 Content and format of an ap- plication.
p.000095: Applications and supplements to ap- proved applications are required to be submitted in the form and
p.000095: contain the information, as appropriate for the par- ticular submission, required under this section. Three copies
p.000095: of the application are required: An archival copy, a re- view copy, and a field copy. An applica- tion for a new
p.000095: chemical entity will gen- erally contain an application form, an index, a summary, five or six technical sections,
p.000095: case report tabulations of pa- tient data, case report forms, drug samples, and labeling, including,
p.000095: if ap- plicable, any Medication Guide re- quired under part 208 of this chapter. Other applications
p.000095: will generally con- tain only some of those items, and in- formation will be limited to that need- ed to
p.000095: support the particular submis- sion. These include an application of the type described in section
p.000095: 505(b)(2) of the act, an amendment, and a sup- plement. The application is required to contain reports of all
p.000095: investigations of the drug product sponsored by the ap- plicant, and all other information about
p.000095: the drug pertinent to an evalua- tion of the application that is received or otherwise obtained by the
p.000095: applicant from any source. FDA will maintain guidance documents on the format and content of applications to
p.000095: assist appli- cants in their preparation.
p.000095: (a) Application form. The applicant shall submit a completed and signed application form that contains
p.000095: the fol- lowing:
p.000095: (1) The name and address of the ap- plicant; the date of the application; the application number if previously
p.000095: issued (for example, if the application is a re- submission, an amendment, or a sup- plement); the name of the
p.000095: drug prod- uct, including its established, propri- etary, code, and chemical names; the dosage form and
p.000095: strength; the route of administration; the identification
p.000095:
p.000095:
p.000095:
p.000095:
p.000095:
p.000095:
p.000095:
p.000095:
p.000095: § 314.50
p.000095: numbers of all investigational new drug applications that are referenced in the application; the
p.000095: identification numbers of all drug master files and other applications under this part that are referenced in
p.000095: the application; and the drug product’s proposed indications for use.
p.000095: (2) A statement whether the submis- sion is an original submission, a 505(b)(2) application, a
p.000095: resubmission, or a supplement to an application under
p.000095: § 314.70.
p.000095: (3) A statement whether the appli- cant proposes to market the drug prod- uct as a prescription or an
p.000095: over-the- counter product.
p.000095: (4) A check-list identifying what en- closures required under this section the applicant is submitting.
p.000095: (5) The applicant, or the applicant’s attorney, agent, or other authorized of- ficial shall sign the
p.000095: application. If the person signing the application does not reside or have a place of business with- in the United
p.000095: States, the application is required to contain the name and ad- dress of, and be countersigned by, an
p.000095: attorney, agent, or other authorized of- ficial who resides or maintains a place of business within the United
p.000095: States.
p.000095: (b) Index. The archival copy of the application is required to contain a comprehensive index by
p.000095: volume num- ber and page number to the summary under paragraph (c) of this section, the technical sections
p.000095: under paragraph (d) of this section, and the supporting in- formation under paragraph (f) of this section.
p.000095: (c) Summary. (1) An application is re- quired to contain a summary of the ap- plication in enough detail
p.000095: that the reader may gain a good general under- standing of the data and information in the application,
p.000095: including an under- standing of the quantitative aspects of the data. The summary is not required for
p.000095: supplements under § 314.70. Re- submissions of an application should contain an updated summary, as
p.000095: appro- priate. The summary should discuss all aspects of the application, and syn- thesize the
p.000095: information into a well- structured and unified document. The summary should be written at approxi- mately
p.000095: the level of detail required for publication in, and meet the editorial standards generally applied by,
p.000095: ref-
p.000096: 96
p.000096: 21 CFR Ch. I (4–1–12 Edition)
p.000096: ereed scientific and medical journals. In addition to the agency personnel re- viewing the summary in the context
p.000096: of their review of the application, FDA may furnish the summary to FDA advi- sory committee members and agency
p.000096: officials whose duties require an under- standing of the application. To the ex- tent possible, data in
p.000096: the summary should be presented in tabular and graphic forms. FDA has prepared a guideline under
p.000096: § 10.90(b) that provides information about how to prepare a summary. The summary required
p.000096: under this paragraph may be used by FDA or the applicant to prepare the Summary Basis of Approval
p.000096: document for public disclosure (under
p.000096: § 314.430(e)(2)(ii)) when the application
p.000096: is approved.
p.000096: (2) The summary is required to con- tain the following information:
p.000096: (i) The proposed text of the labeling, including, if applicable, any Medica- tion Guide required under
p.000096: part 208 of this chapter, for the drug, with annota- tions to the information in the sum- mary and technical
p.000096: sections of the ap- plication that support the inclusion of each statement in the labeling, and, if the
p.000096: application is for a prescription drug, statements describing the rea- sons for omitting a
p.000096: section or sub- section of the labeling format in § 201.57 of this chapter.
p.000096: (ii) A statement identifying the phar- macologic class of the drug and a dis- cussion of the scientific
p.000096: rationale for the drug, its intended use, and the po- tential clinical benefits of the drug product.
p.000096: (iii) A brief description of the mar- keting history, if any, of the drug out- side the United States,
p.000096: including a list of the countries in which the drug has been marketed, a list of any countries in which
p.000096: the drug has been withdrawn from marketing for any reason related to safety or effectiveness, and a list
p.000096: of countries in which applications for marketing are pending. The descrip- tion is required to
p.000096: describe both mar- keting by the applicant and, if known, the marketing history of other persons.
p.000096: (iv) A summary of the chemistry, manufacturing, and controls section of the application.
p.000096:
p.000096:
p.000096:
p.000096:
p.000096:
p.000096:
p.000096:
p.000096: Food and Drug Administration, HHS § 314.50
p.000096:
p.000096:
p.000096: (v) A summary of the nonclinical pharmacology and toxicology section of the application.
p.000096: (vi) A summary of the human phar- macokinetics and bioavailability sec- tion of the application.
p.000096: (vii) A summary of the microbiology section of the application (for anti-in- fective drugs only).
p.000096: (viii) A summary of the clinical data section of the application, including the results of
p.000096: statistical analyses of the clinical trials.
p.000096: (ix) A concluding discussion that pre- sents the benefit and risk consider- ations related to the drug,
p.000096: including a discussion of any proposed additional studies or surveillance the applicant intends to conduct
p.000096: postmarketing.
p.000096: (d) Technical sections. The application is required to contain the technical sections described below.
p.000096: Each tech- nical section is required to contain data and information in sufficient de- tail to
p.000096: permit the agency to make a knowledgeable judgment about wheth- er to approve the application or wheth- er
p.000096: grounds exist under section 505(d) of the act to refuse to approve the appli- cation. The required technical
p.000096: sections are as follows:
p.000096: (1) Chemistry, manufacturing, and con- trols section. A section describing the composition, manufacture,
p.000096: and speci- fication of the drug substance and the drug product, including the following:
p.000096: (i) Drug substance. A full description of the drug substance including its physical and chemical
p.000096: characteristics and stability; the name and address of its manufacturer; the method of syn- thesis (or
p.000096: isolation) and purification of the drug substance; the process con- trols used during manufacture
p.000096: and packaging; and the specifications nec- essary to ensure the identity, strength, quality, and purity of
p.000096: the drug sub- stance and the bioavailability of the drug products made from the sub- stance,
p.000096: including, for example, tests, analytical procedures, and acceptance criteria relating to stability,
p.000096: sterility, particle size, and crystalline form. The application may provide additionally for the use of
p.000096: alternatives to meet any of these requirements, including alter- native sources, process controls, and
p.000096: analytical procedures. Reference to the current edition of the U.S. Pharma-
p.000097: 97
p.000097:
p.000097: copeia and the National Formulary may satisfy relevant requirements in this paragraph.
p.000097: (ii)(a) Drug product. A list of all com- ponents used in the manufacture of the drug product (regardless of
p.000097: whether they appear in the drug product) and a statement of the composition of the drug product; the
p.000097: specifications for each component; the name and address of each manufacturer of the drug prod- uct; a description of
p.000097: the manufacturing and packaging procedures and in-proc- ess controls for the drug product; the specifications
p.000097: necessary to ensure the identity, strength, quality, purity, po- tency, and bioavailability of the drug
p.000097: product, including, for example, tests, analytical procedures, and acceptance criteria relating to sterility,
p.000097: dissolu- tion rate, container closure systems; and stability data with proposed expi- ration dating.
p.000097: The application may provide additionally for the use of al- ternatives to meet any of these re-
p.000097: quirements, including alternative com- ponents, manufacturing and packaging procedures, in-process controls, and an-
p.000097: alytical procedures. Reference to the current edition of the U.S. Pharma- copeia and the National
p.000097: Formulary may satisfy relevant requirements in this paragraph.
p.000097: (b) Unless provided by paragraph (d)(1)(ii)(a) of this section, for each batch of the drug
p.000097: product used to con- duct a bioavailability or bioequiva- lence study described in § 320.38 or
p.000097: § 320.63 of this chapter or used to con- duct a primary stability study: The batch production
p.000097: record; the specifica- tion for each component and for the drug product; the names and addresses of the
p.000097: sources of the active and noncompendial inactive components and of the container and closure
p.000097: sys- tem for the drug product; the name and address of each contract facility in- volved in the
p.000097: manufacture, processing, packaging, or testing of the drug prod- uct and identification of the operation
p.000097: performed by each contract facility; and the results of any test performed on the components used in
p.000097: the manu- facture of the drug product as required by § 211.84(d) of this chapter and on the drug product as
p.000097: required by § 211.165 of this chapter.
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097: § 314.50
p.000097: (c) The proposed or actual master production record, including a descrip- tion of the equipment, to
p.000097: be used for the manufacture of a commercial lot of the drug product or a comparably de- tailed description
p.000097: of the production process for a representative batch of the drug product.
p.000097: (iii) Environmental impact. The appli- cation is required to contain either a claim for categorical
p.000097: exclusion under
p.000097: § 25.30 or 25.31 of this chapter or an en- vironmental assessment under § 25.40 of this chapter.
p.000097: (iv) The applicant may, at its option, submit a complete chemistry, manu- facturing, and controls section 90 to
p.000097: 120 days before the anticipated submission of the remainder of the application. FDA will review
p.000097: such early submis- sions as resources permit.
p.000097: (v) The applicant shall include a statement certifying that the field copy of the application
p.000097: has been pro- vided to the applicant’s home FDA dis- trict office.
p.000097: (2) Nonclinical pharmacology and toxi- cology section. A section describing, with the aid of graphs
p.000097: and tables, ani- mal and in vitro studies with drug, in- cluding the following:
p.000097: (i) Studies of the pharmacological ac- tions of the drug in relation to its pro- posed therapeutic indication and
p.000097: stud- ies that otherwise define the pharma- cologic properties of the drug or are pertinent to possible
p.000097: adverse effects.
p.000097: (ii) Studies of the toxicological ef- fects of the drug as they relate to the drug’s intended clinical
p.000097: uses, includ- ing, as appropriate, studies assessing the drug’s acute, subacute, and chronic toxicity;
p.000097: carcinogenicity; and studies of toxicities related to the drug’s par- ticular mode of administration or
p.000097: con- ditions of use.
p.000097: (iii) Studies, as appropriate, of the ef- fects of the drug on reproduction and on the developing fetus.
p.000097: (iv) Any studies of the absorption, distribution, metabolism, and excre- tion of the drug in animals.
p.000097: (v) For each nonclinical laboratory study subject to the good laboratory practice regulations under part
p.000097: 58 a statement that it was conducted in compliance with the good laboratory practice regulations in
p.000097: part 58, or, if the study was not conducted in compli-
p.000098: 98
p.000098: 21 CFR Ch. I (4–1–12 Edition)
p.000098: ance with those regulations, a brief statement of the reason for the non- compliance.
p.000098: (3) Human pharmacokinetics and bio- availability section. A section describing the human pharmacokinetic
p.000098: data and human bioavailability data, or infor- mation supporting a waiver of the sub- mission of in vivo
p.000098: bioavailability data under subpart B of part 320, including the following:
...
p.000098: (5) Clinical data section. A section de- scribing the clinical investigations of the drug, including the
p.000098: following:
p.000098: (i) A description and analysis of each clinical pharmacology study of the drug, including a brief
p.000098: comparison of the results of the human studies with the animal pharmacology and toxi- cology data.
p.000098: (ii) A description and analysis of each controlled clinical study pertinent to a proposed use of the drug, including
p.000098: the protocol and a description of the statis- tical analyses used to evaluate the study. If the study report
p.000098: is an interim analysis, this is to be noted and a pro- jected completion date provided. Con- trolled
p.000098: clinical studies that have not been analyzed in detail for any reason (e.g., because they have been
p.000098: discon- tinued or are incomplete) are to be in- cluded in this section, including a copy of the protocol and
p.000098: a brief description of the results and status of the study.
p.000098: (iii) A description of each uncon-
p.000098: trolled clinical study, a summary of the results, and a brief statement ex- plaining why the study
p.000098: is classified as uncontrolled.
p.000098: (iv) A description and analysis of any other data or information relevant to an evaluation of the safety and
p.000098: effec- tiveness of the drug product obtained or otherwise received by the applicant from any source,
p.000098: foreign or domestic, including information derived from clinical investigations, including con- trolled
p.000098: and uncontrolled studies of uses of the drug other than those proposed in the application, commercial
p.000098: mar- keting experience, reports in the sci- entific literature, and unpublished sci- entific papers.
p.000098: (v) An integrated summary of the
p.000098: data demonstrating substantial evi- dence of effectiveness for the claimed indications. Evidence is
p.000098: also required to support the dosage and administra- tion section of the labeling, including support for
p.000098: the dosage and dose inter- val recommended. The effectiveness data shall be presented by gender,
p.000098: age, and racial subgroups and shall identify any modifications of dose or dose inter- val needed for specific
p.000098: subgroups. Ef-
p.000099: 99
p.000099:
p.000099: fectiveness data from other subgroups of the population of patients treated, when appropriate, such
p.000099: as patients with renal failure or patients with dif- ferent levels of severity of the disease, also
p.000099: shall be presented.
p.000099: (vi) A summary and updates of safety information, as follows:
p.000099: (a) The applicant shall submit an in- tegrated summary of all available in- formation about the safety
p.000099: of the drug product, including pertinent animal data, demonstrated or potential ad- verse effects of
p.000099: the drug, clinically sig- nificant drug/drug interactions, and other safety considerations, such as
p.000099: data from epidemiological studies of related drugs. The safety data shall be presented by gender,
p.000099: age, and racial subgroups. When appropriate, safety data from other subgroups of the popu- lation of
p.000099: patients treated also shall be presented, such as for patients with renal failure or patients with
p.000099: different levels of severity of the disease. A de- scription of any statistical analyses performed in
p.000099: analyzing safety data should also be included, unless already included under paragraph (d)(5)(ii) of
p.000099: this section.
p.000099: (b) The applicant shall, under section
p.000099: 505(i) of the act, update periodically its pending application with new safety in- formation learned about the drug
p.000099: that may reasonably affect the statement of contraindications, warnings, pre- cautions, and adverse
p.000099: reactions in the draft labeling and, if applicable, any Medication Guide required under part
p.000099: 208 of this chapter. These ‘‘safety up- date reports’’ are required to include the same kinds of
p.000099: information (from clinical studies, animal studies, and other sources) and are required to be submitted
p.000099: in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition,
p.000099: the reports are required to include the case report forms for each patient who died during a clinical
p.000099: study or who did not complete the study because of an adverse event (unless this requirement is waived).
p.000099: The applicant shall submit these reports (1) 4 months after the ini- tial submission; (2) in a resubmission
p.000099: following receipt of a complete re- sponse letter; and (3) at other times as requested by FDA. Prior
p.000099: to the submis- sion of the first such report, applicants
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099: § 314.50
p.000099: are encouraged to consult with FDA re- garding further details on its form and content.
p.000099: (vii) If the drug has a potential for abuse, a description and analysis of studies or information
p.000099: related to abuse of the drug, including a proposal for scheduling under the Controlled Sub- stances Act. A
p.000099: description of any stud- ies related to overdosage is also re- quired, including information on dialy- sis,
p.000099: antidotes, or other treatments, if known.
p.000099: (viii) An integrated summary of the benefits and risks of the drug, includ- ing a discussion of why the
p.000099: benefits ex- ceed the risks under the conditions stated in the labeling.
p.000099: (ix) A statement with respect to each clinical study involving human sub- jects that it either was
p.000099: conducted in compliance with the institutional re- view board regulations in part 56, or was not subject
p.000099: to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the in- formed
p.000099: consent regulations in part 50.
p.000099: (x) If a sponsor has transferred any obligations for the conduct of any clin- ical study to a contract
p.000099: research orga- nization, a statement containing the name and address of the contract re- search
p.000099: organization, identification of the clinical study, and a listing of the obligations transferred. If
p.000099: all obliga- tions governing the conduct of the study have been transferred, a general statement of
p.000099: this transfer—in lieu of a listing of the specific obligations trans- ferred—may be submitted.
p.000099: (xi) If original subject records were audited or reviewed by the sponsor in the course of monitoring any
p.000099: clinical study to verify the accuracy of the case reports submitted to the sponsor, a list identifying each clinical
p.000099: study so au- dited or reviewed.
p.000099: (6) Statistical section. A section de- scribing the statistical evaluation of clinical data,
p.000099: including the following:
p.000099: (i) A copy of the information sub- mitted under paragraph (d)(5)(ii) of this section concerning the
p.000099: description and analysis of each controlled clinical study, and the documentation and sup- porting
p.000099: statistical analyses used in evaluating the controlled clinical stud- ies.
p.000099: 21 CFR Ch. I (4–1–12 Edition)
p.000099: (ii) A copy of the information sub- mitted under paragraph (d)(5)(vi)(a) of this section concerning a
p.000099: summary of information about the safety of the drug product, and the documentation and supporting
p.000099: statistical analyses used in evaluating the safety informa- tion.
p.000099: (7) Pediatric use section. A section de- scribing the investigation of the drug for use in pediatric
p.000099: populations, includ- ing an integrated summary of the in- formation (the clinical pharmacology studies,
p.000099: controlled clinical studies, or uncontrolled clinical studies, or other data or information) that is relevant to
p.000099: the safety and effectiveness and bene- fits and risks of the drug in pediatric populations for the
p.000099: claimed indica- tions, a reference to the full descrip- tions of such studies provided under
p.000099: paragraphs (d)(3) and (d)(5) of this sec- tion, and information required to be submitted under §
p.000099: 314.55.
p.000099: (e) Samples and labeling. (1) Upon re-
p.000099: quest from FDA, the applicant shall submit the samples described below to the places identified in the
p.000099: agency’s re- quest. FDA will generally ask appli- cants to submit samples directly to two or more
p.000099: agency laboratories that will perform all necessary tests on the samples and validate the applicant’s
p.000099: analytical procedures.
p.000099: (i) Four representative samples of the following, each sample in sufficient quantity to permit FDA to
p.000099: perform three times each test described in the application to determine whether the drug substance and the
p.000099: drug product meet the specifications given in the ap- plication:
p.000099: (a) The drug product proposed for marketing;
p.000099: (b) The drug substance used in the drug product from which the samples of the drug product were taken; and
p.000099: (c) Reference standards and blanks (except that reference standards recog- nized in an official compendium
p.000099: need not be submitted).
p.000099: (ii) Samples of the finished market package, if requested by FDA.
p.000099: (2) The applicant shall submit the following in the archival copy of the application:
p.000099: (i) Three copies of the analytical pro- cedures and related descriptive infor- mation contained in the
p.000099: chemistry,
p.000100: 100
p.000100:
p.000100:
p.000100:
p.000100:
p.000100:
p.000100:
p.000100:
p.000100: Food and Drug Administration, HHS § 314.50
p.000100:
p.000100:
p.000100: manufacturing, and controls section under paragraph (d)(1) of this section for the drug substance and
p.000100: the drug product that are necessary for FDA’s laboratories to perform all necessary tests on the samples
p.000100: and to validate the applicant’s analytical procedures. The related descriptive information in- cludes a
p.000100: description of each sample; the proposed regulatory specifications for the drug; a detailed description
p.000100: of the methods of analysis; supporting data for accuracy, specificity, precision and ruggedness; and
p.000100: complete results of the applicant’s tests on each sample.
p.000100: (ii) Copies of the label and all label-
p.000100: ing for the drug product (including, if applicable, any Medication Guide re- quired under part 208 of
p.000100: this chapter) for the drug product (4 copies of draft labeling or 12 copies of final printed la- beling).
p.000100: (f) Case report forms and tabulations. The archival copy of the application is required to contain the
p.000100: following case report tabulations and case report forms:
p.000100: (1) Case report tabulations. The appli- cation is required to contain tabula- tions of the data from
p.000100: each adequate and well-controlled study under
p.000100: § 314.126 (Phase 2 and Phase 3 studies as described in §§ 312.21 (b) and (c) of this chapter), tabulations of
p.000100: the data from the earliest clinical pharmacology studies (Phase 1 studies as described in
p.000100: § 312.21(a) of this chapter), and tabula- tions of the safety data from other clinical studies.
p.000100: Routine submission of other patient data from uncontrolled studies is not required. The tabulations are
p.000100: required to include the data on each patient in each study, except that the applicant may delete those
p.000100: tabula- tions which the agency agrees, in ad- vance, are not pertinent to a review of the drug’s safety or
p.000100: effectiveness. Upon request, FDA will discuss with the ap- plicant in a ‘‘pre-NDA’’ conference those
p.000100: tabulations that may be appro- priate for such deletion. Barring un- foreseen circumstances,
p.000100: tabulations agreed to be deleted at such a con- ference will not be requested during the
p.000100: conduct of FDA’s review of the ap- plication. If such unforeseen cir- cumstances do occur, any
p.000100: request for deleted tabulations will be made by the director of the FDA division respon-
p.000100:
p.000100: sible for reviewing the application, in accordance with paragraph (f)(3) of this section.
p.000100: (2) Case report forms. The application is required to contain copies of indi- vidual case report forms
p.000100: for each pa- tient who died during a clinical study or who did not complete the study be- cause of an
p.000100: adverse event, whether be- lieved to be drug related or not, includ- ing patients receiving reference drugs or
p.000100: placebo. This requirement may be waived by FDA for specific studies if the case report forms are
p.000100: unnecessary for a proper review of the study.
p.000100: (3) Additional data. The applicant shall submit to FDA additional case re- port forms and tabulations
p.000100: needed to conduct a proper review of the applica- tion, as requested by the director of the FDA division
p.000100: responsible for re- viewing the application. The appli- cant’s failure to submit information re- quested by
p.000100: FDA within 30 days after re- ceipt of the request may result in the agency viewing any eventual submis- sion
p.000100: as a major amendment under
p.000100: § 314.60 and extending the review period as necessary. If desired by the appli- cant, the FDA division
p.000100: director will verify in writing any request for addi- tional data that was made orally.
p.000100: (4) Applicants are invited to meet with FDA before submitting an appli- cation to discuss the
p.000100: presentation and format of supporting information. If the applicant and FDA agree, the appli- cant may submit
p.000100: tabulations of patient data and case report forms in a form other than hard copy, for example, on
p.000100: microfiche or computer tapes.
p.000100: (g) Other. The following general re- quirements apply to the submission of information within the summary
p.000100: under paragraph (c) of this section and within the technical sections under paragraph
p.000100: (d) of this section.
p.000100: (1) The applicant ordinarily is not re- quired to resubmit information pre- viously submitted, but may
p.000100: incor- porate the information by reference. A reference to information submitted previously is
p.000100: required to identify the file by name, reference number, vol- ume, and page number in the agency’s
p.000100: records where the information can be found. A reference to information sub- mitted to the agency by a person
p.000100: other
p.000101: 101
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101: § 314.50
p.000101: than the applicant is required to con- tain a written statement that author- izes the reference and that is
p.000101: signed by the person who submitted the informa- tion.
p.000101: (2) The applicant shall submit an ac- curate and complete English trans- lation of each part of the
p.000101: application that is not in English. The applicant shall submit a copy of each original lit- erature
p.000101: publication for which an English translation is submitted.
p.000101: (3) If an applicant who submits a new drug application under section 505(b) of the act obtains a ‘‘right of reference
p.000101: or use,’’ as defined under § 314.3(b), to an investigation described in clause (A) of section 505(b)(1) of the
p.000101: act, the appli- cant shall include in its application a written statement signed by the owner of the data
p.000101: from each such investiga- tion that the applicant may rely on in support of the approval of its
p.000101: applica- tion, and provide FDA access to, the underlying raw data that provide the basis for the report of
p.000101: the investigation submitted in its application.
p.000101: (h) Patent information. The applica- tion is required to contain the patent information described under §
p.000101: 314.53.
p.000101: (i) Patent certification—(1) Contents. A 505(b)(2) application is required to con- tain the following:
p.000101: (i) Patents claiming drug, drug product, or method of use. (A) Except as provided in paragraph (i)(2) of this
p.000101: section, a certification with respect to each pat- ent issued by the United States Patent and Trademark Office
p.000101: that, in the opin- ion of the applicant and to the best of its knowledge, claims a drug (the drug product
p.000101: or drug substance that is a component of the drug product) on which investigations that are
p.000101: relied upon by the applicant for approval of its application were conducted or that claims an approved
p.000101: use for such drug and for which information is required to be filed under section 505(b) and (c) of the
p.000101: act and § 314.53. For each such patent, the applicant shall provide the patent number and certify, in
p.000101: its opin- ion and to the best of its knowledge, one of the following circumstances:
p.000101: (1) That the patent information has not been submitted to FDA. The appli- cant shall entitle such a
p.000101: certification ‘‘Paragraph I Certification’’;
p.000101: 21 CFR Ch. I (4–1–12 Edition)
p.000101: (2) That the patent has expired. The applicant shall entitle such a certifi- cation ‘‘Paragraph II
p.000101: Certification’’;
p.000101: (3) The date on which the patent will expire. The applicant shall entitle such a certification ‘‘Paragraph III
p.000101: Certifi- cation’’; or
p.000101: (4) That the patent is invalid, unen- forceable, or will not be infringed by the manufacture, use, or
p.000101: sale of the drug product for which the application is submitted. The applicant shall enti- tle such a
p.000101: certification ‘‘Paragraph IV Certification’’. This certification shall be submitted in the following form:
p.000101: I, (name of applicant), certify that Patent No. llllll (is invalid, unenforceable, or ill not be infringed
p.000101: by the manufacture, use, or sale of) (name of proposed drug product) for which this application
p.000101: is submitted.
p.000101: The certification shall be accompanied by a statement that the applicant will comply with the
p.000101: requirements under
p.000101: § 314.52(a) with respect to providing a notice to each owner of the patent or their representatives and
p.000101: to the holder of the approved application for the drug product which is claimed by the patent or a
p.000101: use of which is claimed by the patent and with the requirements under § 314.52(c) with respect to
p.000101: the content of the notice.
p.000101: (B) If the drug on which investiga- tions that are relied upon by the appli- cant were conducted is itself a
p.000101: licensed generic drug of a patented drug first approved under section 505(b) of the act, the
p.000101: appropriate patent certifi- cation under this section with respect to each patent that claims the first-ap-
p.000101: proved patented drug or that claims an approved use for such a drug.
p.000101: (ii) No relevant patents. If, in the opin- ion of the applicant and to the best of its knowledge, there are no
p.000101: patents de- scribed in paragraph (i)(1)(i) of this sec- tion, a certification in the following form:
p.000101: In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the drug
p.000101: or drugs on which investiga- tions that are relied upon in this application were conducted or that claim a
p.000101: use of such drug or drugs.
p.000101: (iii) Method of use patent. (A) If infor- mation that is submitted under section 505(b) or (c) of the act and §
p.000101: 314.53 is for
p.000102: 102
p.000102:
p.000102:
p.000102:
p.000102:
p.000102:
p.000102:
p.000102:
p.000102: Food and Drug Administration, HHS § 314.50
p.000102:
p.000102:
p.000102: a method of use patent, and the label- ing for the drug product for which the applicant is seeking
p.000102: approval does not include any indications that are cov- ered by the use patent, a statement ex- plaining that
p.000102: the method of use patent does not claim any of the proposed in- dications.
p.000102: (B) If the labeling of the drug product for which the applicant is seeking ap- proval includes an indication
p.000102: that, ac- cording to the patent information sub- mitted under section 505(b) or (c) of the act and § 314.53 or
p.000102: in the opinion of the applicant, is claimed by a use patent, the applicant shall submit an applica- ble
p.000102: certification under paragraph (i)(1)(i) of this section.
p.000102: (2) Method of manufacturing patent. An applicant is not required to make a certification with respect to
p.000102: any pat- ent that claims only a method of man- ufacturing the drug product for which the applicant is seeking
p.000102: approval.
p.000102: (3) Licensing agreements. If a 505(b)(2) application is for a drug or method of using a drug claimed by
p.000102: a patent and the applicant has a licensing agree- ment with the patent owner, the appli- cant shall
p.000102: submit a certification under paragraph (i)(1)(i)(A)(4) of this section (‘‘Paragraph IV Certification’’) as
p.000102: to that patent and a statement that it has been granted a patent license. If the patent owner consents to an
p.000102: immediate effective date upon approval of the 505(b)(2) application, the application shall contain a
p.000102: written statement from the patent owner that it has a licens- ing agreement with the applicant and that it
p.000102: consents to an immediate effec- tive date.
p.000102: (4) Late submission of patent informa-
p.000102: tion. If a patent described in paragraph (i)(1)(i)(A) of this section is issued and the holder of the
p.000102: approved application for the patented drug does not submit the required information on the patent within 30
p.000102: days of issuance of the pat- ent, an applicant who submitted a 505(b)(2) application that, before
p.000102: the submission of the patent information, contained an appropriate patent cer- tification is not
p.000102: required to submit an amended certification. An applicant whose 505(b)(2) application is filed after a late
p.000102: submission of patent informa- tion or whose 505(b)(2) application was previously filed but did not contain
p.000102: an
p.000102:
p.000102: appropriate patent certification at the time of the patent submission shall submit a certification under
p.000102: paragraph (i)(1)(i) or (i)(1)(ii) of this section or a statement under paragraph (i)(1)(iii) of this section
p.000102: as to that patent.
p.000102: (5) Disputed patent information. If an applicant disputes the accuracy or rel- evance of patent
p.000102: information sub- mitted to FDA, the applicant may seek a confirmation of the correctness of the patent
p.000102: information in accordance with the procedures under § 314.53(f). Unless the patent information is with-
p.000102: drawn or changed, the applicant must submit an appropriate certification for each relevant patent.
p.000102: (6) Amended certifications. A certifi- cation submitted under paragraphs (i)(1)(i) through (i)(1)(iii)
p.000102: of this section may be amended at any time before the effective date of the approval of the ap- plication. An applicant
p.000102: shall submit an amended certification as an amend- ment to a pending application or by letter to an
p.000102: approved application. If an applicant with a pending application voluntarily makes a patent certifi-
p.000102: cation for an untimely filed patent, the applicant may withdraw the patent certification for the untimely filed
p.000102: pat- ent. Once an amendment or letter for the change in certification has been submitted, the
p.000102: application will no longer be considered to be one con- taining the prior certification.
p.000102: (i) After finding of infringement. An ap- plicant who has submitted a certifi- cation under paragraph
p.000102: (i)(1)(i)(A)(4) of this section and is sued for patent in- fringement within 45 days of the re- ceipt of
p.000102: notice sent under § 314.52 shall amend the certification if a final judg- ment in the action is entered
p.000102: finding the patent to be infringed unless the final judgment also finds the patent to be invalid. In the
p.000102: amended certifi- cation, the applicant shall certify under paragraph (i)(1)(i)(A)(3) of this
p.000102: section that the patent will expire on a specific date.
p.000102: (ii) After removal of a patent from the list. If a patent is removed from the list, any applicant
p.000102: with a pending ap- plication (including a tentatively ap- proved application with a delayed ef- fective
p.000102: date) who has made a certifi- cation with respect to such patent
p.000103: 103
p.000103:
p.000103:
p.000103:
p.000103:
p.000103:
p.000103:
p.000103:
p.000103:
p.000103: § 314.50
p.000103: shall amend its certification. The ap- plicant shall certify under paragraph (i)(1)(ii) of this section
p.000103: that no patents described in paragraph (i)(1)(i) of this section claim the drug or, if other rel- evant
p.000103: patents claim the drug, shall amend the certification to refer only to those relevant patents. In the
p.000103: amend- ment, the applicant shall state the rea- son for the change in certification (that the patent is or
p.000103: has been removed from the list). A patent that is the sub- ject of a lawsuit under § 314.107(c) shall not be
p.000103: removed from the list until FDA determines either that no delay in ef- fective dates of approval is
p.000103: required under that section as a result of the lawsuit, that the patent has expired, or that any such period
p.000103: of delay in effec- tive dates of approval is ended. An ap- plicant shall submit an amended cer-
p.000103: tification as an amendment to a pend- ing application. Once an amendment for the change has been
p.000103: submitted, the application will no longer be consid- ered to be one containing a certifi- cation
p.000103: under paragraph (i)(1)(i)(A)(4) of this section.
p.000103: (iii) Other amendments. (A) Except as
p.000103: provided in paragraphs (i)(4) and (i)(6)(iii)(B) of this section, an appli- cant shall amend a
p.000103: submitted certifi- cation if, at any time before the effec- tive date of the approval of the applica- tion, the
p.000103: applicant learns that the sub- mitted certification is no longer accu- rate.
p.000103: (B) An applicant is not required to amend a submitted certification when information on an otherwise
p.000103: applicable patent is submitted after the effective date of approval for the 505(b)(2) appli- cation.
p.000103: (j) Claimed exclusivity. A new drug product, upon approval, may be enti- tled to a period of
p.000103: marketing exclu- sivity under the provisions of § 314.108. If an applicant believes its drug prod- uct is
p.000103: entitled to a period of exclu- sivity, it shall submit with the new drug application prior
p.000103: to approval the following information:
p.000103: (1) A statement that the applicant is claiming exclusivity.
p.000103: (2) A reference to the appropriate paragraph under § 314.108 that supports its claim.
p.000103: (3) If the applicant claims exclusivity under § 314.108(b)(2), information to
p.000103: 21 CFR Ch. I (4–1–12 Edition)
p.000103: show that, to the best of its knowledge or belief, a drug has not previously been approved under section
p.000103: 505(b) of the act containing any active moiety in the drug for which the applicant is seeking approval.
p.000103: (4) If the applicant claims exclusivity under § 314.108(b)(4) or (b)(5), the fol- lowing information to
p.000103: show that the application contains ‘‘new clinical in- vestigations’’ that are ‘‘essential to ap- proval of
p.000103: the application or supple- ment’’ and were ‘‘conducted or spon- sored by the applicant:’’
p.000103: (i) ‘‘Ne clinical investigations.’’ A cer- tification that to the best of the appli- cant’s knowledge each of the
p.000103: clinical investigations included in the applica- tion meets the definition of ‘‘new clin- ical
p.000103: investigation’’ set forth in
p.000103: § 314.108(a).
p.000103: (ii) ‘‘Essential to approval.’’ A list of all published studies or publicly avail- able reports of
p.000103: clinical investigations known to the applicant through a lit- erature search that are relevant to the conditions
p.000103: for which the applicant is seeking approval, a certification that the applicant has thoroughly searched
p.000103: the scientific literature and, to the best of the applicant’s knowledge, the list is complete and
p.000103: accurate and, in the applicant’s opinion, such published studies or publicly available reports do not provide a
p.000103: sufficient basis for the approval of the conditions for which the applicant is seeking approval with- out
p.000103: reference to the new clinical inves- tigation(s) in the application, and an explanation as to why the studies
p.000103: or reports are insufficient.
p.000103: (iii) ‘‘Conducted or sponsored by.’’ If
p.000103: the applicant was the sponsor named in the Form FDA–1571 for an investiga- tional new drug application
p.000103: (IND) under which the new clinical investiga- tion(s) that is essential to the approval of its application was
p.000103: conducted, iden- tification of the IND by number. If the applicant was not the sponsor of the IND under which
p.000103: the clinical investiga- tion(s) was conducted, a certification that the applicant or its predecessor in interest
p.000103: provided substantial support for the clinical investigation(s) that is essential to the approval of its
p.000103: applica- tion, and information supporting the certification. To demonstrate ‘‘sub- stantial support,’’
p.000103: an applicant must
p.000104: 104
p.000104:
p.000104:
p.000104:
p.000104:
p.000104:
p.000104:
p.000104:
p.000104: Food and Drug Administration, HHS § 314.52
p.000104:
p.000104:
p.000104: either provide a certified statement from a certified public accountant that the applicant provided 50
p.000104: percent or more of the cost of conducting the study or provide an explanation of why FDA should
p.000104: consider the applicant to have conducted or sponsored the study if the applicant’s financial contribu-
p.000104: tion to the study is less than 50 percent or the applicant did not sponsor the in- vestigational new drug. A
p.000104: predecessor in interest is an entity, e.g., a corpora- tion, that the applicant has taken over, merged with, or
p.000104: purchased, or from which the applicant has purchased all rights to the drug. Purchase of non- exclusive
p.000104: rights to a clinical investiga- tion after it is completed is not suffi- cient to satisfy this definition.
p.000104: (k) Financial certification or disclosure
p.000104: statement. The application shall contain a financial certification or disclosure statement or both as required
p.000104: by part 54 of this chapter.
p.000104: (l) Format of an original application—
p.000104: (1) Archival copy. The applicant must submit a complete archival copy of the application that contains the
p.000104: informa- tion required under paragraphs (a) through (f) of this section. FDA will maintain the
p.000104: archival copy during the review of the application to permit in- dividual reviewers to refer to informa-
p.000104: tion that is not contained in their par- ticular technical sections of the appli- cation, to give other agency
p.000104: personnel access to the application for official business, and to maintain in one place a complete
p.000104: copy of the application. Ex- cept as required by paragraph (l)(1)(i) of this section, applicants may submit
p.000104: the archival copy on paper or in elec- tronic format provided that electronic submissions are made in
p.000104: accordance with part 11 of this chapter.
p.000104: (i) Labeling. The content of labeling
p.000104: required under § 201.100(d)(3) of this chapter (commonly referred to as the package insert or
p.000104: professional label- ing), including all text, tables, and fig- ures, must be submitted to the agency in
p.000104: electronic format as described in paragraph (l)(5) of this section. This re- quirement is in addition to the
...
p.000104: separately bound with a copy of the application form required under paragraph (a) of this section and a copy of the
p.000104: summary required under paragraph (c) of this section.
p.000104: (3) Field copy. The applicant must
p.000104: submit a field copy of the application that contains the technical section de- scribed in paragraph
p.000104: (d)(1) of this sec- tion, a copy of the application form re- quired under paragraph (a) of this sec- tion, a
p.000104: copy of the summary required under paragraph (c) of this section, and a certification that the field copy is
p.000104: a true copy of the technical section de- scribed in paragraph (d)(1) of this sec- tion contained in the
p.000104: archival and re- view copies of the application.
p.000104: (4) Binding folders. The applicant may
p.000104: obtain from FDA sufficient folders to bind the archival, the review, and the field copies of the
p.000104: application.
p.000104: (5) Electronic format submissions. Elec- tronic format submissions must be in a form that FDA can process, review,
p.000104: and archive. FDA will periodically issue guidance on how to provide the elec- tronic submission
p.000104: (e.g., method of transmission, media, file formats, prep- aration and organization of files).
p.000104: [50 FR 7493, Feb. 22, 1985]
p.000104: EDITORIAL NOTE: For FEDERAL REGISTER ci-
p.000104: tations affecting § 314.50, see the List of CFR Sections Affected, which appears in the Finding Aids
p.000104: section of the printed volume and at .fdsys.gov.
p.000104:
p.000104: § 314.52 Notice of certification of inva- lidity or noninfringement of a pat- ent.
p.000104: (a) Notice of certification. For each patent which claims the drug or drugs on which investigations
p.000104: that are relied upon by the applicant for approval of its application were conducted or which claims
p.000104: a use for such drug or drugs and which the applicant certifies under § 314.50(i)(1)(i)(A)(4) that a patent is
p.000104: invalid, unenforceable, or will not be
p.000105: 105
p.000105:
p.000105:
p.000105:
p.000105:
p.000105:
p.000105:
p.000105:
p.000105:
p.000105: § 314.52
p.000105: infringed, the applicant shall send no- tice of such certification by registered or certified mail,
p.000105: return receipt re- quested to each of the following per- sons:
p.000105: (1) Each owner of the patent that is the subject of the certification or the representative designated by
p.000105: the owner to receive the notice. The name and ad- dress of the patent owner or its rep- resentative may be
p.000105: obtained from the United States Patent and Trademark Office; and
p.000105: (2) The holder of the approved appli- cation under section 505(b) of the act for each drug product which is
p.000105: claimed by the patent or a use of which is claimed by the patent and for which the applicant is
p.000105: seeking approval, or, if the application holder does not reside or maintain a place of business within the
p.000105: United States, the application holder’s attorney, agent, or other au- thorized official. The name and
p.000105: address of the application holder or its attor- ney, agent, or authorized official may be obtained from
p.000105: the Orange Book Staff, Office of Generic Drugs, 7500 Standish Pl., Rockville, MD 20855.
p.000105: (3) This paragraph does not apply to a use patent that claims no uses for which the applicant is
p.000105: seeking ap- proval.
p.000105: (b) Sending the notice. The applicant shall send the notice required by para- graph (a) of this section
p.000105: when it re- ceives from FDA an acknowledgment letter stating that its application has been filed. At the
p.000105: same time, the appli- cant shall amend its application to in- clude a statement certifying that the notice
p.000105: has been provided to each person identified under paragraph (a) of this section and that the notice met
p.000105: the content requirement under paragraph
p.000105: (c) of this section.
p.000105: (c) Content of a notice. In the notice, the applicant shall cite section 505(b)(3)(B) of the act
p.000105: and shall include, but not be limited to, the following in- formation:
p.000105: (1) A statement that a 505(b)(2) appli- cation submitted by the applicant has been filed by FDA.
p.000105: (2) The application number.
p.000105: (3) The established name, if any, as defined in section 502(e)(3) of the act, of the proposed drug product.
p.000105: 21 CFR Ch. I (4–1–12 Edition)
p.000105: (4) The active ingredient, strength, and dosage form of the proposed drug product.
p.000105: (5) The patent number and expiration date, as submitted to the agency or as known to the applicant, of each
p.000105: patent alleged to be invalid, unenforceable, or not infringed.
p.000105: (6) A detailed statement of the fac- tual and legal basis of the applicant’s opinion that the patent is
p.000105: not valid, unenforceable, or will not be infringed. The applicant shall include in the de- tailed statement:
p.000105: (i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is
p.000105: not in- fringed.
p.000105: (ii) For each claim of a patent al- leged to be invalid or unenforceable, a full and detailed
p.000105: explanation of the grounds supporting the allegation.
p.000105: (7) If the applicant does not reside or have a place of business in the United States, the name and
p.000105: address of an agent in the United States authorized to accept service of process for the ap- plicant.
p.000105: (d) Amendment to an application. If an application is amended to include the certification described in §
p.000105: 314.50(i), the applicant shall send the notice required by paragraph (a) of this section at the same time that
p.000105: the amendment to the application is submitted to FDA.
p.000105: (e) Documentation of receipt of notice. The applicant shall amend its applica- tion to document receipt
p.000105: of the notice required under paragraph (a) of this section by each person provided the no- tice. The
p.000105: applicant shall include a copy of the return receipt or other similar evidence of the date the notification
p.000105: was received. FDA will accept as ade- quate documentation of the date of re- ceipt a return receipt or
p.000105: a letter ac- knowledging receipt by the person pro- vided the notice. An applicant may rely on another form
p.000105: of documentation only if FDA has agreed to such docu- mentation in advance. A copy of the notice itself
p.000105: need not be submitted to the agency.
p.000105: (f) Approval. If the requirements of this section are met, the agency will presume the notice to be
p.000105: complete and sufficient, and it will count the day fol- lowing the date of receipt of the notice
p.000106: 106
p.000106:
p.000106:
p.000106:
p.000106:
p.000106:
p.000106:
p.000106:
p.000106: Food and Drug Administration, HHS § 314.53
p.000106:
p.000106:
p.000106: by the patent owner or its representa- tive and by the approved application holder as the first day of the
p.000106: 45-day pe- riod provided for in section 505(c)(3)(C) of the act. FDA may, if the applicant amends its
p.000106: application with a written statement that a later date should be used, count from such later date.
p.000106: [59 FR 50362, Oct. 3, 1994, as amended at 68 FR
p.000106: 36703, June 18, 2003; 69 FR 11310, Mar. 10, 2004;
p.000106: 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24,
p.000106: 2009]
p.000106:
p.000106: § 314.53 Submission of patent informa- tion.
p.000106: (a) Who must submit patent informa- tion. This section applies to any appli- cant who submits to FDA
p.000106: a new drug application or an amendment to it under section 505(b) of the act and
p.000106: § 314.50 or a supplement to an approved application under § 314.70, except as provided in paragraph
p.000106: (d)(2) of this sec- tion.
p.000106: (b) Patents for hich information must
p.000106: be submitted and patents for hich infor- mation must not be submitted—(1) General requirements. An applicant
p.000106: described in paragraph (a) of this section shall sub- mit the required information on the declaration
p.000106: form set forth in paragraph
p.000106: (c) of this section for each patent that claims the drug or a method of using the drug that is the
p.000106: subject of the new drug application or amendment or sup- plement to it and with respect to which a claim of
p.000106: patent infringement could reasonably be asserted if a person not licensed by the owner of the patent en- gaged
p.000106: in the manufacture, use, or sale of the drug product. For purposes of this part, such patents consist
p.000106: of drug substance (active ingredient) patents, drug product (formulation and com- position) patents,
p.000106: and method-of-use patents. For patents that claim the drug substance, the applicant shall submit
p.000106: information only on those pat- ents that claim the drug substance that is the subject of the pending or
p.000106: ap- proved application or that claim a drug substance that is the same as the ac- tive ingredient that is
p.000106: the subject of the approved or pending application. For patents that claim a polymorph that is
p.000106: the same as the active ingre- dient described in the approved or pending application, the
p.000106: applicant shall certify in the declaration forms
p.000106:
p.000106: that the applicant has test data, as set forth in paragraph (b)(2) of this section, demonstrating that a drug
p.000106: product containing the polymorph will perform the same as the drug product described in the new drug application.
p.000106: For pat- ents that claim a drug product, the ap- plicant shall submit information only on those patents that
p.000106: claim a drug product, as is defined in § 314.3, that is described in the pending or approved
p.000106: application. For patents that claim a method of use, the applicant shall sub- mit information only on those
p.000106: patents that claim indications or other condi- tions of use that are described in the pending or approved
p.000106: application. The applicant shall separately identify each pending or approved method of use and
p.000106: related patent claim. For ap- proved applications, the applicant sub- mitting the method-of-use patent shall
p.000106: identify with specificity the section of the approved labeling that corresponds to the method of use
p.000106: claimed by the patent submitted. Process patents, pat- ents claiming packaging, patents claiming
p.000106: metabolites, and patents claiming intermediates are not covered by this section, and information on
p.000106: these patents must not be submitted to FDA.
p.000106: (2) Test Data for Submission of Patent Information for Patents That Claim a Polymorph. The test data,
p.000106: referenced in paragraph (b)(1) of this section, must include the following:
p.000106: (i) A full description of the poly- morphic form of the drug substance, in- cluding its physical and
p.000106: chemical char- acteristics and stability; the method of synthesis (or isolation) and purifi- cation of
p.000106: the drug substance; the proc- ess controls used during manufacture and packaging; and such specifications
p.000106: and analytical methods as are nec- essary to assure the identity, strength, quality, and purity of the
p.000106: polymorphic form of the drug substance;
p.000106: (ii) The executed batch record for a drug product containing the poly- morphic form of the
p.000106: drug substance and documentation that the batch was manufactured under current good man- ufacturing practice
p.000106: requirements;
p.000106: (iii) Demonstration of bioequivalence between the executed batch of the drug product that contains the polymorphic
p.000107: 107
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107: § 314.53
p.000107: form of the drug substance and the drug product as described in the NDA;
p.000107: (iv) A list of all components used in the manufacture of the drug product containing the polymorphic form
p.000107: and a statement of the composition of the drug product; a statement of the speci- fications and
p.000107: analytical methods for each component; a description of the manufacturing and packaging proce- dures
p.000107: and in-process controls for the drug product; such specifications and analytical methods as are necessary to
p.000107: assure the identity, strength, quality, purity, and bioavailability of the drug product, including release and
p.000107: stability data complying with the approved product specifications to demonstrate pharmaceutical
p.000107: equivalence and com- parable product stability; and
p.000107: (v) Comparative in vitro dissolution
p.000107: testing on 12 dosage units each of the executed test batch and the new drug application product.
p.000107: (c) Reporting requirements—(1) General requirements. An applicant described in paragraph (a) of this section
p.000107: shall sub- mit the required patent information described in paragraph (c)(2) of this section for
p.000107: each patent that meets the requirements described in paragraph
p.000107: (b) of this section. We will not accept the patent information unless it is complete and submitted
p.000107: on the appro- priate forms, FDA Forms 3542 or 3542a. These forms may be obtained on the Internet at
p.000107: http:// .fda.gov by searching for ‘‘forms’’.
p.000107: (2) Drug substance (active ingredient),
p.000107: drug product (formulation or composi- tion), and method-of-use patents—(i) Original Declaration.
p.000107: For each patent that claims a drug substance (active ingredient), drug product (formulation and
p.000107: composition), or method of use, the applicant shall submit FDA Form 3542a. The following information
p.000107: and verification is required:
p.000107: (A) New drug application number;
p.000107: (B) Name of new drug application sponsor;
p.000107: (C) Trade name (or proposed trade name) of new drug;
p.000107: (D) Active ingredient(s) of new drug;
p.000107: (E) Strength(s) of new drug;
p.000107: (F) Dosage form of new drug;
p.000107: (G) United States patent number, issue date, and expiration date of pat- ent submitted;
p.000107: 21 CFR Ch. I (4–1–12 Edition)
p.000107: (H) The patent owner’s name, full ad- dress, phone number and, if available, fax number and e-mail address;
p.000107: (I) The name, full address, phone number and, if available, fax number and e-mail address of an
p.000107: agent or rep- resentative who resides or maintains a place of business within the United States
p.000107: authorized to receive notice of patent certification under sections 505(b)(3) and 505(j)(2)(B) of the
p.000107: act and
p.000107: §§ 314.52 and 314.95 (if patent owner or new drug application applicant or hold- er does not reside or have
p.000107: a place of business within the United States);
p.000107: (J) Information on whether the pat- ent has been submitted previously for the new drug application;
p.000107: (K) Information on whether the expi- ration date is a new expiration date if the patent had been
p.000107: submitted pre- viously for listing;
p.000107: (L) Information on whether the pat- ent is a product-by-process patent in which the product claimed is novel;
p.000107: (M) Information on the drug sub- stance (active ingredient) patent in- cluding the following:
p.000107: (1) Whether the patent claims the drug substance that is the active ingre- dient in the drug product
p.000107: described in the new drug application or supple- ment;
p.000107: (2) Whether the patent claims a poly- morph that is the same active ingre- dient that is described in the
p.000107: pending application or supplement;
p.000107: (3) Whether the applicant has test data, described in paragraph (b)(2) of this section, demonstrating
p.000107: that a drug product containing the polymorph will perform the same as the drug product described in the
p.000107: new drug application or supplement, and a description of the polymorphic form(s) claimed by the patent for
p.000107: which such test data exist;
p.000107: (4) Whether the patent claims only a metabolite of the active ingredient; and
p.000107: (5) Whether the patent claims only an intermediate;
p.000107: (N) Information on the drug product (composition/formulation) patent in- cluding the following:
p.000107: (1) Whether the patent claims the drug product for which approval is being sought, as defined in §
p.000107: 314.3; and
p.000107: (2) Whether the patent claims only an intermediate;
p.000108: 108
p.000108:
p.000108:
p.000108:
p.000108:
p.000108:
p.000108:
p.000108:
p.000108: Food and Drug Administration, HHS § 314.53
p.000108:
p.000108:
p.000108: (O) Information on each method-of- use patent including the following:
p.000108: (1) Whether the patent claims one or more methods of using the drug prod- uct for which use
p.000108: approval is being sought and a description of each pend- ing method of use or related indication and related
p.000108: patent claim of the patent being submitted; and
p.000108: (2) Identification of the specific sec- tion of the proposed labeling for the drug product that
p.000108: corresponds to the method of use claimed by the patent submitted;
p.000108: (P) Whether there are no relevant patents that claim the drug substance (active ingredient), drug
p.000108: product (for- mulation or composition) or method(s) of use, for which the applicant is seek- ing approval
p.000108: and with respect to which a claim of patent infringement could reasonably be asserted if a person not
p.000108: licensed by the owner of the patent en- gaged in the manufacture, use, or sale of the drug product;
p.000108: (Q) A signed verification which
p.000108: states:
p.000108: ‘‘The undersigned declares that this is an accurate and complete submission of patent information for the
p.000108: NDA, amendment or sup- plement pending under section 505 of the Federal Food, Drug, and Cosmetic Act.
p.000108: This time-sensitive patent information is sub- mitted pursuant to 21 CFR 314.53. I attest that I am
p.000108: familiar with 21 CFR 314.53 and this submission complies with the require- ments of the regulation. I
p.000108: verify under pen- alty of perjury that the foregoing is true and correct.’’; and
p.000108: (R) Information on whether the ap- plicant, patent owner or attorney, agent, representative or
p.000108: other author- ized official signed the form; the name of the person; and the full address, phone
p.000108: number and, if available, the fax number and e-mail address.
p.000108: (ii) Submission of patent information upon and after approval. Within 30 days after the date of
p.000108: approval of its appli- cation or supplement, the applicant shall submit FDA Form 3542 for each patent
p.000108: that claims the drug substance (active ingredient), drug product (for- mulation and composition), or
p.000108: ap- proved method of use. FDA will rely only on the information submitted on this form and will not
p.000108: list or publish patent information if the patent dec- laration is incomplete or indicates the patent is not
p.000108: eligible for listing. Patent
p.000108:
p.000108: information must also be submitted for patents issued after the date of ap- proval of the new drug
p.000108: application as required in paragraph (c)(2)(ii) of this section. As described in paragraph (d)(4) of
p.000108: this section, patent informa- tion must be submitted to FDA within
p.000108: 30 days of the date of issuance of the patent. If the applicant submits the re- quired patent information
p.000108: within the 30 days, but we notify an applicant that a declaration form is incomplete or shows that the
p.000108: patent is not eligible for listing, the applicant must submit an acceptable declaration form within 15
p.000108: days of FDA notification to be con- sidered timely filed. The following in- formation and verification
p.000108: statement is required:
p.000108: (A) New drug application number;
p.000108: (B) Name of new drug application sponsor;
p.000108: (C) Trade name of new drug;
p.000108: (D) Active ingredient(s) of new drug;
p.000108: (E) Strength(s) of new drug;
p.000108: (F) Dosage form of new drug;
p.000108: (G) Approval date of new drug appli- cation or supplement;
p.000108: (H) United States patent number, issue date, and expiration date of pat- ent submitted;
p.000108: (I) The patent owner’s name, full ad- dress, phone number and, if available, fax number and e-mail address;
p.000108: (J) The name, full address, phone number and, if available, fax number and e-mail address of an
p.000108: agent or rep- resentative who resides or maintains a place of business within the United States
p.000108: authorized to receive notice of patent certification under sections 505(b)(3) and 505(j)(2)(B) of the
p.000108: act and
p.000108: §§ 314.52 and 314.95 (if patent owner or new drug application applicant or hold- er does not reside or have
p.000108: a place of business within the United States);
p.000108: (K) Information on whether the pat- ent has been submitted previously for the new drug application;
p.000108: (L) Information on whether the expi- ration date is a new expiration date if the patent had been
p.000108: submitted pre- viously for listing;
p.000108: (M) Information on whether the pat- ent is a product-by-process patent in which the product claimed is novel;
p.000108: (N) Information on the drug sub- stance (active ingredient) patent in- cluding the following:
p.000109: 109
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109: § 314.53
p.000109: (1) Whether the patent claims the drug substance that is the active ingre- dient in the drug product
p.000109: described in the approved application;
p.000109: (2) Whether the patent claims a poly- morph that is the same as the active ingredient that is described in
p.000109: the ap- proved application;
p.000109: (3) Whether the applicant has test data, described at paragraph (b)(2) of this section, demonstrating
p.000109: that a drug product containing the polymorph will perform the same as the drug product described in the
p.000109: approved application and a description of the polymorphic form(s) claimed by the patent for which
p.000109: such test data exist;
p.000109: (4) Whether the patent claims only a metabolite of the active ingredient; and
p.000109: (5) Whether the patent claims only an intermediate;
p.000109: (O) Information on the drug product (composition/formulation) patent in- cluding the following:
p.000109: (1) Whether the patent claims the ap- proved drug product as defined in
p.000109: § 314.3; and
p.000109: (2) Whether the patent claims only an intermediate;
p.000109: (P) Information on each method-of- use patent including the following:
p.000109: (1) Whether the patent claims one or more approved methods of using the approved drug product and a
p.000109: descrip- tion of each approved method of use or indication and related patent claim of the patent being
p.000109: submitted;
p.000109: (2) Identification of the specific sec- tion of the approved labeling for the drug product that
p.000109: corresponds to the method of use claimed by the patent submitted; and
p.000109: (3) The description of the patented method of use as required for publica- tion;
p.000109: (Q) Whether there are no relevant patents that claim the approved drug substance (active ingredient),
p.000109: the ap- proved drug product (formulation or composition) or approved method(s) of use and with respect
p.000109: to which a claim of patent infringement could reason- ably be asserted if a person not li-
p.000109: censed by the owner of the patent en- gaged in the manufacture, use, or sale of the drug product;
p.000109: (R) A signed verification which states: ‘‘The undersigned declares that
p.000109: 21 CFR Ch. I (4–1–12 Edition)
p.000109: this is an accurate and complete sub- mission of patent information for the NDA, amendment or
p.000109: supplement ap- proved under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-sensitive
p.000109: patent information is submitted pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR
p.000109: 314.53 and this submission complies with the requirements of the regula- tion. I verify under penalty
p.000109: of perjury that the foregoing is true and cor- rect.’’; and
p.000109: (S) Information on whether the appli- cant, patent owner or attorney, agent, representative or other authorized
p.000109: offi- cial signed the form; the name of the person; and the full address, phone number and, if
p.000109: available, the fax num- ber and e-mail address.
p.000109: (3) No relevant patents. If the appli- cant believes that there are no relevant patents that claim the
p.000109: drug substance (active ingredient), drug product (for- mulation or composition), or the meth- od(s) of use for
p.000109: which the applicant has received approval, and with respect to which a claim of patent infringement could
p.000109: reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use,
p.000109: or sale of the drug product, the applicant will verify this information in the ap- propriate forms, FDA
p.000109: Forms 3542 or 3542a.
p.000109: (4) Authorized signature. The declara- tions required by this section shall be signed by the
p.000109: applicant or patent owner, or the applicant’s or patent owner’s attorney, agent (representa-
p.000109: tive), or other authorized official.
p.000109: (d) When and here to submit patent information—(1) Original application. An applicant shall submit with
p.000109: its original application submitted under this part, including an application described in section 505(b)(2)
p.000109: of the act, the infor- mation described in paragraph (c) of this section on each drug (ingredient),
p.000109: drug product (formulation and com- position), and method of use patent issued before the
p.000109: application is filed with FDA and for which patent infor- mation is required to be submitted under
p.000109: this section. If a patent is issued after the application is filed with FDA but before the application is
p.000109: approved, the applicant shall, within 30 days of
p.000110: 110
p.000110:
p.000110:
p.000110:
p.000110:
p.000110:
p.000110:
p.000110:
p.000110: Food and Drug Administration, HHS § 314.53
p.000110:
p.000110:
p.000110: the date of issuance of the patent, sub- mit the required patent information in an amendment to the application under
p.000110: § 314.60.
p.000110: (2) Supplements. (i) An applicant shall submit patent information required under paragraph (c) of this
p.000110: section for a patent that claims the drug, drug product, or method of use for which ap- proval is sought
p.000110: in any of the following supplements:
p.000110: (A) To change the formulation;
p.000110: (B) To add a new indication or other condition of use, including a change in route of administration;
p.000110: (C) To change the strength;
p.000110: (D) To make any other patented change regarding the drug, drug prod- uct, or any method of use.
p.000110: (ii) If the applicant submits a supple- ment for one of the changes listed under paragraph (d)(2)(i) of
p.000110: this section and existing patents for which informa- tion has already been submitted to FDA claim the
p.000110: changed product, the applicant shall submit a certification with the supplement identifying the patents
p.000110: that claim the changed prod- uct.
p.000110: (iii) If the applicant submits a sup- plement for one of the changes listed under paragraph (d)(2)(i) of
p.000110: this section and no patents, including previously submitted patents, claim the changed product, it shall so
p.000110: certify.
p.000110: (iv) The applicant shall comply with the requirements for amendment of formulation or composition and
p.000110: meth- od of use patent information under paragraphs (c)(2)(ii) and (d)(3) of this section.
p.000110: (3) Patent information deadline. If a patent is issued for a drug, drug prod- uct, or method of
p.000110: use after an applica- tion is approved, the applicant shall submit to FDA the required patent in-
p.000110: formation within 30 days of the date of issuance of the patent.
p.000110: (4) Copies. The applicant shall submit two copies of each submission of patent information, an archival copy
p.000110: and a copy for the chemistry, manufacturing, and controls section of the review copy, to the Central
p.000110: Document Room, Center for Drug Evaluation and Re- search, Food and Drug Administration, 5901–B Ammendale
p.000110: Rd., Beltsville, MD 20705–1266. The applicant shall submit the patent information by letter sepa-
p.000110:
p.000110: rate from, but at the same time as, submission of the supplement.
p.000110: (5) Submission date. Patent informa- tion shall be considered to be sub- mitted to FDA as of the date
p.000110: the infor- mation is received by the Central Doc- ument Room.
p.000110: (6) Identification. Each submission of patent information, except information submitted with an original
p.000110: application, and its mailing cover shall bear promi- nent identification as to its contents, i.e., ‘‘Patent
p.000110: Information,’’ or, if sub- mitted after approval of an applica- tion, ‘‘Time Sensitive Patent Informa-
p.000110: tion.’’
p.000110: (e) Public disclosure of patent informa- tion. FDA will publish in the list the patent number and
p.000110: expiration date of each patent that is required to be, and is, submitted to FDA by an applicant, and
p.000110: for each use patent, the approved indications or other conditions of use covered by a patent. FDA will
p.000110: publish such patent information upon approval of the application, or, if the patent in- formation is submitted
p.000110: by the appli- cant after approval of an application as provided under paragraph (d)(2) of this section, as
p.000110: soon as possible after the submission to the agency of the patent information. Patent information sub- mitted
p.000110: by the last working day of a month will be published in that month’s supplement to the list.
p.000110: Patent information received by the Agency be- tween monthly publication of supple- ments to the list will be placed
p.000110: on pub- lic display in FDA’s Division of Free- dom of Information. A request for cop- ies of the file shall
p.000110: be sent in writing to the Division of Freedom of Information (ELEM–1029), Food and Drug Adminis- tration, 12420
p.000110: Parklawn Dr., Element Bldg., Rockville, MD 20857.
p.000110: (f) Correction of patent information er-
p.000110: rors. If any person disputes the accu- racy or relevance of patent information submitted to the agency under this
p.000110: sec- tion and published by FDA in the list, or believes that an applicant has failed to submit required patent
p.000110: information, that person must first notify the agen- cy in writing stating the grounds for disagreement. Such
p.000110: notification should be directed to the Office of Generic Drugs, OGD Document Room, Atten- tion:
p.000110: Orange Book Staff, 7500 Standish Pl., Rockville, MD 20855. The agency
p.000111: 111
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111: § 314.54
p.000111: will then request of the applicable new drug application holder that the cor- rectness of the patent
p.000111: information or omission of patent information be con- firmed. Unless the application holder withdraws or amends
p.000111: its patent infor- mation in response to FDA’s request, the agency will not change the patent information
p.000111: in the list. If the new drug application holder does not change the patent information submitted to FDA, a
p.000111: 505(b)(2) application or an abbre- viated new drug application under sec- tion 505(j) of the act
p.000111: submitted for a drug that is claimed by a patent for which information has been submitted must, despite
p.000111: any disagreement as to the correctness of the patent informa- tion, contain an appropriate certifi-
p.000111: cation for each listed patent.
p.000111: [59 FR 50363, Oct. 3, 1994, as amended at 68 FR
p.000111: 36703, June 18, 2003; 69 FR 13473, Mar. 23, 2004;
p.000111: 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24,
p.000111: 2009; 76 FR 31470, June 1, 2011]
p.000111:
p.000111: § 314.54 Procedure for submission of an application requiring investiga- tions for approval of a new
p.000111: indica- tion for, or other change from, a listed drug.
p.000111: (a) The act does not permit approval of an abbreviated new drug application for a new indication, nor does it
p.000111: permit approval of other changes in a listed drug if investigations, other than bio- availability or
p.000111: bioequivalence studies, are essential to the approval of the change. Any person seeking approval of a
p.000111: drug product that represents a modi- fication of a listed drug (e.g., a new in- dication or new dosage form)
p.000111: and for which investigations, other than bio- availability or bioequivalence studies, are essential to
p.000111: the approval of the changes may, except as provided in paragraph (b) of this section, submit a
p.000111: 505(b)(2) application. This application need contain only that information needed to support the
p.000111: modification(s) of the listed drug.
p.000111: (1) The applicant shall submit a com- plete archival copy of the application that contains the following:
p.000111: (i) The information required under
p.000111: § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and
p.000111: (g), except that § 314.50(d)(1)(ii)(c) shall contain the proposed or actual master production record,
p.000111: including a descrip- tion of the equipment, to be used for
p.000111: 21 CFR Ch. I (4–1–12 Edition)
p.000111: the manufacture of a commercial lot of the drug product.
p.000111: (ii) The information required under
p.000111: § 314.50 (d)(2), (d)(4) (if an anti-infective
p.000111: drug), (d)(5), (d)(6), and (f) as needed to support the safety and effectiveness of the drug product.
p.000111: (iii) Identification of the listed drug for which FDA has made a finding of safety and effectiveness and
p.000111: on which finding the applicant relies in seeking approval of its proposed drug product by established
p.000111: name, if any, propri- etary name, dosage form, strength, route of administration, name of listed drug’s
p.000111: application holder, and listed drug’s approved application number.
p.000111: (iv) If the applicant is seeking ap- proval only for a new indication and not for the indications approved
p.000111: for the listed drug on which the applicant re- lies, a certification so stating.
p.000111: (v) Any patent information required under section 505(b)(1) of the act with respect to any patent which
p.000111: claims the drug for which approval is sought or a method of using such drug and to which a claim
p.000111: of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in
p.000111: the manufacture, use, or sale of the drug product.
p.000111: (vi) Any patent certification or state- ment required under section 505(b)(2) of the act with respect to any
p.000111: relevant patents that claim the listed drug or that claim any other drugs on which investigations relied
p.000111: on by the appli- cant for approval of the application were conducted, or that claim a use for the listed
p.000111: or other drug.
p.000111: (vii) If the applicant believes the change for which it is seeking approval is entitled to a period of
p.000111: exclusivity, the information required under
p.000111: § 314.50(j).
p.000111: (2) The applicant shall submit a re- view copy that contains the technical sections described in §
p.000111: 314.50(d)(1), ex- cept that § 314.50(d)(1)(ii)(c) shall con- tain the proposed or actual master pro- duction
p.000111: record, including a description of the equipment, to be used for the manufacture of a commercial lot of the
p.000111: drug product, and paragraph (d)(3), and the technical sections described in paragraphs (d)(2), (d)(4),
p.000111: (d)(5), (d)(6), and (f) when needed to support the modification. Each of the technical
p.000112: 112
p.000112:
p.000112:
p.000112:
p.000112:
p.000112:
p.000112:
p.000112:
p.000112: Food and Drug Administration, HHS § 314.55
p.000112:
p.000112:
p.000112: sections in the review copy is required to be separately bound with a copy of the information required
p.000112: under § 314.50 (a), (b), and (c) and a copy of the pro- posed labeling.
p.000112: (3) The information required by
p.000112: § 314.50 (d)(2), (d)(4) (if an anti-infective
p.000112: drug), (d)(5), (d)(6), and (f) for the listed drug on which the applicant relies shall be satisfied by reference to
p.000112: the listed drug under paragraph (a)(1)(iii) of this section.
p.000112: (4) The applicant shall submit a field copy of the application that contains the technical section
p.000112: described in
p.000112: § 314.50(d)(1), a copy of the information required under § 314.50(a) and (c), and certification that the
p.000112: field copy is a true copy of the technical section de- scribed in § 314.50(d)(1) contained in the archival and
p.000112: review copies of the appli- cation.
p.000112: (b) An application may not be sub- mitted under this section for a drug product whose only difference from
p.000112: the reference listed drug is that:
p.000112: (1) The extent to which its active in- gredient(s) is absorbed or otherwise made available to the
p.000112: site of action is less than that of the reference listed drug; or
p.000112: (2) The rate at which its active ingre- dient(s) is absorbed or otherwise made available to the site of
p.000112: action is unin- tentionally less than that of the ref- erence listed drug.
p.000112: [57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec.
p.000112: 28, 1992, as amended at 58 FR 47351, Sept. 8,
p.000112: 1993; 59 FR 50364, Oct. 3, 1994]
p.000112: § 314.55 Pediatric use information.
p.000112: (a) Required assessment. Except as pro- vided in paragraphs (b), (c), and (d) of this section, each application
p.000112: for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of
p.000112: administration shall con- tain data that are adequate to assess the safety and effectiveness of the drug
p.000112: product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and
p.000112: administra- tion for each pediatric subpopulation for which the drug is safe and effective. Where the course of the
p.000112: disease and the effects of the drug are sufficiently similar in adults and pediatric pa- tients,
p.000112: FDA may conclude that pedi- atric effectiveness can be extrapolated
p.000112:
p.000112: from adequate and well-controlled studies in adults usually supplemented with other information
p.000112: obtained in pe- diatric patients, such as pharmaco- kinetic studies. Studies may not be needed in
p.000112: each pediatric age group, if data from one age group can be extrap- olated to another. Assessments of safe- ty and
p.000112: effectiveness required under this section for a drug product that rep- resents a meaningful therapeutic
p.000112: ben- efit over existing treatments for pedi- atric patients must be carried out using appropriate
p.000112: formulations for each age group(s) for which the assess- ment is required.
p.000112: (b) Deferred submission. (1) FDA may, on its own initiative or at the request of an applicant, defer
p.000112: submission of some or all assessments of safety and effectiveness described in paragraph (a) of this section
p.000112: until after approval of the drug product for use in adults. De- ferral may be granted if, among other
p.000112: reasons, the drug is ready for approval in adults before studies in pediatric pa- tients are complete, or
p.000112: pediatric stud- ies should be delayed until additional safety or effectiveness data have been collected. If
p.000112: an applicant requests de- ferred submission, the request must provide a certification from the appli-
p.000112: cant of the grounds for delaying pedi- atric studies, a description of the planned or ongoing
p.000112: studies, and evi- dence that the studies are being or will be conducted with due diligence and at the earliest
p.000112: possible time.
p.000112: (2) If FDA determines that there is an adequate justification for tempo- rarily delaying the
p.000112: submission of as- sessments of pediatric safety and effec- tiveness, the drug product may be ap- proved for
p.000112: use in adults subject to the requirement that the applicant submit the required assessments within a spec-
p.000112: ified time.
p.000112: (c) Waivers—(1) General. FDA may grant a full or partial waiver of the re- quirements of paragraph (a) of this
p.000112: sec- tion on its own initiative or at the re- quest of an applicant. A request for a waiver must
p.000112: provide an adequate jus- tification.
p.000112: (2) Full aiver. An applicant may re- quest a waiver of the requirements of paragraph (a) of this
p.000112: section if the ap- plicant certifies that:
p.000113: 113
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113: § 314.60
p.000113: (i) The drug product does not rep- resent a meaningful therapeutic ben- efit over existing
p.000113: treatments for pedi- atric patients and is not likely to be used in a substantial number of pedi- atric
p.000113: patients;
p.000113: (ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so
p.000113: small or geographically dispersed; or
p.000113: (iii) There is evidence strongly sug- gesting that the drug product would be ineffective or unsafe in all
p.000113: pediatric age groups.
p.000113: (3) Partial aiver. An applicant may request a waiver of the requirements of paragraph (a) of this section
p.000113: with re- spect to a specified pediatric age group, if the applicant certifies that:
p.000113: (i) The drug product does not rep- resent a meaningful therapeutic ben- efit over existing
p.000113: treatments for pedi- atric patients in that age group, and is not likely to be used in a substantial number of
p.000113: patients in that age group;
p.000113: (ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group
p.000113: is so small or geographically dispersed;
p.000113: (iii) There is evidence strongly sug- gesting that the drug product would be ineffective or unsafe in that age
p.000113: group; or
p.000113: (iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary
p.000113: for that age group have failed.
p.000113: (4) FDA action on aiver. FDA shall grant a full or partial waiver, as appro- priate, if the agency finds that
p.000113: there is a reasonable basis on which to con- clude that one or more of the grounds for waiver
p.000113: specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the
p.000113: ground that it is not possible to develop a pedi- atric formulation, the waiver will cover only those
p.000113: pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that
p.000113: the product would be ineffective or unsafe in pediatric populations, this information will be included in
p.000113: the product’s labeling.
p.000113: (5) Definition of ‘‘meaningful thera- peutic benefit’’. For purposes of this sec- tion and § 201.23 of this
p.000113: chapter, a drug will be considered to offer a meaningful
p.000113: 21 CFR Ch. I (4–1–12 Edition)
p.000113: therapeutic benefit over existing thera- pies if FDA estimates that:
p.000113: (i) If approved, the drug would rep- resent a significant improvement in the treatment, diagnosis, or
p.000113: prevention of a disease, compared to marketed products adequately labeled for that use in the
p.000113: relevant pediatric popu- lation. Examples of how improvement might be demonstrated include, for ex- ample,
p.000113: evidence of increased effective- ness in treatment, prevention, or diag- nosis of disease, elimination
p.000113: or sub- stantial reduction of a treatment-lim- iting drug reaction, documented en- hancement of
p.000113: compliance, or evidence of safety and effectiveness in a new subpopulation; or
p.000113: (ii) The drug is in a class of drugs or
p.000113: for an indication for which there is a need for additional therapeutic op- tions.
p.000113: (d) Exemption for orphan drugs. This section does not apply to any drug for an indication or indications
p.000113: for which orphan designation has been granted under part 316, subpart C, of this chap- ter.
p.000113: [63 FR 66670, Dec. 2, 1998]
p.000113:
p.000113: § 314.60 Amendments to an unap- proved application, supplement, or resubmission.
p.000113: (a) FDA generally assumes that when an original application, supplement to an approved application, or
p.000113: resubmis- sion of an application or supplement is submitted to the agency for review, the applicant believes that
p.000113: the agency can approve the application, supplement, or resubmission as submitted. How- ever, the
p.000113: applicant may submit an amendment to an application that has been filed under § 314.101 but is not
p.000113: yet approved.
p.000113: (b)(1) Submission of a major amend-
p.000113: ment to an original application, effi- cacy supplement, or resubmission of an application or efficacy
p.000113: supplement within 3 months of the end of the ini- tial review cycle constitutes an agree- ment by the
p.000113: applicant under section 505(c) of the act to extend the initial review cycle by 3 months. (For
p.000113: ref- erences to a resubmission of an appli- cation or efficacy supplement in para- graph (b) of this
p.000113: section, the timeframe for reviewing the resubmission is the ‘‘review cycle’’ rather than the ‘‘initial
p.000114: 114
p.000114:
p.000114:
p.000114:
p.000114:
p.000114:
p.000114:
p.000114:
p.000114: Food and Drug Administration, HHS § 314.60
p.000114:
p.000114:
p.000114: review cycle.’’) FDA may instead defer review of the amendment until the sub- sequent review cycle. If the
p.000114: agency ex- tends the initial review cycle for an original application, efficacy supple- ment, or
p.000114: resubmission under this para- graph, the division responsible for re- viewing the application, supplement,
p.000114: or resubmission will notify the appli- cant of the extension. The initial re- view cycle for an original
p.000114: application, efficacy supplement, or resubmission of an application or efficacy supplement may be extended only
p.000114: once due to sub- mission of a major amendment. FDA may, at its discretion, review any sub- sequent
p.000114: major amendment during the initial review cycle (as extended) or defer review until the subsequent
p.000114: re- view cycle.
p.000114: (2) Submission of a major amend-
p.000114: ment to an original application, effi- cacy supplement, or resubmission of an application or efficacy
p.000114: supplement more than 3 months before the end of the initial review cycle will not extend the cycle. FDA may,
p.000114: at its discretion, review such an amendment during the initial review cycle or defer review until the
p.000114: subsequent review cycle.
p.000114: (3) Submission of an amendment to an original application, efficacy sup- plement, or resubmission of an
p.000114: applica- tion or efficacy supplement that is not a major amendment will not extend the initial review cycle. FDA
p.000114: may, at its discretion, review such an amendment during the initial review cycle or defer review until the
p.000114: subsequent review cycle.
...
p.000114: under this paragraph, the division re- sponsible for reviewing the supplement will notify the applicant of
p.000114: the exten- sion. The initial review cycle for a manufacturing supplement may be ex- tended only once
p.000114: due to submission of a major amendment. FDA may, at its discretion, review any subsequent
p.000114:
p.000114: major amendment during the initial review cycle (as extended) or defer re- view until the subsequent
p.000114: review cycle.
p.000114: (5) Submission of an amendment to a supplement other than an efficacy or manufacturing supplement will not ex-
p.000114: tend the initial review cycle. FDA may, at its discretion, review such an amendment during the
p.000114: initial review cycle or defer review until the subse- quent review cycle.
p.000114: (6) A major amendment may not in- clude data to support an indication or claim that was not
p.000114: included in the original application, supplement, or re- submission, but it may include data to support a
p.000114: minor modification of an in- dication or claim that was included in the original application,
p.000114: supplement, or resubmission.
p.000114: (7) When FDA defers review of an amendment until the subsequent re- view cycle, the agency will
p.000114: notify the applicant of the deferral in the com- plete response letter sent to the appli- cant under §
p.000114: 314.110 of this part.
p.000114: (c)(1) An unapproved application may not be amended if all of the following conditions apply:
p.000114: (i) The unapproved application is for a drug for which a previous application has been approved and granted a
p.000114: period of exclusivity in accordance with sec- tion 505(c)(3)(D)(ii) of the act that has not expired;
p.000114: (ii) The applicant seeks to amend the unapproved application to include a published report of an
p.000114: investigation that was conducted or sponsored by the applicant entitled to exclusivity for the drug;
p.000114: (iii) The applicant has not obtained a right of reference to the investigation described in paragraph
p.000114: (c)(1)(ii) of this section; and
p.000114: (iv) The report of the investigation described in paragraph (c)(1)(ii) of this section would be essential
p.000114: to the ap- proval of the unapproved application.
p.000114: (2) The submission of an amendment described in paragraph (c)(1) of this section will cause the
p.000114: unapproved ap- plication to be deemed to be withdrawn by the applicant under § 314.65 on the date of receipt
p.000114: by FDA of the amend- ment. The amendment will be consid- ered a resubmission of the application, which
p.000114: may not be accepted except as
p.000115: 115
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115: § 314.65
p.000115: provided in accordance with section 505(c)(3)(D)(ii) of the act.
p.000115: (d) The applicant shall submit a field copy of each amendment to
p.000115: § 314.50(d)(1). The applicant shall in- clude in its submission of each such amendment to FDA a
p.000115: statement certi- fying that a field copy of the amend- ment has been sent to the applicant’s home FDA
p.000115: district office.
p.000115: [50 FR 7493, Feb. 22, 1985, as amended at 57
p.000115: FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8,
p.000115: 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr.
p.000115: 8, 2004; 73 FR 39608, July 10, 2008]
p.000115:
p.000115: § 314.65 Withdrawal by the applicant of an unapproved application.
p.000115: An applicant may at any time with- draw an application that is not yet ap- proved by notifying the Food and Drug
p.000115: Administration in writing. If, by the time it receives such notice, the agen- cy has identified any
p.000115: deficiencies in the application, we will list such defi- ciencies in the letter we send the appli- cant
p.000115: acknowledging the withdrawal. A decision to withdraw the application is without prejudice to refiling. The agen- cy
p.000115: will retain the application and will provide a copy to the applicant on re- quest under the fee schedule in
p.000115: § 20.45 of FDA’s public information regulations.
p.000115: [50 FR 7493, Feb. 22, 1985, as amended at 68
p.000115: FR 25287, May 12, 2003; 73 FR 39609, July 10,
p.000115: 2008]
p.000115:
p.000115: § 314.70 Supplements and other changes to an approved application.
p.000115: (a) Changes to an approved application. (1)(i) Except as provided in paragraph (a)(1)(ii) of this section, the
p.000115: applicant must notify FDA about each change in each condition established in an ap- proved application
p.000115: beyond the vari- ations already provided for in the ap- plication. The notice is required to de- scribe
p.000115: the change fully. Depending on the type of change, the applicant must notify FDA about the change in a
p.000115: sup- plement under paragraph (b) or (c) of this section or by inclusion of the in- formation in the
p.000115: annual report to the application under paragraph (d) of this
p.000115: section.
p.000115: (ii) The submission and grant of a written request for an exception or al- ternative under § 201.26 of
p.000115: this chapter satisfies the applicable requirements in paragraphs (a) through (c) of this sec-
p.000115: 21 CFR Ch. I (4–1–12 Edition)
p.000115: tion. However, any grant of a request for an exception or alternative under
p.000115: § 201.26 of this chapter must be reported as part of the annual report to the ap- plication under paragraph
p.000115: (d) of this section.
p.000115: (2) The holder of an approved applica- tion under section 505 of the act must assess the effects of the
p.000115: change before distributing a drug product made with a manufacturing change.
p.000115: (3) Notwithstanding the requirements of paragraphs (b) and (c) of this sec- tion, an applicant must make a
p.000115: change provided for in those paragraphs in ac- cordance with a regulation or guidance that provides for a less
p.000115: burdensome no- tification of the change (for example, by submission of a supplement that does not
p.000115: require approval prior to dis- tribution of the product or in an an- nual report).
p.000115: (4) The applicant must promptly re- vise all promotional labeling and ad- vertising to make it consistent
p.000115: with any labeling change implemented in accordance with paragraphs (b) and (c) of this section.
p.000115: (5) Except for a supplement providing for a change in the labeling, the appli- cant must include in each
p.000115: supplement and amendment to a supplement pro- viding for a change under paragraph (b) or (c) of this section a
p.000115: statement certi- fying that a field copy has been pro- vided in accordance with § 314.440(a)(4).
p.000115: (6) A supplement or annual report must include a list of all changes con- tained in the supplement
p.000115: or annual re- port. For supplements, this list must be provided in the cover letter.
p.000115: (b) Changes requiring supplement sub- mission and approval prior to distribution of the product made
p.000115: using the change (major changes). (1) A supplement must be submitted for any change in the drug
p.000115: substance, drug product, produc- tion process, quality controls, equip- ment, or facilities that has a
p.000115: substan- tial potential to have an adverse effect on the identity, strength, quality, pu- rity, or potency of
p.000115: the drug product as these factors may relate to the safety or effectiveness of the drug product.
p.000115: (2) These changes include, but are not limited to:
p.000115: (i) Except those described in para- graphs (c) and (d) of this section,
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p.000116: Food and Drug Administration, HHS § 314.70
p.000116:
p.000116:
p.000116: changes in the qualitative or quan- titative formulation of the drug prod- uct, including inactive
p.000116: ingredients, or in the specifications provided in the approved application;
p.000116: (ii) Changes requiring completion of studies in accordance with part 320 of this chapter to
p.000116: demonstrate the equivalence of the drug product to the drug product as manufactured without the change
p.000116: or to the reference listed drug;
p.000116: (iii) Changes that may affect drug substance or drug product sterility as- surance, such as changes
p.000116: in drug sub- stance, drug product, or component sterilization method(s) or an addition, deletion, or
p.000116: substitution of steps in an aseptic processing operation;
p.000116: (iv) Changes in the synthesis or man- ufacture of the drug substance that may affect the impurity profile
p.000116: and/or the physical, chemical, or biological properties of the drug substance;
p.000116: (v) The following labeling changes:
p.000116: (A) Changes in labeling, except those described in paragraphs (c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of
p.000116: this section;
p.000116: (B) If applicable, any change to a Medication Guide required under part 208 of this chapter, except
p.000116: for changes in the information specified in
p.000116: § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and
p.000116: (C) Any change to the information required by § 201.57(a) of this chapter, with the following exceptions that
p.000116: may be reported in an annual report under paragraph (d)(2)(x) of this section:
p.000116: (1) Removal of a listed section(s) specified in § 201.57(a)(5) of this chapter; and
p.000116: (2) Changes to the most recent revi- sion date of the labeling as specified in
p.000116: § 201.57(a)(15) of this chapter.
p.000116: (vi) Changes in a drug product con- tainer closure system that controls the drug product delivered to a
p.000116: patient or changes in the type (e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl chloride,
p.000116: vial to syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a packaging component
p.000116: that may affect the impu- rity profile of the drug product.
p.000116: (vii) Changes solely affecting a nat- ural product, a recombinant DNA-de- rived protein/polypeptide, or a
p.000116: complex
p.000116:
p.000116: or conjugate of a drug substance with a monoclonal antibody for the following:
p.000116: (A) Changes in the virus or adven- titious agent removal or inactivation method(s);
p.000116: (B) Changes in the source material or cell line; and
p.000116: (C) Establishment of a new master cell bank or seed.
p.000116: (viii) Changes to a drug product under an application that is subject to a validity assessment
p.000116: because of sig- nificant questions regarding the integ- rity of the data supporting that appli- cation.
p.000116: (3) The applicant must obtain ap- proval of a supplement from FDA prior to distribution of a drug
p.000116: product made using a change under paragraph (b) of this section. Except for submissions under paragraph
p.000116: (e) of this section, the following information must be con- tained in the supplement:
p.000116: (i) A detailed description of the pro- posed change;
p.000116: (ii) The drug product(s) involved;
p.000116: (iii) The manufacturing site(s) or area(s) affected;
p.000116: (iv) A description of the methods used and studies performed to assess the effects of the change;
p.000116: (v) The data derived from such stud- ies;
p.000116: (vi) For a natural product, a recom- binant DNA-derived protein/ polypeptide, or a
p.000116: complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and a list
p.000116: of relevant standard oper- ating procedures must be provided in addition to the requirements in para-
p.000116: graphs (b)(3)(iv) and (b)(3)(v) of this section; and
p.000116: (vii) For sterilization process and test methodologies related to steriliza- tion process validation,
p.000116: relevant vali- dation protocols and a list of relevant standard operating procedures must be provided in
p.000116: addition to the require- ments in paragraphs (b)(3)(iv) and (b)(3)(v) of this section.
p.000116: (4) An applicant may ask FDA to ex- pedite its review of a supplement for public health reasons or if
p.000116: a delay in making the change described in it would impose an extraordinary hard- ship on the
p.000116: applicant. Such a supple- ment and its mailing cover should be
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p.000117:
p.000117:
p.000117:
p.000117:
p.000117:
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p.000117: plainly marked: ‘‘Prior Approval Sup- plement-Expedited Review Requested.’’
p.000117: (c) Changes requiring supplement sub- mission at least 30 days prior to distribu- tion of the drug
p.000117: product made using the change (moderate changes). (1) A supple- ment must be submitted for any
p.000117: change in the drug substance, drug product, production process, quality controls, equipment, or
p.000117: facilities that has a moderate potential to have an adverse effect on the identity,
p.000117: strength, quality, purity, or potency of the drug product as these factors may relate to the safety or
p.000117: effectiveness of the drug product. If the supplement provides for a labeling change under
p.000117: paragraph (c)(6)(iii) of this section, 12 copies of the final printed labeling must be included.
p.000117: (2) These changes include, but are not limited to:
p.000117: (i) A change in the container closure system that does not affect the quality of the drug product, except
p.000117: those de- scribed in paragraphs (b) and (d) of this section; and
p.000117: (ii) Changes solely affecting a nat- ural protein, a recombinant DNA-de- rived protein/polypeptide or a
p.000117: complex or conjugate of a drug substance with a monoclonal antibody, including:
p.000117: (A) An increase or decrease in pro- duction scale during finishing steps that involves different
p.000117: equipment; and
p.000117: (B) Replacement of equipment with that of a different design that does not affect the process methodology or proc-
p.000117: ess operating parameters.
p.000117: (iii) Relaxation of an acceptance cri- terion or deletion of a test to comply with an official
p.000117: compendium that is consistent with FDA statutory and reg- ulatory requirements.
p.000117: (3) A supplement submitted under paragraph (c)(1) of this section is re- quired to give a full
p.000117: explanation of the basis for the change and identify the date on which the change is to be made.
p.000117: The supplement must be labeled ‘‘Supplement—Changes Being Effected in 30 Days’’ or, if applicable
p.000117: under paragraph (c)(6) of this section, ‘‘Sup- plement—Changes Being Effected.’’
p.000117: (4) Pending approval of the supple- ment by FDA, except as provided in paragraph (c)(6) of this
p.000117: section, dis- tribution of the drug product made using the change may begin not less
p.000117: 21 CFR Ch. I (4–1–12 Edition)
p.000117: than 30 days after receipt of the supple- ment by FDA. The information listed in paragraphs (b)(3)(i)
p.000117: through (b)(3)(vii) of this section must be con- tained in the supplement.
p.000117: (5) The applicant must not distribute the drug product made using the change if within 30 days
p.000117: following FDA’s receipt of the supplement, FDA informs the applicant that either:
p.000117: (i) The change requires approval prior to distribution of the drug prod- uct in accordance with
p.000117: paragraph (b) of this section; or
p.000117: (ii) Any of the information required under paragraph (c)(4) of this section is missing; the applicant must
p.000117: not dis- tribute the drug product made using the change until the supplement has been amended to provide
p.000117: the missing information.
p.000117: (6) The agency may designate a cat- egory of changes for the purpose of pro- viding that, in the case of a
p.000117: change in such category, the holder of an ap- proved application may commence dis- tribution of the
p.000117: drug product involved upon receipt by the agency of a supple- ment for the change. These changes in- clude, but are
p.000117: not limited to:
p.000117: (i) Addition to a specification or changes in the methods or controls to provide increased
p.000117: assurance that the drug substance or drug product will have the characteristics of identity,
p.000117: strength, quality, purity, or potency that it purports or is represented to possess;
p.000117: (ii) A change in the size and/or shape of a container for a nonsterile drug product, except for solid
p.000117: dosage forms, without a change in the labeled amount of drug product or from one container
p.000117: closure system to another;
p.000117: (iii) Changes in the labeling to reflect newly acquired information, except for changes to the information
p.000117: required in
p.000117: § 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish
p.000117: any of the following:
p.000117: (A) To add or strengthen a contra- indication, warning, precaution, or ad- verse reaction for which the
p.000117: evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c)
p.000117: of this chapter;
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p.000118: (B) To add or strengthen a statement about drug abuse, dependence, psycho- logical effect, or overdosage;
p.000118: (C) To add or strengthen an instruc- tion about dosage and administration that is intended to increase
p.000118: the safe use of the drug product;
p.000118: (D) To delete false, misleading, or un- supported indications for use or claims for effectiveness; or
p.000118: (E) Any labeling change normally re- quiring a supplement submission and approval prior to distribution of
p.000118: the drug product that FDA specifically re- quests be submitted under this provi- sion.
p.000118: (7) If the agency disapproves the sup- plemental application, it may order the manufacturer to cease
p.000118: distribution of the drug product(s) made with the manufacturing change.
p.000118: (d) Changes to be described in an an- nual report (minor changes). (1) Changes in the drug substance,
p.000118: drug product, production process, quality controls, equipment, or facilities that have a minimal
p.000118: potential to have an adverse effect on the identity, strength, qual- ity, purity, or potency of the
p.000118: drug product as these factors may relate to the safety or effectiveness of the drug product must be
p.000118: documented by the ap- plicant in the next annual report in ac- cordance with § 314.81(b)(2).
p.000118: (2) These changes include, but are not
p.000118: limited to:
p.000118: (i) Any change made to comply with a change to an official compendium, except a change described in
p.000118: paragraph (c)(2)(iii) of this section, that is con- sistent with FDA statutory and regu- latory
p.000118: requirements.
p.000118: (ii) The deletion or reduction of an ingredient intended to affect only the color of the drug product;
p.000118: (iii) Replacement of equipment with that of the same design and operating principles except those
p.000118: equipment changes described in paragraph (c) of this section;
p.000118: (iv) A change in the size and/or shape of a container containing the same number of dosage units for a
p.000118: nonsterile solid dosage form drug product, with- out a change from one container clo- sure system to
p.000118: another;
p.000118: (v) A change within the container closure system for a nonsterile drug product, based upon
p.000118: a showing of
p.000118:
p.000118: equivalency to the approved system under a protocol approved in the appli- cation or published in an
p.000118: official com- pendium;
p.000118: (vi) An extension of an expiration dating period based upon full shelf life data on production
p.000118: batches obtained from a protocol approved in the appli- cation;
p.000118: (vii) The addition or revision of an al- ternative analytical procedure that provides the same or
p.000118: increased assur- ance of the identity, strength, quality, purity, or potency of the material being
p.000118: tested as the analytical proce- dure described in the approved applica- tion, or deletion of an alternative
p.000118: ana- lytical procedure;
p.000118: (viii) The addition by embossing, de- bossing, or engraving of a code imprint to a solid oral dosage form
p.000118: drug prod- uct other than a modified release dos- age form, or a minor change in an ex- isting code
p.000118: imprint;
p.000118: (ix) A change in the labeling con- cerning the description of the drug product or in the
p.000118: information about how the drug product is supplied, that does not involve a change in the dosage strength or
p.000118: dosage form; and
p.000118: (x) An editorial or similar minor change in labeling, including a change to the information
p.000118: allowed by para- graphs (b)(2)(v)(C)(1) and (2) of this sec- tion.
p.000118: (3) For changes under this category, the applicant is required to submit in the annual report:
p.000118: (i) A statement by the holder of the approved application that the effects of the change have been assessed;
p.000118: (ii) A full description of the manufac- turing and controls changes, including the manufacturing site(s) or area(s)
p.000118: in- volved;
p.000118: (iii) The date each change was imple- mented;
p.000118: (iv) Data from studies and tests per- formed to assess the effects of the change; and,
p.000118: (v) For a natural product, recom- binant DNA-derived protein/ polypeptide, complex or
p.000118: conjugate of a drug substance with a monoclonal anti- body, sterilization process or test methodology
p.000118: related to sterilization process validation, a cross-reference to relevant validation protocols and/or
p.000118: standard operating procedures.
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p.000119: § 314.71
p.000119: (e) Protocols. An applicant may sub- mit one or more protocols describing the specific tests and studies
p.000119: and ac- ceptance criteria to be achieved to demonstrate the lack of adverse effect for specified
p.000119: types of manufacturing changes on the identity, strength, quality, purity, and potency of the
p.000119: drug product as these factors may re- late to the safety or effectiveness of the drug product. Any such
p.000119: protocols, if not included in the approved applica- tion, or changes to an approved pro- tocol, must be
p.000119: submitted as a supple- ment requiring approval from FDA prior to distribution of a drug product
p.000119: produced with the manufacturing change. The supplement, if approved, may subsequently justify a
p.000119: reduced re- porting category for the particular change because the use of the protocol for that type of
p.000119: change reduces the po- tential risk of an adverse effect.
p.000119: (f) Patent information. The applicant
p.000119: must comply with the patent informa- tion requirements under section 505(c)(2) of the act.
p.000119: (g) Claimed exclusivity. If an applicant claims exclusivity under § 314.108 upon approval of a supplement for
p.000119: change to its previously approved drug product, the applicant must include with its supplement the
p.000119: information required under § 314.50(j).
p.000119: [69 FR 18764, Apr. 8, 2004, as amended at 71
p.000119: FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28,
p.000119: 2007; 73 FR 49609, Aug. 22, 2008]
p.000119:
p.000119: § 314.71 Procedures for submission of a supplement to an approved appli- cation.
p.000119: (a) Only the applicant may submit a supplement to an application.
p.000119: (b) All procedures and actions that apply to an application under § 314.50 also apply to supplements,
p.000119: except that the information required in the supple- ment is limited to that needed to sup- port the change.
p.000119: A supplement is re- quired to contain an archival copy and a review copy that include an applica- tion
p.000119: form and appropriate technical sections, samples, and labeling; except that a supplement for a change
p.000119: other than a change in labeling is required also to contain a field copy.
p.000119: (c) All procedures and actions that
p.000119: apply to applications under this part, including actions by applicants and the
p.000119: 21 CFR Ch. I (4–1–12 Edition)
p.000119: Food and Drug Administration, also apply to supplements except as speci- fied otherwise in this part.
p.000119: [50 FR 7493, Feb. 22, 1985, as amended at 50
p.000119: FR 21238, May 23, 1985; 58 FR 47352, Sept. 8,
p.000119: 1993; 67 FR 9586, Mar. 4, 2002; 73 FR 39609,
p.000119: July 10, 2008]
p.000119:
p.000119: § 314.72 Change in ownership of an ap- plication.
p.000119: (a) An applicant may transfer owner- ship of its application. At the time of transfer the new and former owners
p.000119: are required to submit information to the Food and Drug Administration as fol- lows:
p.000119: (1) The former owner shall submit a letter or other document that states that all rights to the
p.000119: application have been transferred to the new owner.
p.000119: (2) The new owner shall submit an application form signed by the new owner and a letter or other
p.000119: document containing the following:
p.000119: (i) The new owner’s commitment to agreements, promises, and conditions made by the former owner
p.000119: and con- tained in the application;
p.000119: (ii) The date that the change in own- ership is effective; and
p.000119: (iii) Either a statement that the new owner has a complete copy of the ap- proved application,
p.000119: including supple- ments and records that are required to be kept under § 314.81, or a request for a copy of
p.000119: the application from FDA’s files. FDA will provide a copy of the application to the new owner under the
p.000119: fee schedule in § 20.45 of FDA’s public information regulations.
p.000119: (b) The new owner shall advise FDA about any change in the conditions in the approved application under
p.000119: § 314.70, except the new owner may advise FDA in the next annual report about a change in the drug
p.000119: product’s label or labeling to change the product’s brand or the name of its manufacturer, pack- er, or
p.000119: distributor.
p.000119: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000119: 1985, as amended at 50 FR 21238, May 23, 1985;
p.000119: 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12,
p.000119: 2003]
p.000119:
p.000119: § 314.80 Postmarketing reporting of adverse drug experiences.
p.000119: (a) Definitions. The following defini- tions of terms apply to this section:
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p.000120:
p.000120:
p.000120: Adverse drug experience. Any adverse event associated with the use of a drug in humans, whether or not
p.000120: considered drug related, including the following: An adverse event occurring in the course of the use
p.000120: of a drug product in professional practice; an adverse event occurring from drug overdose whether
p.000120: accidental or intentional; an adverse event occurring from drug abuse; an adverse event
p.000120: occurring from drug withdrawal; and any failure of expected pharmacological action.
p.000120: Disability. A substantial disruption of
p.000120: a person’s ability to conduct normal life functions.
p.000120: Life-threatening adverse drug experi- ence. Any adverse drug experience that places the patient, in the
p.000120: view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred,
p.000120: i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have
p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
p.000120: includes events that may be symptomatically and pathophysiologically related to an event listed
p.000120: in the labeling, but differ from the event because of greater se-
p.000120:
p.000120: verity or specificity. For example, under this definition, hepatic necrosis would be unexpected
p.000120: (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis.
p.000120: Similarly, cerebral thrombo- embolism and cerebral vasculitis would be unexpected (by virtue of greater
p.000120: specificity) if the labeling only listed cerebral vascular accidents. ‘‘Unex- pected,’’ as used in this
p.000120: definition, re- fers to an adverse drug experience that has not been previously observed (i.e., included in the
p.000120: labeling) rather than from the perspective of such experience not being anticipated from the pharma- cological
p.000120: properties of the pharma- ceutical product.
p.000120: (b) Revie of adverse drug experiences.
p.000120: Each applicant having an approved ap- plication under § 314.50 or, in the case of a 505(b)(2)
p.000120: application, an effective approved application, shall promptly review all adverse drug experience in-
p.000120: formation obtained or otherwise re- ceived by the applicant from any source, foreign or
p.000120: domestic, including information derived from commercial marketing experience, postmarketing clinical
p.000120: investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and
p.000120: unpublished scientific papers. Appli- cants are not required to resubmit to FDA adverse drug
p.000120: experience reports forwarded to the applicant by FDA; however, applicants must submit all followup
p.000120: information on such reports to FDA. Any person subject to the re- porting requirements under paragraph
p.000120: (c) of this section shall also develop
p.000120: written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug
p.000120: experi- ences to FDA.
p.000120: (c) Reporting requirements. The appli- cant shall report to FDA adverse drug experience information, as
p.000120: described in this section. The applicant shall sub- mit two copies of each report described in this section
p.000120: to the Central Docu- ment Room, 5901–B Ammendale Rd., Beltsville, MD 20705–1266. FDA may waive
p.000120: the requirement for the second copy in appropriate instances.
p.000120: (1)(i) Postmarketing 15-day ‘‘Alert re- ports’’. The applicant shall report each adverse drug experience
p.000120: that is both se- rious and unexpected, whether foreign
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p.000121: § 314.80
p.000121: or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of
p.000121: the information by the applicant.
p.000121: (ii) Postmarketing 15-day ‘‘Alert re- ports’’—follo up. The applicant shall promptly investigate
p.000121: all adverse drug experiences that are the subject of these postmarketing 15-day Alert re- ports and
p.000121: shall submit followup reports within 15 calendar days of receipt of new information or as requested by
p.000121: FDA. If additional information is not obtainable, records should be main- tained of the unsuccessful
p.000121: steps taken to seek additional information. Post- marketing 15-day Alert reports and followups to them
p.000121: shall be submitted under separate cover.
p.000121: (iii) Submission of reports. The re-
p.000121: quirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of postmarketing
p.000121: 15-day Alert reports, shall also apply to any person other than the applicant (non- applicant) whose
p.000121: name appears on the label of an approved drug product as a manufacturer, packer, or distributor. To
p.000121: avoid unnecessary duplication in the submission to FDA of reports re- quired by paragraphs
p.000121: (c)(1)(i) and (c)(1)(ii) of this section, obligations of a nonapplicant may be met by submis- sion of all
p.000121: reports of serious adverse drug experiences to the applicant. If a nonapplicant elects to submit adverse
p.000121: drug experience reports to the appli- cant rather than to FDA, the non- applicant shall submit each
p.000121: report to the applicant within 5 calendar days of receipt of the report by the non- applicant, and
p.000121: the applicant shall then comply with the requirements of this section. Under this circumstance, the
p.000121: nonapplicant shall maintain a record of this action which shall include:
p.000121: (A) A copy of each adverse drug expe-
p.000121: rience report;
p.000121: (B) The date the report was received by the nonapplicant;
p.000121: (C) The date the report was sub- mitted to the applicant; and
p.000121: (D) The name and address of the ap- plicant.
p.000121: (iv) Report identification. Each report submitted under this paragraph shall bear prominent identification
p.000121: as to its contents, i.e., ‘‘15-day Alert report,’’ or ‘‘15-day Alert report-followup.’’
p.000121: 21 CFR Ch. I (4–1–12 Edition)
p.000121: (2) Periodic adverse drug experience re- ports. (i) The applicant shall report each adverse drug
p.000121: experience not re- ported under paragraph (c)(1)(i) of this section at quarterly intervals, for 3
p.000121: years from the date of approval of the application, and then at annual inter- vals. The applicant shall
p.000121: submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on
p.000121: the date of approval of the application) and each annual report within 60 days of the anniversary date of
p.000121: approval of the application. Upon written notice, FDA may extend or re- establish the requirement that
p.000121: an ap- plicant submit quarterly reports, or re- quire that the applicant submit reports under this section at
p.000121: different times than those stated. For example, the agency may reestablish a quarterly re- porting
p.000121: requirement following the ap- proval of a major supplement. Fol- lowup information to adverse drug
p.000121: ex- periences submitted in a periodic re- port may be submitted in the next peri- odic report.
p.000121: (ii) Each periodic report is required
p.000121: to contain: (a) a narrative summary and analysis of the information in the report and an analysis
p.000121: of the 15-day Alert reports submitted during the re- porting interval (all 15-day Alert re- ports
p.000121: being appropriately referenced by the applicant’s patient identification number, adverse reaction term(s),
p.000121: and date of submission to FDA); (b) a FDA Form 3500A (Adverse Reaction Report) for each adverse drug
p.000121: experience not reported under paragraph (c)(1)(i) of this section (with an index consisting of a line
p.000121: listing of the applicant’s pa- tient identification number and ad- verse reaction term(s)); and (c) a
p.000121: his- tory of actions taken since the last re- port because of adverse drug experi- ences (for example,
p.000121: labeling changes or studies initiated).
p.000121: (iii) Periodic reporting, except for in-
p.000121: formation regarding 15-day Alert re- ports, does not apply to adverse drug experience information
p.000121: obtained from postmarketing studies (whether or not conducted under an investigational new drug
p.000121: application), from reports in the scientific literature, and from for- eign marketing experience.
p.000121: (d) Scientific literature. (1) A 15-day Alert report based on information from
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p.000122:
p.000122:
p.000122:
p.000122:
p.000122: Food and Drug Administration, HHS § 314.80
p.000122:
p.000122:
p.000122: the scientific literature is required to be accompanied by a copy of the pub- lished article. The 15-day
p.000122: reporting re- quirements in paragraph (c)(1)(i) of this section (i.e., serious, unexpected ad- verse drug
p.000122: experiences) apply only to reports found in scientific and medical journals either as case reports or as the
p.000122: result of a formal clinical trial.
p.000122: (2) As with all reports submitted under paragraph (c)(1)(i) of this sec- tion, reports based on the
p.000122: scientific lit- erature shall be submitted on FDA Form 3500A or comparable format as prescribed by
p.000122: paragraph (f) of this sec- tion. In cases where the applicant be- lieves that preparing the FDA
p.000122: Form 3500A constitutes an undue hardship, the applicant may arrange with the Of- fice of Surveillance and
p.000122: Epidemiology for an acceptable alternative reporting format.
p.000122: (e) Postmarketing studies. (1) An appli-
p.000122: cant is not required to submit a 15-day Alert report under paragraph (c) of this section for an adverse drug
p.000122: experience obtained from a postmarketing study (whether or not conducted under an in- vestigational new drug
p.000122: application) un- less the applicant concludes that there is a reasonable possibility that the drug
p.000122: caused the adverse experience.
p.000122: (2) The applicant shall separate and clearly mark reports of adverse drug experiences that occur during a
p.000122: post- marketing study as being distinct from those experiences that are being re- ported spontaneously to
p.000122: the applicant.
p.000122: (f) Reporting FDA Form 3500A. (1) Ex- cept as provided in paragraph (f)(3) of this section, the
p.000122: applicant shall com- plete FDA Form 3500A for each report of an adverse drug experience (foreign events
p.000122: may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form).
p.000122: (2) Each completed FDA Form 3500A should refer only to an individual pa- tient or a single attached
p.000122: publication.
p.000122: (3) Instead of using FDA Form 3500A, an applicant may use a computer-gen- erated FDA Form 3500A or other
p.000122: alter- native format (e.g., a computer-gen- erated tape or tabular listing) provided that:
p.000122: (i) The content of the alternative for- mat is equivalent in all elements of in- formation to those specified
p.000122: in FDA Form 3500A; and
p.000122:
p.000122: (ii) The format is agreed to in ad- vance by the Office of Surveillance and Epidemiology.
p.000122: (4) FDA Form 3500A and instructions for completing the form are available on the Internet at http://
p.000122: .fda.gov/ med atch/index.html.
p.000122: (g) Multiple reports. An applicant should not include in reports under this section any
p.000122: adverse drug experi- ences that occurred in clinical trials if they were previously submitted as part of the
p.000122: approved application. If a report applies to a drug for which an appli- cant holds more than one approved
p.000122: ap- plication, the applicant should submit the report to the application that was first approved. If a
p.000122: report refers to more than one drug marketed by an ap- plicant, the applicant should submit the report
p.000122: to the application for the drug listed first in the report.
p.000122: (h) Patient privacy. An applicant
p.000122: should not include in reports under this section the names and addresses of individual patients; instead,
p.000122: the appli- cant should assign a unique code num- ber to each report, preferably not more than eight characters
p.000122: in length. The applicant should include the name of the reporter from whom the informa- tion was
p.000122: received. Names of patients, health care professionals, hospitals, and geographical identifiers in
p.000122: adverse drug experience reports are not releas- able to the public under FDA’s public information
p.000122: regulations in part 20.
p.000122: (i) Recordkeeping. The applicant shall
p.000122: maintain for a period of 10 years records of all adverse drug experiences known to the
p.000122: applicant, including raw data and any correspondence relating to adverse drug experiences.
p.000122: (j) Withdra al of approval. If an appli- cant fails to establish and maintain records and make
p.000122: reports required under this section, FDA may withdraw approval of the application and, thus, prohibit
p.000122: continued marketing of the drug product that is the subject of the application.
p.000122: (k) Disclaimer. A report or informa- tion submitted by an applicant under this section (and any release by
p.000122: FDA of that report or information) does not necessarily reflect a conclusion by the applicant or FDA that the
p.000122: report or in- formation constitutes an admission that the drug caused or contributed to
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p.000123:
p.000123:
p.000123:
p.000123:
p.000123:
p.000123:
p.000123: § 314.81
p.000123: an adverse effect. An applicant need not admit, and may deny, that the re- port or information
p.000123: submitted under this section constitutes an admission that the drug caused or contributed to an adverse
p.000123: effect. For purposes of this provision, the term ‘‘applicant’’ also includes any person reporting
p.000123: under paragraph (c)(1)(iii) of this section.
p.000123: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000123: 1985, as amended at 50 FR 21238, May 23, 1985;
p.000123: 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13,
p.000123: 1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17983,
p.000123: Apr. 28, 1992; 62 FR 34168, June 25, 1997; 62 FR
p.000123: 52251, Oct. 7, 1997; 63 FR 14611, Mar. 26, 1998;
p.000123: 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23,
p.000123: 2004; 74 FR 13113, Mar. 26, 2009]
p.000123: § 314.81 Other postmarketing reports.
p.000123: (a) Applicability. Each applicant shall make the reports for each of its ap- proved applications and
p.000123: abbreviated applications required under this sec- tion and section 505(k) of the act.
p.000123: (b) Reporting requirements. The appli- cant shall submit to the Food and Drug Administration at the specified
p.000123: times two copies of the following reports:
p.000123: (1) NDA—Field alert report. The appli- cant shall submit information of the following kinds about
p.000123: distributed drug products and articles to the FDA dis- trict office that is responsible for the facility
p.000123: involved within 3 working days of receipt by the applicant. The infor- mation may be provided by telephone
p.000123: or other rapid communication means, with prompt written followup. The re- port and its mailing cover
p.000123: should be plainly marked: ‘‘NDA—Field Alert Re- port.’’
p.000123: (i) Information concerning any inci- dent that causes the drug product or its labeling to be mistaken
p.000123: for, or ap- plied to, another article.
p.000123: (ii) Information concerning any bac- teriological contamination, or any sig- nificant chemical, physical,
p.000123: or other change or deterioration in the distrib- uted drug product, or any failure of one or more distributed
p.000123: batches of the drug product to meet the specification es- tablished for it in the application.
p.000123: (2) Annual report. The applicant shall submit each year within 60 days of the anniversary date of
p.000123: U.S. approval of the application, two copies of the re- port to the FDA division responsible for
p.000123: reviewing the application. Each an-
p.000123: 21 CFR Ch. I (4–1–12 Edition)
p.000123: nual report is required to be accom- panied by a completed transmittal Form FDA 2252 (Transmittal
p.000123: of Peri- odic Reports for Drugs for Human Use), and must include all the information required under this section
p.000123: that the ap- plicant received or otherwise obtained during the annual reporting interval that ends on the
p.000123: U.S. anniversary date. The report is required to contain in the order listed:
p.000123: (i) Summary. A brief summary of sig- nificant new information from the pre- vious year that might affect the
p.000123: safety, effectiveness, or labeling of the drug product. The report is also required to contain a brief
p.000123: description of actions the applicant has taken or intends to take as a result of this new informa- tion,
p.000123: for example, submit a labeling supplement, add a warning to the label- ing, or initiate a new study.
p.000123: The sum- mary shall briefly state whether label- ing supplements for pediatric use have been submitted and
p.000123: whether new stud- ies in the pediatric population to sup- port appropriate labeling for the pedi- atric
p.000123: population have been initiated. Where possible, an estimate of patient exposure to the drug product, with
p.000123: spe- cial reference to the pediatric popu- lation (neonates, infants, children, and adolescents) shall
p.000123: be provided, includ- ing dosage form.
p.000123: (ii)(a) Distribution data. Information
p.000123: about the quantity of the drug product distributed under the approved applica- tion, including that distributed to
p.000123: dis- tributors. The information is required to include the National Drug Code (NDC) number, the
p.000123: total number of dosage units of each strength or po- tency distributed (e.g., 100,000/5 milli- gram
p.000123: tablets, 50,000/10 milliliter vials), and the quantities distributed for do- mestic use and the quantities
p.000123: distrib- uted for foreign use. Disclosure of fi- nancial or pricing data is not required.
p.000123: (b) Authorized generic drugs. If appli-
p.000123: cable, the date each authorized generic drug (as defined in § 314.3) entered the market, the date each
p.000123: authorized ge- neric drug ceased being distributed, and the corresponding trade or brand name. Each
p.000123: dosage form and/or strength is a different authorized ge- neric drug and should be listed sepa-
p.000123: rately. The first annual report sub- mitted on or after January 25, 2010
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p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124: Food and Drug Administration, HHS § 314.81
p.000124:
p.000124:
p.000124: must include the information listed in this paragraph for any authorized ge- neric drug that was marketed
p.000124: during the time period covered by an annual report submitted after January 1, 1999. If information is
p.000124: included in the annual report with respect to any authorized generic drug, a copy of that portion of the
p.000124: annual report must be sent to the Food and Drug Administration, Center for Drug Evaluation and Research,
p.000124: Of- fice of New Drug Quality Assessment, Bldg. 21, rm. 2562, 10903 New Hampshire Ave., Silver Spring, MD
p.000124: 20993–0002, and marked ‘‘Authorized Generic Submis- sion’’ or, by e-mail, to the Authorized Generics
p.000124: electronic mailbox at AuthorizedGenerics@fda.hhs.gov with ‘‘Authorized Generic Submission’’ indi-
p.000124: cated in the subject line. However, at such time that FDA has required that annual reports be submitted in
p.000124: an elec- tronic format, the information re- quired by this paragraph must be sub- mitted as part
p.000124: of the annual report, in the electronic format specified for sub- mission of annual reports at that time, and not
p.000124: as a separate submission under the preceding sentence in this para- graph.
p.000124: (iii) Labeling. (a) Currently used pro- fessional labeling, patient brochures or package inserts (if any),
p.000124: and a rep- resentative sample of the package la- bels.
p.000124: (b) The content of labeling required under § 201.100(d)(3) of this chapter (i.e., the package insert or
p.000124: professional la- beling), including all text, tables, and figures, must be submitted in elec- tronic
p.000124: format. Electronic format sub- missions must be in a form that FDA can process, review, and archive. FDA
p.000124: will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission,
p.000124: media, file formats, preparation and organiza- tion of files). Submissions under this paragraph must be made
p.000124: in accordance with part 11 of this chapter, except for the requirements of § 11.10(a), (c)
p.000124: through (h), and (k), and the cor- responding requirements of § 11.30.
p.000124: (c) A summary of any changes in la- beling that have been made since the last report listed by date
p.000124: in the order in which they were implemented, or if no changes, a statement of that fact.
p.000124:
p.000124: (iv) Chemistry, manufacturing, and controls changes. (a) Reports of experi- ences, investigations,
p.000124: studies, or tests involving chemical or physical prop- erties, or any other properties of the drug
p.000124: (such as the drug’s behavior or properties in relation to microorga- nisms, including both the effects of
p.000124: the drug on microorganisms and the effects of microorganisms on the drug). These reports are only required for new
p.000124: infor- mation that may affect FDA’s previous conclusions about the safety or effec- tiveness of the drug product.
p.000124: (b) A full description of the manufac- turing and controls changes not requir- ing a supplemental application under
p.000124: § 314.70 (b) and (c), listed by date in the order in which they were implemented.
p.000124: (v) Nonclinical laboratory studies. Cop- ies of unpublished reports and sum- maries of published reports
p.000124: of new toxi- cological findings in animal studies and in vitro studies (e.g., mutage- nicity)
p.000124: conducted by, or otherwise ob- tained by, the applicant concerning the ingredients in the drug product. The
p.000124: applicant shall submit a copy of a pub- lished report if requested by FDA.
p.000124: (vi) Clinical data. (a) Published clin- ical trials of the drug (or abstracts of them), including clinical
p.000124: trials on safe- ty and effectiveness; clinical trials on new uses; biopharmaceutic, pharmaco- kinetic, and
p.000124: clinical pharmacology studies; and reports of clinical experi- ence pertinent to safety (for example,
p.000124: epidemiologic studies or analyses of ex- perience in a monitored series of pa- tients) conducted by or
p.000124: otherwise ob- tained by the applicant. Review arti- cles, papers describing the use of the drug product
p.000124: in medical practice, pa- pers and abstracts in which the drug is used as a research tool, promotional articles,
p.000124: press clippings, and papers that do not contain tabulations or summaries of original data should
p.000124: not be reported.
p.000124: (b) Summaries of completed unpub- lished clinical trials, or prepublication manuscripts if available, conducted
p.000124: by, or otherwise obtained by, the appli- cant. Supporting information should not be reported. (A
p.000124: study is considered completed 1 year after it is concluded.)
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p.000125:
p.000125:
p.000125:
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p.000125:
p.000125: § 314.81
p.000125: (c) Analysis of available safety and efficacy data in the pediatric popu- lation and changes proposed
p.000125: in the la- beling based on this information. An assessment of data needed to ensure appropriate
p.000125: labeling for the pediatric population shall be included.
p.000125: (vii) Status reports of postmarketing study commitments. A status report of each postmarketing study
p.000125: of the drug product concerning clinical safety, clinical efficacy, clinical pharma- cology, and
p.000125: nonclinical toxicology that is required by FDA (e.g., accelerated approval clinical benefit studies, pedi-
p.000125: atric studies) or that the applicant has committed, in writing, to conduct ei- ther at the time of approval
p.000125: of an ap- plication for the drug product or a sup- plement to an application, or after ap- proval of the
p.000125: application or a supple- ment. For pediatric studies, the status report shall include a statement indi-
p.000125: cating whether postmarketing clinical studies in pediatric populations were required by FDA under § 201.23
p.000125: of this chapter. The status of these post- marketing studies shall be reported an- nually until FDA
p.000125: notifies the appli- cant, in writing, that the agency con- curs with the applicant’s determina-
p.000125: tion that the study commitment has been fulfilled or that the study is ei- ther no longer feasible
p.000125: or would no longer provide useful information.
p.000125: (a) Content of status report. The fol- lowing information must be provided for each postmarketing study
p.000125: reported under this paragraph:
p.000125: (1) Applicant’s name.
p.000125: (2) Product name. Include the ap- proved drug product’s established name and proprietary name, if any.
p.000125: (3) NDA, ANDA, and supplement num- ber.
p.000125: (4) Date of U.S. approval of NDA or ANDA.
p.000125: (5) Date of postmarketing study commit- ment.
p.000125: (6) Description of postmarketing study commitment. The description must in- clude sufficient information to
p.000125: unique- ly describe the study. This information may include the purpose of the study, the type of study, the
p.000125: patient popu- lation addressed by the study and the indication(s) and dosage(s) that are to be studied.
p.000125: 21 CFR Ch. I (4–1–12 Edition)
p.000125: (7) Schedule for completion and report- ing of the postmarketing study commit- ment. The schedule
p.000125: should include the actual or projected dates for submis- sion of the study protocol to FDA,
p.000125: completion of patient accrual or initi- ation of an animal study, completion of the study, submission of
p.000125: the final study report to FDA, and any addi- tional milestones or submissions for which
p.000125: projected dates were specified as part of the commitment. In addition, it should include a revised schedule, as
p.000125: appropriate. If the schedule has been previously revised, provide both the original schedule and the
p.000125: most recent, previously submitted revision.
p.000125: (8) Current status of the postmarketing study commitment. The status of each postmarketing study should
p.000125: be cat- egorized using one of the following terms that describes the study’s status on the
p.000125: anniversary date of U.S. ap- proval of the application or other agreed upon date:
p.000125: (i) Pending. The study has not been initiated, but does not meet the cri- terion for delayed.
p.000125: (ii) Ongoing. The study is proceeding according to or ahead of the original schedule described under
p.000125: paragraph (b)(2)(vii)(a)(7) of this section.
p.000125: (iii) Delayed. The study is behind the original schedule described under para- graph (b)(2)(vii)(a)(7) of this
p.000125: section.
p.000125: (iv) Terminated. The study was ended before completion but a final study re- port has not been submitted to
p.000125: FDA.
p.000125: (v) Submitted. The study has been completed or terminated and a final study report has been
p.000125: submitted to FDA.
p.000125: (9) Explanation of the study’s status. Provide a brief description of the sta- tus of the study,
p.000125: including the patient accrual rate (expressed by providing the number of patients or subjects en-
p.000125: rolled to date, and the total planned enrollment), and an explanation of the study’s status identified
p.000125: under para- graph (b)(2)(vii)(a)(8) of this section. If the study has been completed, include the date
p.000125: the study was completed and the date the final study report was sub- mitted to FDA, as applicable. Provide a
p.000125: revised schedule, as well as the rea- son(s) for the revision, if the schedule under paragraph
p.000125: (b)(2)(vii)(a)(7) of this
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p.000126:
p.000126:
p.000126:
p.000126:
p.000126:
p.000126:
p.000126: Food and Drug Administration, HHS § 314.81
p.000126:
p.000126:
p.000126: section has changed since the last re- port.
p.000126: (b) Public disclosure of information. Ex- cept for the information described in this paragraph, FDA may
p.000126: publicly dis- close any information described in paragraph (b)(2)(vii) of this section, concerning
p.000126: a postmarketing study, if the agency determines that the infor- mation is necessary to identify the ap-
p.000126: plicant or to establish the status of the study, including the reasons, if any, for failure to conduct, complete,
p.000126: and re- port the study. Under this section, FDA will not publicly disclose trade se- crets, as defined in
p.000126: § 20.61 of this chap- ter, or information, described in § 20.63 of this chapter, the disclosure of which would
p.000126: constitute an unwarranted inva- sion of personal privacy.
p.000126: (viii) Status of other postmarketing
p.000126: studies. A status report of any post- marketing study not included under paragraph (b)(2)(vii)
p.000126: of this section that is being performed by, or on behalf of, the applicant. A status report is to be
p.000126: included for any chemistry, manu- facturing, and controls studies that the applicant has agreed to perform and for
p.000126: all product stability studies.
p.000126: (ix) Log of outstanding regulatory busi- ness. To facilitate communications be- tween FDA and the
p.000126: applicant, the re- port may, at the applicant’s discretion, also contain a list of any open regu- latory
p.000126: business with FDA concerning the drug product subject to the appli- cation (e.g., a list of the applicant’s
p.000126: un- answered correspondence with the agency, a list of the agency’s unan- swered
p.000126: correspondence with the appli- cant).
p.000126: (3) Other reporting—(i) Advertisements and promotional labeling. The applicant shall submit specimens
p.000126: of mailing pieces and any other labeling or adver- tising devised for promotion of the drug product at
p.000126: the time of initial dis- semination of the labeling and at the time of initial publication of the adver-
p.000126: tisement for a prescription drug prod- uct. Mailing pieces and labeling that are designed to contain
p.000126: samples of a drug product are required to be com- plete, except the sample of the drug product may be
p.000126: omitted. Each submis- sion is required to be accompanied by a completed transmittal Form FDA–2253 (Transmittal
p.000126: of Advertisements and
p.000126:
p.000126: Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product’s
p.000126: current profes- sional labeling. Form FDA–2253 is available on the Internet at http://
p.000126: .fda.gov/opacom/morechoices/ fdaforms/cder.html.
p.000126: (ii) Special reports. Upon written re- quest the agency may require that the applicant submit the reports
p.000126: under this section at different times than those stated.
p.000126: (iii) Notification of discontinuance. (a) An applicant who is the sole manufac- turer of an approved drug
p.000126: product must notify FDA in writing at least 6 months prior to discontinuance of
p.000126: manufacture of the drug product if:
p.000126: (1) The drug product is life sup- porting, life sustaining, or intended for use in the prevention of a
p.000126: serious dis- ease or condition; and
p.000126: (2) The drug product was not origi- nally derived from human tissue and replaced by a recombinant product.
p.000126: (b) Notifications required by para- graph (b)(3)(iii)(a) of this section must be submitted to FDA
p.000126: either electroni- cally or by phone according to instruc- tions on FDA’s Drug Shortages Web site at:
p.000126: http:// .fda.gov/Drugs/ DrugSafety/DrugShortages.
p.000126: (c) FDA will publicly disclose a list of all drug products to be discontinued under paragraph
p.000126: (b)(3)(iii)(a) of this section. If the notification period is re- duced under § 314.91, the list will state
p.000126: the reason(s) for such reduction and the anticipated date that manufac- turing will cease.
p.000126: (d) For purposes of this section and
p.000126: § 314.91, the terms ‘‘discontinuance’’ and ‘‘sole manufacturer’’ are defined as follows:
p.000126: Discontinuance means any interrup- tion in manufacturing of a drug prod- uct described in paragraph
p.000126: (b)(3)(iii)(a) of this section for sale in the United States that could lead to a potential disruption in
p.000126: supply of the drug prod- uct, whether the interruption is in- tended to be temporary or permanent.
p.000126: Sole manufacturer means an applicant that is the only entity currently manu- facturing a drug product of a
p.000126: specific strength, dosage form, or route of ad- ministration for sale in the United
p.000127: 127
p.000127:
p.000127:
p.000127:
p.000127:
p.000127:
p.000127:
p.000127:
p.000127:
p.000127: § 314.90
p.000127: States, whether the product is manu- factured by the applicant or for the ap- plicant under contract with
p.000127: one or more different entities.
p.000127: (iv) Withdra al of approved drug prod- uct from sale. (a) The applicant shall submit on Form FDA
p.000127: 2657 (Drug Prod- uct Listing), within 15 working days of the withdrawal from sale of a drug product, the
p.000127: following information:
p.000127: (1) The National Drug Code (NDC) number.
p.000127: (2) The identity of the drug product by established name and by proprietary name.
p.000127: (3) The new drug application or ab- breviated application number.
p.000127: (4) The date of withdrawal from sale. It is requested but not required that the reason for withdrawal of the
p.000127: drug product from sale be included with the information.
p.000127: (b) The applicant shall submit each Form FDA–2657 to the Records Reposi- tory Team (HFD–143), Center for
p.000127: Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
p.000127: (c) Reporting under paragraph (b)(3)(iv) of this section constitutes compliance with the
p.000127: requirements under § 207.30(a) of this chapter to re- port ‘‘at the discretion of the reg-
p.000127: istrant when the change occurs.’’
p.000127: (c) General requirements—(1) Multiple applications. For all reports required by this section, the applicant shall
p.000127: submit the information common to more than one application only to the application first approved, and shall not
p.000127: report sep- arately on each application. The sub- mission is required to identify all the applications to
p.000127: which the report ap- plies.
p.000127: (2) Patient identification. Applicants should not include in reports under this section the names and
p.000127: addresses of individual patients; instead, the appli- cant should code the patient names whenever
p.000127: possible and retain the code in the applicant’s files. The applicant shall maintain sufficient patient
p.000127: iden- tification information to permit FDA, by using that information alone or along with records
p.000127: maintained by the investigator of a study, to identify the name and address of individual pa- tients;
p.000127: this will ordinarily occur only when the agency needs to investigate
p.000127: 21 CFR Ch. I (4–1–12 Edition)
p.000127: the reports further or when there is reason to believe that the reports do not represent actual results
p.000127: obtained.
p.000127: (d) Withdra al of approval. If an ap- plicant fails to make reports required under this section, FDA
p.000127: may withdraw approval of the application and, thus, prohibit continued marketing of the drug product
p.000127: that is the subject of the application.
p.000127: (Collection of information requirements ap- proved by the Office of Management and Budget under control
p.000127: number 0910–0001)
p.000127: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000127: 1985, as amended at 50 FR 21238, May 23, 1985;
p.000127: 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28,
p.000127: 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan.
p.000127: 5, 1999; 65 FR 64617, Oct. 30, 2000; 66 FR 10815,
p.000127: Feb. 20, 2001; 68 FR 69019, Dec. 11, 2003; 69 FR
p.000127: 18766, Apr. 8, 2004; 69 FR 48775, Aug. 11, 2004;
p.000127: 72 FR 58999, Oct. 18, 2007; 74 FR 13113, Mar. 26,
p.000127: 2009; 74 FR 37167, July 28, 2009; 76 FR 78539,
p.000127: Dec. 19, 2011]
p.000127:
p.000127: § 314.90 Waivers.
p.000127: (a) An applicant may ask the Food and Drug Administration to waive under this section any
p.000127: requirement that applies to the applicant under
p.000127: §§ 314.50 through 314.81. An applicant may ask FDA to waive under
p.000127: § 314.126(c) any criteria of an adequate and well-controlled study described in
p.000127: § 314.126(b). A waiver request under this section is required to be submitted with supporting documentation
p.000127: in an application, or in an amendment or supplement to an application. The waiver request is
p.000127: required to contain one of the following:
p.000127: (1) An explanation why the appli- cant’s compliance with the require- ment is unnecessary or
p.000127: cannot be achieved;
p.000127: (2) A description of an alternative submission that satisfies the purpose of the requirement; or
p.000127: (3) Other information justifying a waiver.
p.000127: (b) FDA may grant a waiver if it finds one of the following:
p.000127: (1) The applicant’s compliance with the requirement is unnecessary for the agency to evaluate the
p.000127: application or compliance cannot be achieved;
p.000127: (2) The applicant’s alternative sub- mission satisfies the requirement; or
p.000128: 128
p.000128:
p.000128:
p.000128:
p.000128:
p.000128:
p.000128:
p.000128:
p.000128: Food and Drug Administration, HHS § 314.91
p.000128:
p.000128:
p.000128: (3) The applicant’s submission other- wise justifies a waiver.
p.000128: [50 FR 7493, Feb. 22, 1985, as amended at 50
p.000128: FR 21238, May 23, 1985; 67 FR 9586, Mar. 4,
p.000128: 2002]
p.000128:
p.000128: § 314.91 Obtaining a reduction in the discontinuance notification period.
p.000128: (a) What is the discontinuance notifica- tion period? The discontinuance notifi- cation period is the
p.000128: 6-month period re- quired under § 314.81(b)(3)(iii)(a). The discontinuance notification period be- gins
p.000128: when an applicant who is the sole manufacturer of certain products noti- fies FDA that it will discontinue
p.000128: manu- facturing the product. The discontinu- ance notification period ends when manufacturing ceases.
p.000128: (b) When can FDA reduce the dis-
p.000128: continuance notification period? FDA can reduce the 6-month discontinuance no- tification period when it
p.000128: finds good cause exists for the reduction. FDA may find good cause exists based on in- formation certified
p.000128: by an applicant in a request for a reduction of the dis- continuance notification period. In
p.000128: limited circumstances, FDA may find good cause exists based on information already known to the agency.
p.000128: These circumstances can include the with- drawal of the drug from the market based upon formal FDA
p.000128: regulatory ac- tion (e.g., under the procedures de- scribed in § 314.150 for the publication of a
p.000128: notice of opportunity for a hearing describing the basis for the proposed withdrawal of a drug from the market) or
p.000128: resulting from the applicant’s con- sultations with the agency.
p.000128: (c) Ho can an applicant request a re- duction in the discontinuance notification period? (1) The applicant
p.000128: must certify in a written request that, in its opinion and to the best of its knowledge, good cause exists
p.000128: for the reduction. The ap- plicant must submit the following cer- tification:
p.000128: The undersigned certifies that good cause exists for a reduction in the 6-month notifi- cation period
p.000128: required in § 314.81(b)(3)(iii)(a) for discontinuing the manufacture of (name of the drug product).
p.000128: The following cir- cumstances establish good cause (one or more of the circumstances in paragraph (d) of
p.000128: this section).
p.000128: (2) The certification must be signed by the applicant or the applicant’s at- torney, agent (representative),
p.000128: or other
p.000128:
p.000128: authorized official. If the person sign- ing the certification does not reside or have a place of
p.000128: business within the United States, the certification must contain the name and address of, and must also
p.000128: be signed by, an attorney, agent, or other authorized official who resides or maintains a place of business
p.000128: within the United States.
p.000128: (3) For drugs regulated by the Center for Drug Evaluation and Research (CDER) or the Center for
p.000128: Biologics Evaluation and Research (CBER), one copy of the certification must be sub- mitted to the Drug
p.000128: Shortage Coordi- nator at the address of the Director of CDER, one copy to the CDER Drug
p.000128: Registration and Listing Team, Divi- sion of Compliance Risk Management and Surveillance in CDER, and
p.000128: one copy to either the director of the re- view division in CDER responsible for reviewing the application,
p.000128: or the direc- tor of the office in CBER responsible for reviewing the application.
p.000128: (d) What circumstances and information can establish good cause for a reduction in the discontinuance
p.000128: notification period?
p.000128: (1) A public health problem may result from continuation of manufacturing for the 6-month period. This
p.000128: certifi- cation must include a detailed descrip- tion of the potential threat to the pub- lic health.
p.000128: (2) A biomaterials shortage prevents the continuation of the manufacturing for the 6-month period. This
p.000128: certifi- cation must include a detailed descrip- tion of the steps taken by the applicant in an attempt to secure
p.000128: an adequate supply of biomaterials to enable manu- facturing to continue for the 6-month period and an
p.000128: explanation of why the biomaterials could not be secured.
p.000128: (3) A liability problem may exist for the manufacturer if the manufacturing is continued for the 6-month
p.000128: period. This certification must include a de- tailed description of the potential li- ability problem.
p.000128: (4) Continuation of the manufac- turing for the 6-month period may cause substantial economic
p.000128: hardship for the manufacturer. This certifi- cation must include a detailed descrip- tion of the
p.000128: financial impact of con- tinuing to manufacture the drug prod- uct over the 6-month period.
p.000129: 129
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129: § 314.92
p.000129: (5) The manufacturer has filed for bankruptcy under chapter 7 or 11 of title 11, United States
p.000129: Code (11 U.S.C. 701 et seq. and 1101 et seq.). This certifi- cation must be accompanied by docu-
p.000129: mentation of the filing or proof that the filing occurred.
p.000129: (6) The manufacturer can continue distribution of the drug product to sat- isfy existing market need for 6
p.000129: months. This certification must include a de- tailed description of the manufactur- er’s processes to
p.000129: ensure such distribu- tion for the 6-month period.
p.000129: (7) Other good cause exists for the re- duction. This certification must in- clude a detailed description of
p.000129: the need for a reduction.
p.000129: [72 FR 58999, Oct. 18, 2007]
p.000129:
p.000129: Subpart C—Abbreviated Applications
p.000129:
p.000129: SOURCE: 57 FR 17983, Apr. 28, 1992, unless
p.000129: otherwise noted.
p.000129:
p.000129: § 314.92 Drug products for which ab- breviated applications may be sub- mitted.
p.000129: (a) Abbreviated applications are suit- able for the following drug products within the limits set
p.000129: forth under
p.000129: § 314.93:
p.000129: (1) Drug products that are the same as a listed drug. A ‘‘listed drug’’ is de- fined in § 314.3.
p.000129: For determining the suitability of an abbreviated new drug application, the term ‘‘same as’’ means identical
p.000129: in active ingredient(s), dosage form, strength, route of administra- tion, and conditions of use, except that
p.000129: conditions of use for which approval cannot be granted because of exclu- sivity or an
p.000129: existing patent may be omitted. If a listed drug has been vol- untarily withdrawn from or not offered for
p.000129: sale by its manufacturer, a person who wishes to submit an abbreviated new drug application for the drug
p.000129: shall comply with § 314.122.
p.000129: (2) [Reserved]
p.000129: (3) Drug products that have been de- clared suitable for an abbreviated new drug application submission
p.000129: by FDA through the petition procedures set forth under § 10.30 of this chapter and
p.000129: § 314.93.
p.000129: 21 CFR Ch. I (4–1–12 Edition)
p.000129: (b) FDA will publish in the list listed drugs for which abbreviated applica- tions may be submitted.
p.000129: The list is available from the Superintendent of Documents, U.S. Government Printing Office, Washington,
p.000129: DC 20402, 202–783– 3238.
p.000129: [57 FR 17983, Apr. 28, 1992, as amended at 64
p.000129: FR 401, Jan. 5, 1999]
p.000129:
p.000129: § 314.93 Petition to request a change from a listed drug.
p.000129: (a) The only changes from a listed drug for which the agency will accept a petition under this section are
p.000129: those changes described in paragraph (b) of this section. Petitions to submit abbre- viated new drug
p.000129: applications for other changes from a listed drug will not be approved.
p.000129: (b) A person who wants to submit an abbreviated new drug application for a drug product which is not
p.000129: identical to a listed drug in route of administra- tion, dosage form, and strength, or in which one
p.000129: active ingredient is sub- stituted for one of the active ingredi- ents in a listed combination drug, must
p.000129: first obtain permission from FDA to submit such an abbreviated applica- tion.
p.000129: (c) To obtain permission to submit an abbreviated new drug application for a change described in paragraph
p.000129: (b) of this section, a person must submit and obtain approval of a petition request- ing the change. A
p.000129: person seeking per- mission to request such a change from a reference listed drug shall submit a petition
p.000129: in accordance with § 10.20 of this chapter and in the format specified in § 10.30 of this chapter. The
p.000129: petition shall contain the information specified in § 10.30 of this chapter and any addi- tional information
p.000129: required by this sec- tion. If any provision of § 10.20 or § 10.30 of this chapter is inconsistent with any provision
p.000129: of this section, the provisions of this section apply.
p.000129: (d) The petitioner shall identify a
p.000129: listed drug and include a copy of the proposed labeling for the drug product that is the subject of
p.000129: the petition and a copy of the approved labeling for the listed drug. The petitioner may, under limited
p.000129: circumstances, identify more than one listed drug, for example, when the proposed drug product is a com-
p.000129: bination product that differs from the
p.000130: 130
p.000130:
p.000130:
p.000130:
p.000130:
p.000130:
p.000130:
p.000130:
p.000130: Food and Drug Administration, HHS § 314.93
p.000130:
p.000130:
p.000130: combination reference listed drug with regard to an active ingredient, and the different active ingredient
p.000130: is an active ingredient of a listed drug. The peti- tioner shall also include information to show that:
p.000130: (1) The active ingredients of the pro- posed drug product are of the same pharmacological or
p.000130: therapeutic class as those of the reference listed drug.
...
p.000130: § 314.94; or
p.000130: (B) The petition does not contain in- formation to show that the different active ingredient of the drug
p.000130: product is of the same pharmacological or thera- peutic class as the ingredient of the
p.000130:
p.000130: reference listed drug that is to be changed and that the drug product can be expected to have the same
p.000130: thera- peutic effect as the reference listed drug when administered to patients for each condition of
p.000130: use in the listed drug’s labeling for which the applicant seeks approval; or
p.000130: (C) The different active ingredient is not an active ingredient in a listed drug or a drug that
p.000130: meets the require- ments of section 201(p) of the act; or
p.000130: (D) The remaining active ingredients are not identical to those of the listed combination drug; or
p.000130: (iv) Any of the proposed changes from the listed drug would jeopardize the safe or effective use of
p.000130: the product so as to necessitate significant labeling changes to address the newly intro- duced safety or
p.000130: effectiveness problem; or
p.000130: (v) FDA has determined that the ref- erence listed drug has been withdrawn from sale for safety or
p.000130: effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily with- drawn from sale
p.000130: and the agency has not determined whether the with- drawal is for safety or effectiveness
p.000130: reasons.
p.000130: (2) For purposes of this paragraph, ‘‘investigations must be conducted’’ means that information
p.000130: derived from animal or clinical studies is necessary to show that the drug product is safe or effective. Such
p.000130: information may be contained in published or unpublished reports.
p.000130: (3) If FDA approves a petition sub- mitted under this section, the agency’s response may describe what
p.000130: additional information, if any, will be required to support an abbreviated new drug appli- cation for the drug
p.000130: product. FDA may, at any time during the course of its re- view of an abbreviated new drug appli- cation,
p.000130: request additional information required to evaluate the change ap- proved under the petition.
p.000130: (f) FDA may withdraw approval of a petition if the agency receives any in- formation demonstrating that the
p.000130: peti- tion no longer satisfies the conditions under paragraph (e) of this section.
p.000131: 131
p.000131:
p.000131:
p.000131:
p.000131:
p.000131:
p.000131:
p.000131:
p.000131:
p.000131: § 314.94
p.000131:
p.000131: § 314.94 Content and format of an ab- breviated application.
p.000131: Abbreviated applications are re- quired to be submitted in the form and contain the information required
p.000131: under this section. Three copies of the appli- cation are required, an archival copy, a review copy, and a field
p.000131: copy. FDA will maintain guidance documents on the format and content of applications to assist applicants in
p.000131: their preparation.
p.000131: (a) Abbreviated ne drug applications.
p.000131: Except as provided in paragraph (b) of this section, the applicant shall submit a complete archival copy of
p.000131: the abbre- viated new drug application that in- cludes the following:
p.000131: (1) Application form. The applicant shall submit a completed and signed application form that contains
p.000131: the in- formation described under § 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant shall state
p.000131: whether the submission is an abbreviated application under this section or a supplement to an abbre-
p.000131: viated application under § 314.97.
p.000131: (2) Table of contents. the archival copy
p.000131: of the abbreviated new drug applica- tion is required to contain a table of contents that shows the
p.000131: volume num- ber and page number of the contents of the submission.
p.000131: (3) Basis for abbreviated ne drug ap- plication submission. An abbreviated new drug application must
p.000131: refer to a listed drug. Ordinarily, that listed drug will be the drug product selected by the agency as the
p.000131: reference standard for conducting bioequivalence testing. The application shall contain:
p.000131: (i) The name of the reference listed
p.000131: drug, including its dosage form and strength. For an abbreviated new drug application based on an
p.000131: approverd peti- tion under § 10.30 of this chapter or
p.000131: § 314.93, the reference listed drug must be the same as the listed drug approved in the petition.
p.000131: (ii) A statement as to whether, ac- cording to the information published in the list, the reference listed drug
p.000131: is en- titled to a period of marketing exclu- sivity under section 505(j)(4)(D) of the act.
p.000131: (iii) For an abbreviated new drug ap- plication based on an approved petition under § 10.30 of this chapter or §
p.000131: 314.93, a reference to FDA-assigned docket num- ber for the petition and a copy of
p.000131: 21 CFR Ch. I (4–1–12 Edition)
p.000131: FDA’s correspondence approving the petition.
p.000131: (4) Conditions of use. (i) A statement that the conditions of use prescribed, recommended, or suggested
p.000131: in the la- beling proposed for the drug product have been previously approved for the reference listed
p.000131: drug.
p.000131: (ii) A reference to the applicant’s an- notated proposed labeling and to the currently approved labeling for the
p.000131: ref- erence listed drug provided under para- graph (a)(8) of this section.
p.000131: (5) Active ingredients. (i) For a single- active-ingredient drug product, infor- mation to show that
p.000131: the active ingre- dient is the same as that of the ref- erence single-active-ingredient listed drug, as
p.000131: follows:
p.000131: (A) A statement that the active in- gredient of the proposed drug product is the same as that of the
p.000131: reference listed drug.
p.000131: (B) A reference to the applicant’s an- notated proposed labeling and to the currently approved labeling for the
p.000131: ref- erence listed drug provided under para- graph (a)(8) of this section.
p.000131: (ii) For a combination drug product, information to show that the active in- gredients are the same as those
p.000131: of the reference listed drug except for any dif- ferent active ingredient that has been the subject of an
p.000131: approved petition, as follows:
p.000131: (A) A statement that the active in- gredients of the proposed drug product are the same as those of
p.000131: the reference listed drug, or if one of the active in- gredients differs from one of the active ingredients of
p.000131: the reference listed drug and the abbreviated application is sub- mitted under the approval of a petition under §
p.000131: 314.93 to vary such active ingre- dient, information to show that the other active ingredients of the
p.000131: drug product are the same as the other ac- tive ingredients of the reference listed drug, information to
p.000131: show that the dif- ferent active ingredient is an active in- gredient of another listed drug or of a drug that
p.000131: does not meet the definition of ‘‘new drug’’ in section 201(p) of the act, and such other information
p.000131: about the different active ingredient that FDA may require.
p.000131: (B) A reference to the applicant’s an- notated proposed labeling and to the
p.000132: 132
p.000132:
p.000132:
p.000132:
p.000132:
p.000132:
p.000132:
p.000132:
p.000132: Food and Drug Administration, HHS § 314.94
p.000132:
p.000132:
p.000132: currently approved labeling for the ref- erence listed drug provided under para- graph (a)(8) of this section.
p.000132: (6) Route of administration, dosage form, and strength. (i) Information to show that the route
p.000132: of administration, dosage form, and strength of the drug product are the same as those of the reference
p.000132: listed drug except for any dif- ferences that have been the subject of an approved petition, as follows:
p.000132: (A) A statement that the route of ad- ministration, dosage form, and strength of the proposed
p.000132: drug product are the same as those of the reference listed drug.
p.000132: (B) A reference to the applicant’s an- notated proposed labeling and to the currently approved labeling for the
p.000132: ref- erence listed drug provided under para- graph (a)(8) of this section.
p.000132: (ii) If the route of administration, dosage form, or strength of the drug product differs from the
p.000132: reference list- ed drug and the abbreviated applica- tion is submitted under an approved petition
p.000132: under § 314.93, such informa- tion about the different route of ad- ministration, dosage form, or
p.000132: strength that FDA may require.
p.000132: (7) Bioequivalence. (i) Information that shows that the drug product is bioequivalent to the
p.000132: reference listed drug upon which the applicant relies. A complete study report must be sub- mitted for
p.000132: the bioequivalence study upon which the applicant relies for ap- proval. For all other bioequivalence
p.000132: studies conducted on the same drug product formulation as defined in
p.000132: § 320.1(g) of this chapter, the applicant must submit either a complete or sum- mary report. If a summary
p.000132: report of a bioequivalence study is submitted and FDA determines that there may be bio- equivalence issues or
p.000132: concerns with the product, FDA may require that the ap- plicant submit a complete report of the bioequivalence study to
p.000132: FDA; or
p.000132: (ii) If the abbreviated new drug appli- cation is submitted under a petition approved under § 314.93, the
p.000132: results of any bioavailability of bioequivalence testing required by the agency, or any other
p.000132: information required by the agency to show that the active ingredi- ents of the proposed drug product
p.000132: are of the same pharmacological or thera- peutic class as those in the reference
p.000132:
p.000132: listed drug and that the proposed drug product can be expected to have the same therapeutic effect as
p.000132: the ref- erence listed drug. If the proposed drug product contains a different active in- gredient than the
p.000132: reference listed drug, FDA will consider the proposed drug product to have the same therapeutic effect as the
p.000132: reference listed drug if the applicant provides information dem- onstrating that:
p.000132: (A) There is an adequate scientific basis for determining that substitution of the specific proposed dose of the
p.000132: dif- ferent active ingredient for the dose of the member of the same pharma- cological or
p.000132: therapeutic class in the reference listed drug will yield a re- sulting drug product whose safety and
p.000132: effectiveness have not been adversely affected.
p.000132: (B) The unchanged active ingredients in the proposed drug product are bio- equivalent to those in the
p.000132: reference listed drug.
p.000132: (C) The different active ingredient in the proposed drug product is bioequiva- lent to an approved dosage form
p.000132: con- taining that ingredient and approved for the same indication as the proposed drug product or is
p.000132: bioequivalent to a drug product offered for that indication which does not meet the definition of ‘‘new drug’’
p.000132: under section 201(p) of the act.
p.000132: (iii) For each in vivo bioequivalence study contained in the abbreviated new drug application, a description
p.000132: of the analytical and statistical methods used in each study and a statement with re- spect to each study that it
p.000132: either was conducted in compliance with the in- stitutional review board regulations in part 56 of this
p.000132: chapter, or was not sub- ject to the regulations under § 56.104 or
p.000132: § 56.105 of this chapter and that each study was conducted in compliance with the informed consent
p.000132: regulations in part 50 of this chapter.
p.000132: (8) Labeling—(i) Listed drug labeling. A copy of the currently approved labeling (including, if applicable, any
p.000132: Medica- tion Guide required under part 208 of this chapter) for the listed drug re- ferred to in
p.000132: the abbreviated new drug application, if the abbreviated new drug application relies on a reference
p.000132: listed drug.
p.000133: 133
p.000133:
p.000133:
p.000133:
p.000133:
p.000133:
p.000133:
p.000133:
p.000133:
p.000133: § 314.94
p.000133: (ii) Copies of proposed labeling. Copies of the label and all labeling for the drug product
p.000133: including, if applicable, any Medication Guide required under part 208 of this chapter (4 copies of
p.000133: draft labeling or 12 copies of final printed labeling).
p.000133: (iii) Statement on proposed labeling. A statement that the applicant’s pro- posed labeling including,
p.000133: if applicable, any Medication Guide required under part 208 of this chapter is the same as the labeling of
p.000133: the reference listed drug except for differences annotated and explained under paragraph (a)(8)(iv) of this
p.000133: section.
p.000133: (iv) Comparison of approved and pro- posed labeling. A side-by-side compari- son of the applicant’s proposed
p.000133: labeling including, if applicable, any Medica- tion Guide required under part 208 of this chapter with
p.000133: the approved labeling for the reference listed drug with all differences annotated and explained. Labeling
p.000133: (including the container label, package insert, and, if applica- ble, Medication Guide) proposed for
p.000133: the drug product must be the same as the labeling approved for the reference list- ed drug, except for changes
p.000133: required be- cause of differences approved under a petition filed under § 314.93 or because the drug product
p.000133: and the reference list- ed drug are produced or distributed by different manufacturers. Such dif-
p.000133: ferences between the applicant’s pro- posed labeling and labeling approved for the reference listed
p.000133: drug may in- clude differences in expiration date, formulation, bioavailability, or phar- macokinetics,
p.000133: labeling revisions made to comply with current FDA labeling guidelines or other guidance, or omis- sion of
p.000133: an indication or other aspect of labeling protected by patent or ac- corded exclusivity under
p.000133: section 505(j)(5)(F) of the act.
p.000133: (9) Chemistry, manufacturing, and con-
p.000133: trols. (i) The information required under § 314.50(d)(1), except that
p.000133: § 314.50(d)(1)(ii)(c) shall contain the pro- posed or actual master production record, including a
p.000133: description of the equipment, to be used for the manufac- ture of a commercial lot of the drug product.
p.000133: (ii) Inactive ingredients. Unless other- wise stated in paragraphs (a)(9)(iii) through (a)(9)(v) of this
p.000133: section, an ap-
p.000133: 21 CFR Ch. I (4–1–12 Edition)
p.000133: plicant shall identify and characterize the inactive ingredients in the pro- posed drug product and
p.000133: provide infor- mation demonstrating that such inac- tive ingredients do not affect the safe- ty or
p.000133: efficacy of the proposed drug product.
p.000133: (iii) Inactive ingredient changes per-
p.000133: mitted in drug products intended for par- enteral use. Generally, a drug product intended for parenteral
p.000133: use shall con- tain the same inactive ingredients and in the same concentration as the ref- erence listed
p.000133: drug identified by the ap- plicant under paragraph (a)(3) of this section. However, an applicant may seek
p.000133: approval of a drug product that differs from the reference listed drug in preservative, buffer, or
p.000133: antioxidant provided that the applicant identifies and characterizes the differences and provides
p.000133: information demonstrating that the differences do not affect the safety or efficacy of the proposed drug
p.000133: product.
p.000133: (iv) Inactive ingredient changes per-
p.000133: mitted in drug products intended for oph- thalmic or otic use. Generally, a drug product intended
p.000133: for ophthalmic or otic use shall contain the same inac- tive ingredients and in the same con-
p.000133: centration as the reference listed drug identified by the applicant under para- graph (a)(3) of this
p.000133: section. However, an applicant may seek approval of a drug product that differs from the ref- erence
p.000133: listed drug in preservative, buff- er, substance to adjust tonicity, or thickening agent provided that
p.000133: the ap- plicant identifies and characterizes the differences and provides information demonstrating that the
p.000133: differences do not affect the safety or efficacy of the proposed drug product, except that, in a product
p.000133: intended for ophthalmic use, an applicant may not change a buffer or substance to adjust tonicity for
p.000133: the purpose of claiming a therapeutic ad- vantage over or difference from the listed drug, e.g., by
p.000133: using a balanced salt solution as a diluent as opposed to an isotonic saline solution, or by mak- ing a
p.000133: significant change in the pH or other change that may raise questions of irritability.
p.000133: (v) Inactive ingredient changes per-
p.000133: mitted in drug products intended for top- ical use. Generally, a drug product in- tended for topical
p.000133: use, solutions for
p.000134: 134
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134: Food and Drug Administration, HHS § 314.94
p.000134:
p.000134:
p.000134: aerosolization or nebulization, and nasal solutions shall contain the same inactive ingredients as
p.000134: the reference listed drug identified by the applicant under paragraph (a)(3) of this section. However, an
p.000134: abbreviated application may include different inactive ingredi- ents provided that the applicant identi- fies
p.000134: and characterizes the differences and provides information dem- onstrating that the differences
p.000134: do not affect the safety or efficacy of the pro- posed drug product.
p.000134: (10) Samples. The information re- quired under § 314.50(e)(1) and (e)(2)(i). Samples need not be
p.000134: submitted until requested by FDA.
p.000134: (11) Other. The information required under § 314.50(g).
p.000134: (12) Patent certification—(i) Patents claiming drug, drug product, or method of use. (A) Except as
p.000134: provided in para- graph (a)(12)(iv) of this section, a cer- tification with respect to each patent
p.000134: issued by the United States Patent and Trademark Office that, in the opinion of the applicant and to the
p.000134: best of its knowledge, claims the reference listed drug or that claims a use of such listed drug for which the
p.000134: applicant is seeking approval under section 505(j) of the act and for which information is required to be filed
p.000134: under section 505(b) and (c) of the act and § 314.53. For each such patent, the applicant shall provide
p.000134: the patent number and certify, in its opin- ion and to the best of its knowledge, one of the following
p.000134: circumstances:
p.000134: (1) That the patent information has not been submitted to FDA. The appli- cant shall entitle such a
p.000134: certification ‘‘Paragraph I Certification’’;
p.000134: (2) That the patent has expired. The applicant shall entitle such a certifi- cation ‘‘Paragraph II
p.000134: Certification’’;
p.000134: (3) The date on which the patent will expire. The applicant shall entitle such a certification ‘‘Paragraph III
p.000134: Certifi- cation’’; or
p.000134: (4) That the patent is invalid, unen- forceable, or will not be infringed by the manufacture, use, or
p.000134: sale of the drug product for which the abbreviated application is submitted. The applicant shall entitle
p.000134: such a certification ‘‘Paragraph IV Certification’’. This cer- tification shall be submitted in the fol- lowing
p.000134: form:
p.000134:
p.000134: I, (name of applicant), certify that Patent No. llllll (is invalid, unenforceable, or ill not be infringed
p.000134: by the manufacture, use, or sale of) (name of proposed drug product) for
p.000134: which this application is submitted.
p.000134: The certification shall be accompanied by a statement that the applicant will comply with the
p.000134: requirements under
p.000134: § 314.95(a) with respect to providing a notice to each owner of the patent or their representatives and
p.000134: to the holder of the approved application for the list- ed drug, and with the requirements under §
p.000134: 314.95(c) with respect to the content of the notice.
p.000134: (B) If the abbreviated new drug appli- cation refers to a listed drug that is itself a licensed generic
p.000134: product of a patented drug first approved under sec- tion 505(b) of the act, the appropriate patent
p.000134: certification under paragraph (a)(12)(i) of this section with respect to each patent that claims the first-ap-
p.000134: proved patented drug or that claims a use for such drug.
p.000134: (ii) No relevant patents. If, in the opin-
p.000134: ion of the applicant and to the best of its knowledge, there are no patents de- scribed in paragraph
p.000134: (a)(12)(i) of this section, a certification in the following form:
p.000134: In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the listed drug
p.000134: referred to in this ap- plication or that claim a use of the listed drug.
p.000134: (iii) Method of use patent. (A) If pat- ent information is submitted under section 505(b) or (c)
p.000134: of the act and
p.000134: § 314.53 for a patent claiming a method of using the listed drug, and the label- ing for the drug
p.000134: product for which the applicant is seeking approval does not include any indications that are cov- ered by
p.000134: the use patent, a statement ex- plaining that the method of use patent does not claim any of the proposed in-
p.000134: dications.
p.000134: (B) If the labeling of the drug product for which the applicant is seeking ap- proval includes an indication
p.000134: that, ac- cording to the patent information sub- mitted under section 505(b) or (c) of the act and § 314.53 or
p.000134: in the opinion of the applicant, is claimed by a use patent, an applicable certification under para-
p.000134: graph (a)(12)(i) of this section.
p.000134: (iv) Method of manufacturing patent.
p.000134: An applicant is not required to make a
p.000135: 135
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135: § 314.94
p.000135: certification with respect to any pat- ent that claims only a method of man- ufacturing the listed drug.
p.000135: (v) Licensing agreements. If the abbre- viated new drug application is for a drug or method of using a
p.000135: drug claimed by a patent and the applicant has a li- censing agreement with the patent owner, a
p.000135: certification under paragraph (a)(12)(i)(A)(4) of this section (‘‘Para- graph IV Certification’’) as to that pat-
p.000135: ent and a statement that it has been granted a patent license.
p.000135: (vi) Late submission of patent informa- tion. If a patent on the listed drug is issued and the holder
p.000135: of the approved application for the listed drug does not submit the required information on the patent within 30 days
p.000135: of issuance of the patent, an applicant who submitted an abbreviated new drug application for that drug
p.000135: that contained an appro- priate patent certification before the submission of the patent information is not
p.000135: required to submit an amended cer- tification. An applicant whose abbre- viated new drug application is
p.000135: sub- mitted after a late submission of pat- ent information, or whose pending ab- breviated application
p.000135: was previously submitted but did not contain an ap- propriate patent certification at the time of
p.000135: the patent submission, shall submit a certification under paragraph (a)(12)(i) of this section or a
p.000135: statement under paragraph (a)(12)(iii) of this sec- tion as to that patent.
p.000135: (vii) Disputed patent information. If an
p.000135: applicant disputes the accuracy or rel- evance of patent information sub- mitted to FDA, the applicant
p.000135: may seek a confirmation of the correctness of the patent information in accordance with the
p.000135: procedures under § 314.53(f). Unless the patent information is with- drawn or changed, the applicant
p.000135: shall submit an appropriate certification for each relevant patent.
p.000135: (viii) Amended certifications. A certifi- cation submitted under paragraphs (a)(12)(i) through
p.000135: (a)(12)(iii) of this sec- tion may be amended at any time be- fore the effective date of the approval
p.000135: of the application. However, an appli- cant who has submitted a paragraph IV patent certification may not
p.000135: change it to a paragraph III certification if a pat- ent infringement suit has been filed against another
p.000135: paragraph IV applicant
p.000135: 21 CFR Ch. I (4–1–12 Edition)
p.000135: unless the agency has determined that no applicant is entitled to 180-day ex- clusivity or the patent
p.000135: expires before the lawsuit is resolved or expires after the suit is resolved but before the end of the
p.000135: 180-day exclusivity period. If an applicant with a pending application voluntarily makes a patent
...
p.000135: amendment to a pending application or by letter to an approved application. Once an amendment or letter is sub-
p.000135: mitted, the application will no longer be considered to contain the prior cer- tification.
p.000135: (A) After finding of infringement. An applicant who has submitted a certifi- cation under paragraph
p.000135: (a)(12)(i)(A)(4) of this section and is sued for patent infringement within 45 days of the re- ceipt of
p.000135: notice sent under § 314.95 shall amend the certification if a final judg- ment in the action against the
p.000135: appli- cant is entered finding the patent to be infringed. In the amended certification, the applicant shall
p.000135: certify under para- graph (a)(12)(i)(A)(3) of this section that the patent will expire on a specific date.
p.000135: Once an amendment or letter for the change has been submitted, the ap- plication will no longer be considered
p.000135: to be one containing a certification under paragraph (a)(12)(i)(A)(4) of this section. If a final
p.000135: judgment finds the patent to be invalid and infringed, an amended certification is not required.
p.000135: (B) After removal of a patent from the list. If a patent is removed from the list, any applicant with
p.000135: a pending ap- plication (including a tentatively ap- proved application with a delayed ef- fective date)
p.000135: who has made a certifi- cation with respect to such patent shall amend its certification. The ap-
p.000135: plicant shall certify under paragraph (a)(12)(ii) of this section that no pat- ents described in paragraph
p.000135: (a)(12)(i) of this section claim the drug or, if other relevant patents claim the drug, shall amend the
p.000135: certification to refer only to those relevant patents. In the amend- ment, the applicant shall state the rea- son
p.000135: for the change in certification (that the patent is or has been removed
p.000136: 136
p.000136:
p.000136:
p.000136:
p.000136:
p.000136:
p.000136:
p.000136:
p.000136: Food and Drug Administration, HHS § 314.94
p.000136:
p.000136:
p.000136: from the list). A patent that is the sub- ject of a lawsuit under § 314.107(c) shall not be removed from the list
p.000136: until FDA determines either that no delay in ef- fective dates of approval is required under that
p.000136: section as a result of the lawsuit, that the patent has expired, or that any such period of delay in effec-
p.000136: tive dates of approval is ended. An ap- plicant shall submit an amended cer- tification. Once an
p.000136: amendment or let- ter for the change has been submitted, the application will no longer be con- sidered
p.000136: to be one containing a certifi- cation under paragraph (a)(12)(i)(A)(4) of this section.
p.000136: (C) Other amendments. (1) Except as
p.000136: provided in paragraphs (a)(12)(vi) and (a)(12)(viii)(C)(2) of this section, an ap- plicant shall amend a
p.000136: submitted cer- tification if, at any time before the ef- fective date of the approval of the ap-
p.000136: plication, the applicant learns that the submitted certification is no longer ac- curate.
p.000136: (2) An applicant is not required to amend a submitted certification when information on a patent on the
p.000136: listed drug is submitted after the effective date of approval of the abbreviated ap- plication.
p.000136: (13) Financial certification or disclosure statement. An abbreviated application shall contain a financial
p.000136: certification or disclosure statement as required by part 54 of this chapter.
p.000136: (b) Drug products subject to the Drug Efficacy Study Implementation (DESI) re- vie . If the abbreviated new
p.000136: drug appli- cation is for a duplicate of a drug prod- uct that is subject to FDA’s DESI re- view (a review
p.000136: of drug products ap- proved as safe between 1938 and 1962) or other DESI-like review and the drug product
p.000136: evaluated in the review is a listed drug, the applicant shall comply with the provisions of paragraph
p.000136: (a) of this section.
p.000136: (c) [Reserved]
p.000136: (d) Format of an abbreviated applica- tion. (1) The applicant must submit a complete archival copy of
p.000136: the abbre- viated application as required under paragraphs (a) and (c) of this section. FDA will
p.000136: maintain the archival copy during the review of the application to permit individual reviewers to refer to
p.000136: information that is not contained in their particular technical sections of
p.000136:
p.000136: the application, to give other agency personnel access to the application for official business, and to
p.000136: maintain in one place a complete copy of the appli- cation.
p.000136: (i) Format of submission. An applicant may submit portions of the archival copy of the abbreviated
p.000136: application in any form that the applicant and FDA agree is acceptable, except as provided in paragraph
p.000136: (d)(1)(ii) of this section.
p.000136: (ii) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter (commonly referred
p.000136: to as the package insert or professional label- ing), including all text, tables, and fig- ures, must be
p.000136: submitted to the agency in electronic format as described in paragraph (d)(1)(iii) of this
p.000136: section. This requirement applies to the con- tent of labeling for the proposed drug product only and is
p.000136: in addition to the requirements of paragraph (a)(8)(ii) of this section that copies of the for-
p.000136: matted label and all proposed labeling be submitted. Submissions under this paragraph must be made in
p.000136: accordance with part 11 of this chapter, except for the requirements of § 11.10(a), (c) through
p.000136: (h), and (k), and the cor- responding requirements of § 11.30.
p.000136: (iii) Electronic format submissions.
p.000136: Electronic format submissions must be in a form that FDA can process, re- view, and archive. FDA will
p.000136: periodi- cally issue guidance on how to provide the electronic submission (e.g., method of transmission,
p.000136: media, file formats, preparation and organization of files).
p.000136: (2) For abbreviated new drug applica- tions, the applicant shall submit a re- view copy of the abbreviated
p.000136: applica- tion that contains two separate sec- tions. One section shall contain the in- formation described
p.000136: 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
p.000136: copy of the analytical proce- dures and descriptive information needed by FDA’s laboratories to
p.000136: per- form tests on samples of the proposed drug product and to validate the appli- cant’s analytical procedures.
p.000136: The other section shall contain the information described under paragraphs (a)(3), (a)(7), and (a)(8)
p.000136: of this section. Each of the sections in the review copy is re- quired to contain a copy of the applica- tion
p.000136: form described under § 314.50(a).
p.000137: 137
p.000137:
p.000137:
p.000137:
p.000137:
p.000137:
p.000137:
p.000137:
p.000137:
p.000137: § 314.95
p.000137: (3) [Reserved]
p.000137: (4) The applicant may obtain from FDA sufficient folders to bind the ar- chival, the review, and
p.000137: the field copies of the abbreviated application.
p.000137: (5) The applicant shall submit a field copy of the abbreviated application that contains the technical
p.000137: section de- scribed in paragraph (a)(9) of this sec- tion, a copy of the application form re- quired under
p.000137: paragraph (a)(1) of this section, and a certification that the field copy is a true copy of the
p.000137: tech- nical section described in paragraph (a)(9) of this section contained in the archival and review
p.000137: copies of the ab- breviated application.
p.000137: [57 FR 17983, Apr. 28, 1992; 57 FR 29353, July
p.000137: 1, 1992, as amended at 58 FR 47352, Sept. 8,
p.000137: 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb.
p.000137: 2, 1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401,
p.000137: Jan. 5, 1999; 65 FR 56479, Sept. 19, 2000; 67 FR
p.000137: 77672, Dec. 19, 2002; 68 FR 69019, Dec. 11, 2003;
p.000137: 69 FR 18766, Apr. 8, 2004; 74 FR 2861, Jan. 16,
p.000137: 2009; 76 FR 13880, Mar. 15, 2011]
p.000137:
p.000137: § 314.95 Notice of certification of inva- lidity or noninfringement of a pat- ent.
p.000137: (a) Notice of certification. For each patent that claims the listed drug or that claims a use for
p.000137: such listed drug for which the applicant is seeking ap- proval and that the applicant certifies under §
p.000137: 314.94(a)(12) is invalid, unen- forceable, or will not be infringed, the applicant shall send notice of
p.000137: such cer- tification by registered or certified mail, return receipt requested to each of the following
p.000137: persons:
p.000137: (1) Each owner of the patent which is
p.000137: the subject of the certification or the representative designated by the owner to receive the notice. The name
p.000137: and ad- dress of the patent owner or its rep- resentative may be obtained from the United States Patent
p.000137: and Trademark Office; and
p.000137: (2) The holder of the approved appli- cation under section 505(b) of the act for the listed drug that
p.000137: is claimed by the patent and for which the applicant is seeking approval, or, if the applica- tion holder
p.000137: does not reside or maintain a place of business within the United States, the application holder’s attor-
p.000137: ney, agent, or other authorized official. The name and address of the applica- tion holder or its attorney,
p.000137: agent, or authorized official may be obtained
p.000137: 21 CFR Ch. I (4–1–12 Edition)
p.000137: from the Orange Book Staff, Office of Generic Drugs, 7500 Standish Pl., Rock- ville, MD 20855.
p.000137: (3) This paragraph does not apply to a use patent that claims no uses for which the applicant is
p.000137: seeking ap- proval.
p.000137: (b) Sending the notice. The applicant shall send the notice required by para- graph (a) of this section
p.000137: when it re- ceives from FDA an acknowledgment letter stating that its abbreviated new drug application
p.000137: is sufficiently com- plete to permit a substantive review. At the same time, the applicant shall amend
p.000137: its abbreviated new drug appli- cation to include a statement certi- fying that the notice has been
p.000137: provided to each person identified under para- graph (a) of this section and that the notice met the
p.000137: content requirements under paragraph (c) of this section.
p.000137: (c) Contents of a notice. In the notice,
p.000137: the applicant shall cite section 505(j)(2)(B)(ii) of the act and shall in- clude, but not be
p.000137: limited to, the fol- lowing information:
p.000137: (1) A statement that FDA has re- ceived an abbreviated new drug appli- cation submitted by the
p.000137: applicant con- taining any required bioavailability or bioequivalence data or information.
p.000137: (2) The abbreviated application num- ber.
p.000137: (3) The established name, if any, as defined in section 502(e)(3) of the act, of the proposed drug product.
p.000137: (4) The active ingredient, strength, and dosage form of the proposed drug product.
p.000137: (5) The patent number and expiration date, as submitted to the agency or as known to the applicant, of each
p.000137: patent alleged to be invalid, unenforceable, or not infringed.
p.000137: (6) A detailed statement of the fac- tual and legal basis of the applicant’s opinion that the patent is
p.000137: not valid, unenforceable, or will not be infringed. The applicant shall include in the de- tailed statement:
p.000137: (i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is
p.000137: not in- fringed.
p.000137: (ii) For each claim of a patent al- leged to be invalid or unenforceable, a full and detailed
p.000137: explanation of the grounds supporting the allegation.
p.000138: 138
p.000138:
p.000138:
p.000138:
p.000138:
p.000138:
p.000138:
p.000138:
p.000138: Food and Drug Administration, HHS § 314.98
p.000138:
p.000138:
p.000138: (7) If the applicant does not reside or have a place of business in the United States, the name and
p.000138: address of an agent in the United States authorized to accept service of process for the ap- plicant.
p.000138: (d) Amendment to an abbreviated appli- cation. If an abbreviated application is amended to include the
p.000138: certification described in § 314.94(a)(12)(i)(A)(4), the applicant shall send the notice required by paragraph
p.000138: (a) of this section at the same time that the amendment to the abbreviated application is submitted to FDA.
p.000138: (e) Documentation of receipt of notice.
p.000138: The applicant shall amend its abbre- viated application to document receipt of the notice required under
p.000138: paragraph
p.000138: (a) of this section by each person pro- vided the notice. The applicant shall include a copy of the
p.000138: return receipt or other similar evidence of the date the notification was received. FDA will ac- cept as
p.000138: adequate documentation of the date of receipt a return receipt or a let- ter acknowledging receipt by the per-
p.000138: son provided the notice. An applicant may rely on another form of docu- mentation only if FDA has
p.000138: agreed to such documentation in advance. A copy of the notice itself need not be sub- mitted to the agency.
p.000138: (f) Approval. If the requirements of
p.000138: this section are met, FDA will presume the notice to be complete and suffi- cient, and it will count
p.000138: the day fol- lowing the date of receipt of the notice by the patent owner or its representa- tive and by the
p.000138: approved application holder as the first day of the 45-day pe- riod provided for in section
p.000138: 505(j)(4)(B)(iii) of the act. FDA may, if the applicant provides a written state- ment to FDA that a
p.000138: later date should be used, count from such later date.
p.000138: [59 FR 50366, Oct. 3, 1994, as amended at 68 FR
p.000138: 36705, June 18, 2003; 69 FR 11310, Mar. 10, 2004;
p.000138: 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24,
p.000138: 2009]
p.000138:
p.000138: § 314.96 Amendments to an unap- proved abbreviated application.
p.000138: (a) Abbreviated ne drug application.
p.000138: (1) An applicant may amend an abbre- viated new drug application that is submitted under § 314.94,
p.000138: but not yet approved, to revise existing informa- tion or provide additional information.
p.000138:
p.000138: Amendments containing bioequiva- lence studies must contain reports of all bioequivalence studies
p.000138: conducted by the applicant on the same drug product formulation, unless the information has previously been
p.000138: submitted to FDA in the abbreviated new drug applica- tion. A complete study report must be submitted for
p.000138: any bioequivalence study upon which the applicant relies for ap- proval. For all other bioequivalence
p.000138: studies conducted on the same drug product formulation as defined in
p.000138: § 320.1(g) of this chapter, the applicant
p.000138: must submit either a complete or sum- mary report. If a summary report of a bioequivalence study is submitted
p.000138: and FDA determines that there may be bio- equivalence issues or concerns with the product, FDA may require that the
p.000138: ap- plicant submit a complete report of the bioequivalence study to FDA.
p.000138: (2) Submission of an amendment con-
p.000138: taining significant data or information before the end of the initial review cycle constitutes an
p.000138: agreement be- tween FDA and the applicant to extend the initial review cycle only for the time necessary to
p.000138: review the signifi- cant data or information and for no more than 180 days.
p.000138: (b) The applicant shall submit a field
p.000138: copy of each amendment to
p.000138: § 314.94(a)(9). The applicant, other than a foreign applicant, shall include in its submission of each such
p.000138: amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant’s
p.000138: home FDA district office.
p.000138: [57 FR 17983, Apr. 28, 1992, as amended at 58
p.000138: FR 47352, Sept. 8, 1993; 64 FR 401, Jan. 5, 1999;
p.000138: 73 FR 39609, July 10, 2008; 74 FR 2861, Jan. 16,
p.000138: 2009]
p.000138:
p.000138: § 314.97 Supplements and other changes to an approved abbre- viated application.
p.000138: The applicant shall comply with the requirements of §§ 314.70 and 314.71 re- garding the submission
p.000138: of supple- mental applications and other changes to an approved abbreviated applica- tion.
p.000138: § 314.98 Postmarketing reports.
p.000138: (a) Except as provided in paragraph
p.000138: (b) of this section, each applicant hav- ing an approved abbreviated new drug
p.000139: 139
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139: § 314.99
p.000139: application under § 314.94 that is effec- tive shall comply with the require- ments of § 314.80
p.000139: regarding the report- ing and recordkeeping of adverse drug experiences.
p.000139: (b) Each applicant shall submit one copy of each report required under
p.000139: § 314.80 to the Central Document Room, Center for Drug Evaluation and Re- search, Food and Drug
p.000139: Administration, 5901–B Ammendale Rd., Beltsville, MD 20705–1266.
p.000139: (c) Each applicant shall make the re- ports required under § 314.81 and section 505(k) of the act for each
p.000139: of its ap- proved abbreviated applications.
p.000139: [57 FR 17983, Apr. 28, 1992, as amended at 64
p.000139: FR 401, Jan. 5, 1999; 74 FR 13113, Mar. 26, 2009]
p.000139:
p.000139: § 314.99 Other responsibilities of an applicant of an abbreviated applica- tion.
p.000139: (a) An applicant shall comply with the requirements of § 314.65 regarding withdrawal by the applicant of
p.000139: an un- approved abbreviated application and
p.000139: § 314.72 regarding a change in ownership of an abbreviated application.
p.000139: (b) An applicant may ask FDA to waive under this section any require- ment that applies to the
p.000139: applicant under §§ 314.92 through 314.99. The appli- cant shall comply with the require- ments for a waiver
p.000139: under § 314.90.
p.000139:
p.000139: Subpart D—FDA Action on Appli- cations and Abbreviated Ap- plications
p.000139: SOURCE: 50 FR 7493, Feb. 22, 1985, unless
p.000139: otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992.
p.000139:
p.000139: § 314.100 Timeframes for reviewing ap- plications and abbreviated applica- tions.
p.000139: (a) Except as provided in paragraph
p.000139: (c) of this section, within 180 days of receipt of an application for a new drug under section 505(b) of the act
p.000139: or an ab- breviated application for a new drug under section 505(j) of the act, FDA will review it and
p.000139: send the applicant ei- ther an approval letter under § 314.105 or a complete response letter under
p.000139: § 314.110. This 180-day period is called the ‘‘initial review cycle.’’
p.000139: (b) At any time before approval, an applicant may withdraw an application
p.000139: 21 CFR Ch. I (4–1–12 Edition)
p.000139: under § 314.65 or an abbreviated applica- tion under § 314.99 and later submit it again for consideration.
p.000139: (c) The initial review cycle may be adjusted by mutual agreement between FDA and an applicant or as provided in
p.000139: §§ 314.60 and 314.96, as the result of a major amendment.
p.000139: [73 FR 39609, July 10, 2008]
p.000139:
p.000139: § 314.101 Filing an application and re- ceiving an abbreviated new drug application.
p.000139: (a)(1) Within 60 days after FDA re- ceives an application, the agency will determine whether the application
p.000139: may be filed. The filing of an application means that FDA has made a threshold determination that the
p.000139: application is sufficiently complete to permit a sub- stantive review.
p.000139: (2) If FDA finds that none of the rea- sons in paragraphs (d) and (e) of this section for refusing to file
p.000139: the applica- tion apply, the agency will file the ap- plication and notify the applicant in writing. The
p.000139: date of filing will be the date 60 days after the date FDA re- ceived the application. The date of
p.000139: fil- ing begins the 180-day period described in section 505(c) of the act. This 180-day period is called the
p.000139: ‘‘filing clock.’’
p.000139: (3) If FDA refuses to file the applica- tion, the agency will notify the appli- cant in writing and
p.000139: state the reason under paragraph (d) or (e) of this sec- tion for the refusal. If FDA refuses to file
p.000139: the application under paragraph (d) of this section, the applicant may re- quest in writing within 30 days
p.000139: of the date of the agency’s notification an in- formal conference with the agency about whether the
p.000139: agency should file the application. If, following the infor- mal conference, the applicant requests that
p.000139: FDA file the application (with or without amendments to correct the de- ficiencies), the agency will file the
p.000139: ap- plication over protest under paragraph (a)(2) of this section, notify the appli- cant in writing, and
p.000139: review it as filed. If the application is filed over protest, the date of filing will be the date 60
p.000139: days after the date the applicant re- quested the informal conference. The applicant need not resubmit a
p.000139: copy of
p.000140: 140
p.000140:
p.000140:
p.000140:
p.000140:
p.000140:
p.000140:
p.000140:
p.000140: Food and Drug Administration, HHS § 314.101
p.000140:
p.000140:
p.000140: an application that is filed over pro- test. If FDA refuses to file the applica- tion under paragraph (e) of
p.000140: this sec- tion, the applicant may amend the ap- plication and resubmit it, and the agency will
p.000140: make a determination under this section whether it may be filed.
p.000140: (b)(1) An abbreviated new drug appli- cation will be reviewed after it is sub- mitted to determine
p.000140: whether the ab- breviated application may be received. Receipt of an abbreviated new drug ap- plication means
p.000140: that FDA has made a threshold determination that the ab- breviated application is sufficiently
p.000140: complete to permit a substantive re- view.
p.000140: (2) If FDA finds that none of the rea- sons in paragraphs (d) and (e) of this section for considering the
p.000140: abbreviated new drug application not to have been received applies, the agency will re- ceive the
p.000140: abbreviated new drug applica- tion and notify the applicant in writ- ing.
p.000140: (3) If FDA considers the abbreviated new drug application not to have been received under paragraph (d)
p.000140: or (e) of this section, FDA will notify the appli- cant, ordinarily by telephone. The ap- plicant may then:
p.000140: (i) Withdraw the abbreviated new drug application under § 314.99; or
p.000140: (ii) Amend the abbreviated new drug application to correct the deficiencies; or
p.000140: (iii) Take no action, in which case FDA will refuse to receive the abbre- viated new drug application.
p.000140: (c) [Reserved]
p.000140: (d) FDA may refuse to file an applica- tion or may not consider an abbre- viated new drug application
p.000140: to be re- ceived if any of the following applies:
p.000140: (1) The application does not contain a completed application form.
p.000140: (2) The application is not submitted in the form required under § 314.50 or
p.000140: § 314.94.
p.000140: (3) The application or abbreviated ap- plication is incomplete because it does not on its face contain
p.000140: information re- quired under section 505(b), section 505(j), or section 507 of the act and
p.000140: § 314.50 or § 314.94.
p.000140: (4) The applicant fails to submit a complete environmental assessment, which addresses each of the items
p.000140: spec-
p.000140:
p.000140: ified in the applicable format under
p.000140: § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is
p.000140: subject to cat- egorical exclusion under § 25.30 or § 25.31 of this chapter.
p.000140: (5) The application or abbreviated ap- plication does not contain an accurate and complete English
p.000140: translation of each part of the application that is not in English.
p.000140: (6) The application does not contain a statement for each nonclinical labora- tory study that it was
p.000140: conducted in compliance with the requirements set forth in part 58 of this chapter, or, for each study
p.000140: not conducted in compli- ance with part 58 of this chapter, a brief statement of the reason for
p.000140: the noncompliance.
p.000140: (7) The application does not contain a statement for each clinical study that it was conducted in compliance
p.000140: with the institutional review board regula- tions in part 56 of this chapter, or was not subject to
p.000140: those regulations, and that it was conducted in compliance with the informed consent regulations in part
p.000140: 50 of this chapter, or, if the study was subject to but was not con- ducted in compliance with those
p.000140: regu- lations, the application does not con- tain a brief statement of the reason for the noncompliance.
p.000140: (8) The drug product that is the sub-
p.000140: ject of the submission is already cov- ered by an approved application or ab- breviated application and the
p.000140: applicant of the submission:
p.000140: (i) Has an approved application or ab- breviated application for the same drug product; or
p.000140: (ii) Is merely a distributor and/or re- packager of the already approved drug product.
p.000140: (9) The application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and
p.000140: is eligible for approval under section 505(j) of the act.
p.000140: (e) The agency will refuse to file an application or will consider an abbre- viated new drug
p.000140: application not to have been received if any of the fol- lowing applies:
p.000140: (1) The drug product is subject to li- censing by FDA under the Public Health Service Act
p.000140: (42 U.S.C. 201 et seq.) and subchapter F of this chapter.
p.000141: 141
p.000141:
p.000141:
p.000141:
p.000141:
p.000141:
p.000141:
p.000141:
p.000141:
p.000141: § 314.102
p.000141: (2) In the case of a 505(b)(2) applica- tion or an abbreviated new drug appli- cation, the drug product
p.000141: contains the same active moiety as a drug that:
p.000141: (i) Was approved after September 24, 1984, in an application under section 505(b) of the act, and
p.000141: (ii) Is entitled to a 5-year period of exclusivity under section 505(c)(3)(D)(ii)
p.000141: and (j)(4)(D)(ii) of the act and § 314.108(b)(2), unless the 5-year exclusivity period has elapsed or unless
p.000141: 4 years of the 5-year period have elapsed and the application or abbre- viated application
p.000141: contains a certifi- cation of patent invalidity or non- infringement described
p.000141: in
p.000141: § 314.50(i)(1)(i)(A)(4) or
p.000141: § 314.94(a)(12)(i)(A)(4).
p.000141: (f)(1) Within 180 days after the date of filing, plus the period of time the re- view period was extended (if
p.000141: any), FDA will either:
p.000141: (i) Approve the application; or
p.000141: (ii) Issue a notice of opportunity for a hearing if the applicant asked FDA to provide it an opportunity
p.000141: for a hear- ing on an application in response to a complete response letter.
p.000141: (2) Within 180 days after the date of receipt, plus the period of time the re- view clock was extended
p.000141: (if any), FDA will either approve or disapprove the abbreviated new drug application. If FDA
p.000141: disapproves the abbreviated new drug application, FDA will issue a no- tice of opportunity for hearing if
p.000141: the applicant asked FDA to provide it an opportunity for a hearing on an abbre- viated new drug
p.000141: application in response to a complete response letter.
p.000141: (3) This paragraph does not apply to
p.000141: applications or abbreviated applica- tions that have been withdrawn from FDA review by the applicant.
p.000141: [57 FR 17987, Apr. 28, 1992; 57 FR 29353, July
p.000141: 1, 1992, as amended at 59 FR 50366, Oct. 3,
p.000141: 1994; 62 FR 40599, July 29, 1997; 64 FR 402, Jan.
p.000141: 5, 1999; 73 FR 39609, July 10, 2008]
p.000141:
p.000141: § 314.102 Communications between FDA and applicants.
p.000141: (a) General principles. During the course of reviewing an application or an abbreviated application,
p.000141: FDA shall communicate with applicants about scientific, medical, and procedural issues that
p.000141: arise during the review process. Such communication may
p.000141: 21 CFR Ch. I (4–1–12 Edition)
p.000141: take the form of telephone conversa- tions, letters, or meetings, whichever is most appropriate to discuss
p.000141: the par- ticular issue at hand. Communications shall be appropriately documented in the application in
p.000141: accordance with
p.000141: § 10.65 of this chapter. Further details on the procedures for communication between FDA and applicants
p.000141: are con- tained in a staff manual guide that is publicly available.
p.000141: (b) Notification of easily correctable de- ficiencies. FDA reviewers shall make every reasonable
p.000141: effort to commu- nicate promptly to applicants easily correctable deficiencies found in an ap- plication
p.000141: or an abbreviated application when those deficiencies are discovered, particularly deficiencies concerning
p.000141: chemistry, manufacturing, and con- trols issues. The agency will also in- form applicants promptly of
p.000141: its need for more data or information or for technical changes in the application or the abbreviated
p.000141: application needed to facilitate the agency’s review. This early communication is intended to permit
p.000141: applicants to correct such read- ily identified deficiencies relatively early in the review process and
p.000141: to sub- mit an amendment before the review period has elapsed. Such early commu- nication would not
p.000141: ordinarily apply to major scientific issues, which require consideration of the entire pending ap- plication
p.000141: or abbreviated application by agency managers as well as reviewing staff. Instead, major scientific issues
p.000141: will ordinarily be addressed in a com- plete response letter.
p.000141: (c) Ninety-day conference. Approxi- mately 90 days after the agency re- ceives the application,
p.000141: FDA will pro- vide applicants with an opportunity to meet with agency reviewing officials. The purpose of
p.000141: the meeting will be to inform applicants of the general progress and status of their
p.000141: applica- tions, and to advise applicants of defi- ciencies that have been identified by that time and
p.000141: that have not already been communicated. This meeting will be available on applications for all new chemical
p.000141: entities and major new indi- cations of marketed drugs. Such meet- ings will be held at the applicant’s
p.000141: op- tion, and may be held by telephone if mutually agreed upon. Such meetings
p.000142: 142
p.000142:
p.000142:
p.000142:
p.000142:
p.000142:
p.000142:
p.000142:
p.000142: Food and Drug Administration, HHS § 314.103
p.000142:
p.000142:
p.000142: would not ordinarily be held on abbre- viated applications because they are not submitted for new
p.000142: chemical enti- ties or new indications.
p.000142: (d) End-of-revie conference. At the conclusion of FDA’s review of an NDA as designated by the issuance
p.000142: of a com- plete response letter, FDA will provide the applicant with an opportunity to meet with agency
p.000142: reviewing officials. The purpose of the meeting will be to discuss what further steps need to be taken
p.000142: by the applicant before the ap- plication can be approved. Requests for such meetings must be directed to
p.000142: the director of the division responsible for reviewing the application.
p.000142: (e) Other meetings. Other meetings be-
p.000142: tween FDA and applicants may be held, with advance notice, to discuss sci- entific, medical, and other
p.000142: issues that arise during the review process. Re- quests for meetings shall be directed to the director of
p.000142: the division responsible for reviewing the application or abbre- viated application. FDA will make
p.000142: every attempt to grant requests for meetings that involve important issues and that can be scheduled at
p.000142: mutually convenient times. However, ‘‘drop-in’’ visits (i.e., an unannounced and un- scheduled visit
p.000142: by a company rep- resentative) are discouraged except for urgent matters, such as to discuss an
p.000142: important new safety issue.
p.000142: [57 FR 17988, Apr. 28, 1992; 57 FR 29353, July
p.000142: 1, 1992, as amended at 73 FR 39609, July 10,
p.000142: 2008]
p.000142: § 314.103 Dispute resolution.
...
p.000142: appropriate reviewing offi- cials and management representatives in order to seek a resolution. Ordi-
p.000142: narily, such meetings would be held first with the Division Director, then with the Office
p.000142: Director, and finally with the Center Director if the matter is still unresolved. Requests for such
p.000142: meetings shall be directed to the direc- tor of the division responsible for re- viewing the application or
p.000142: abrreviated application. FDA will make every at- tempt to grant requests for meetings that involve
p.000142: important issues and that can be scheduled at mutually conven- ient times.
p.000142: (3) In requesting a meeting designed
p.000142: to resolve a scientific or medical dis- pute, applicants may suggest that FDA seek the advice of outside
p.000142: experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee
p.000142: members or other consultants, as designated by the agen- cy. Applicants may also bring their own
p.000142: consultants. For major scientific
p.000143: 143
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143: § 314.104
p.000143: and medical policy issues not resolved by informal meetings, FDA may refer the matter to one of its
p.000143: standing advi- sory committees for its consideration and recommendations.
p.000143: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000143: 1985, as amended at 57 FR 17989, Apr. 28, 1992;
p.000143: 73 FR 39609, July 10, 2008]
p.000143:
p.000143: § 314.104 Drugs with potential for abuse.
p.000143: The Food and Drug Administration will inform the Drug Enforcement Ad- ministration under section 201(f) of the
p.000143: Controlled Substances Act (21 U.S.C. 801) when an application or abbreviated application is submitted for
p.000143: a drug that appears to have an abuse poten- tial.
p.000143: [57 FR 17989, Apr. 28, 1992]
p.000143:
p.000143: § 314.105 Approval of an application and an abbreviated application.
p.000143: (a) The Food and Drug Administra- tion will approve an application and send the applicant an approval
p.000143: letter if none of the reasons in § 314.125 for re- fusing to approve the application ap- plies. An approval
p.000143: becomes effective on the date of the issuance of the approval letter, except with regard to an ap- proval
p.000143: under section 505(b)(2) of the act with a delayed effective date. An ap- proval with a delayed effective
p.000143: date is tentative and does not become final until the effective date. A new drug product or
p.000143: antibiotic approved under this paragraph may not be marketed until an approval is effective.
p.000143: (b) FDA will approve an application
p.000143: and issue the applicant an approval let- ter on the basis of draft labeling if the only deficiencies in
p.000143: the application concern editorial or similar minor defi- ciencies in the draft labeling. Such ap- proval will
p.000143: be conditioned upon the ap- plicant incorporating the specified la- beling changes exactly as directed, and upon
p.000143: the applicant submitting to FDA a copy of the final printed labeling prior to marketing.
p.000143: (c) FDA will approve an application
p.000143: after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and
p.000143: con- trols, and labeling, and an abbreviated application after it determines that the drug meets the statutory
p.000143: standards for manufacturing and controls, labeling,
p.000143: 21 CFR Ch. I (4–1–12 Edition)
p.000143: and, where applicable, bioequivalence. While the statutory standards apply to all drugs, the many kinds of drugs
p.000143: that are subject to the statutory standards and the wide range of uses for those drugs demand
p.000143: flexibility in applying the standards. Thus FDA is required to exercise its scientific judgment to de- termine
p.000143: the kind and quantity of data and information an applicant is re- quired to provide for a
p.000143: particular drug to meet the statutory standards. FDA makes its views on drug products and classes of drugs
p.000143: available through guid- ance documents, recommendations, and other statements of policy.
p.000143: (d) FDA will approve an abbreviated
p.000143: new drug application and send the ap- plicant an approval letter if none of the reasons in § 314.127 for
p.000143: refusing to ap- prove the abbreviated new drug appli- cation applies. The approval becomes effective on
p.000143: the date of the issuance of the agency’s approval letter unless the approval letter provides for a
p.000143: delayed effective date. An approval with a de- layed effective date is tentative and does not become
p.000143: final until the effec- tive date. A new drug product approved under this paragraph may not be intro- duced or
p.000143: delivered for introduction into interstate commerce until approval of the abbreviated new drug application is
p.000143: effective. Ordinarily, the effective date of approval will be stated in the ap- proval letter.
p.000143: [57 FR 17989, Apr. 28, 1992, as amended at 64
p.000143: FR 402, Jan. 5, 1999; 65 FR 56479, Sept. 19,
p.000143: 2000; 73 FR 39609, July 10, 2008]
p.000143: § 314.106 Foreign data.
p.000143: (a) General. The acceptance of foreign data in an application generally is gov- erned by § 312.120 of this chapter.
p.000143: (b) As sole basis for marketing approval. An application based solely on foreign clinical data meeting U.S.
p.000143: criteria for marketing approval may be approved if: (1) The foreign data are applicable to the U.S.
p.000143: population and U.S. med- ical practice; (2) the studies have been performed by clinical investigators of
p.000143: recognized competence; and (3) the data may be considered valid without the need for an on-site
p.000143: inspection by FDA or, if FDA considers such an in- spection to be necessary, FDA is able to validate the
p.000143: data through an on-site inspection or other appropriate means.
p.000144: 144
p.000144:
p.000144:
p.000144:
p.000144:
p.000144:
p.000144:
p.000144:
p.000144: Food and Drug Administration, HHS § 314.107
p.000144:
p.000144:
p.000144: Failure of an application to meet any of these criteria will result in the ap- plication not being
p.000144: approvable based on the foreign data alone. FDA will apply this policy in a flexible manner accord- ing to the
p.000144: nature of the drug and the data being considered.
p.000144: (c) Consultation bet een FDA and ap- plicants. Applicants are encouraged to meet with agency officials
p.000144: in a ‘‘pre- submission’’ meeting when approval based solely on foreign data will be sought.
p.000144: [50 FR 7493, Feb. 22, 1985, as amended at 55
p.000144: FR 11580, Mar. 29, 1990]
p.000144:
p.000144: § 314.107 Effective date of approval of a 505(b)(2) application or abbre- viated new drug application
p.000144: under section 505(j) of the act.
p.000144: (a) General. A drug product may be introduced or delivered for introduc- tion into interstate
p.000144: commerce when approval of the application or abbre- viated application for the drug product becomes effective.
p.000144: Except as provided in this section, approval of an applica- tion or abbreviated application for a drug
p.000144: product becomes effective on the date FDA issues an approval letter under § 314.105 for the application
p.000144: or ab- breviated application.
p.000144: (b) Effect of patent on the listed drug. If
p.000144: approval of an abbreviated new drug application submitted under section 505(j) of the act or of a 505(b)(2)
p.000144: applica- tion is granted, that approval will be- come effective in accordance with the following:
p.000144: (1) Date of approval letter. Except as provided in paragraphs (b)(3), (b)(4), and (c) of this section,
p.000144: approval will be- come effective on the date FDA issues an approval letter under § 314.105 if the applicant
p.000144: certifies under § 314.50(i) or
p.000144: § 314.94(a)(12) that:
p.000144: (i) There are no relevant patents; or
p.000144: (ii) The applicant is aware of a rel- evant patent but the patent informa- tion required under section
p.000144: 505 (b) or
p.000144: (c) of the act has not been submitted to FDA; or
p.000144: (iii) The relevant patent has expired; or
p.000144: (iv) The relevant patent is invalid, unenforceable, or will not be infringed.
p.000144: (2) Patent expiration. If the applicant certifies under § 314.50(i) or
p.000144: § 314.94(a)(12) that the relevant patent
p.000144:
p.000144: will expire on a specified date, approval will become effective on the specified date.
p.000144: (3) Disposition of patent litigation. (i)(A) Except as provided in paragraphs (b)(3)(ii), (b)(3)(iii), and
p.000144: (b)(3)(iv) of this section, if the applicant certifies under
p.000144: § 314.50(i) or § 314.94(a)(12) that the rel- evant patent is invalid, unenforceable, or will not be infringed,
p.000144: and the patent owner or its representative or the ex- clusive patent licensee brings suit for patent
p.000144: infringement within 45 days of receipt by the patent owner of the no- tice of certification from the
p.000144: applicant under § 314.52 or § 314.95, approval may be made effective 30 months after the date of the receipt
p.000144: of the notice of cer- tification by the patent owner or by the exclusive licensee (or their rep-
p.000144: resentatives) unless the court has ex- tended or reduced the period because of a failure of either the
p.000144: plaintiff or de- fendant to cooperate reasonably in ex- pediting the action; or
p.000144: (B) If the patented drug product
p.000144: qualifies for 5 years of exclusive mar- keting under § 314.108(b)(2) and the pat- ent owner or its
p.000144: representative or the exclusive patent licensee brings suit for patent infringement during the 1- year
p.000144: period beginning 4 years after the date the patented drug was approved and within 45 days of receipt by
p.000144: the patent owner of the notice of certifi- cation, the approval may be made ef- fective at the
p.000144: expiration of the 71⁄2 years from the date of approval of the application for the patented drug prod- uct.
p.000144: (ii) If before the expiration of the 30-
p.000144: month period, or 71⁄2 years where appli- cable, the court issues a final order that the patent is
p.000144: invalid, unenforce- able, or not infringed, approval may be made effective on the date the court enters
p.000144: judgment;
p.000144: (iii) If before the expiration of the 30- month period, or 71⁄2 years where appli- cable, the court issues a final
p.000144: order or judgment that the patent has been in- fringed, approval may be made effec- tive on the date
p.000144: the court determines that the patent will expire or otherwise orders; or
p.000144: (iv) If before the expiration of the 30- month period, or 71⁄2 years where appli- cable, the court grants a
p.000144: preliminary injunction prohibiting the applicant
p.000145: 145
p.000145:
p.000145:
p.000145:
p.000145:
p.000145:
p.000145:
p.000145:
p.000145:
p.000145: § 314.107
p.000145: from engaging in the commercial man- ufacture or sale of the drug product until the court decides the issues
p.000145: of patent validity and infringement, and if the court later decides that the pat- ent is invalid,
p.000145: unenforceable, or not in- fringed, approval may be made effec- tive on the date the court enters a final order or
p.000145: judgment that the patent is invalid, unenforceable, or not in- fringed.
p.000145: (v) FDA will issue a tentative ap- proval letter when tentative approval is appropriate in accordance
p.000145: with para- graph (b)(3) of this section. In order for an approval to be made effective under paragraph (b)(3) of this
p.000145: section, the ap- plicant must receive an approval letter from the agency indicating that the ap- plication has
p.000145: received final approval. Tentative approval of an application does not constitute ‘‘approval’’ of an
p.000145: application and cannot, absent a final approval letter from the agency, result in an effective approval
p.000145: under para- graph (b)(3) of this section.
p.000145: (4) Multiple certifications. If the appli-
p.000145: cant has submitted certifications under
p.000145: § 314.50(i) or § 314.94(a)(12) for more than one patent, the date of approval will be calculated for each
p.000145: certification, and the approval will become effective on the last applicable date.
p.000145: (c) Subsequent abbreviated ne drug application submission. (1) If an abbre- viated new drug
p.000145: application contains a certification that a relevant patent is invalid, unenforceable, or will not be
p.000145: infringed and the application is for a generic copy of the same listed drug for which one or more
p.000145: substantially com- plete abbreviated new drug applica- tions were previously submitted con- taining a
p.000145: certification that the same patent was invalid, unenforceable, or would not be infringed, approval of the
p.000145: subsequent abbreviated new drug appli- cation will be made effective no sooner than 180 days from whichever of
p.000145: the following dates is earlier:
p.000145: (i) The date the applicant submitting
p.000145: the first application first commences commercial marketing of its drug product; or
p.000145: (ii) The date of a decision of the court holding the relevant patent in- valid, unenforceable, or
p.000145: not infringed.
p.000145: (2) For purposes of paragraph (c)(1) of this section, the ‘‘applicant submitting
p.000145: 21 CFR Ch. I (4–1–12 Edition)
p.000145: the first application’’ is the applicant that submits an application that is both substantially
p.000145: complete and con- tains a certification that the patent was invalid, unenforceable, or not in- fringed
p.000145: prior to the submission of any other application for the same listed drug that is both substantially
p.000145: com- plete and contains the same certifi- cation. A ‘‘substantially complete’’ ap- plication must contain
p.000145: the results of any required bioequivalence studies, or, if applicable, a request for a waiver of such studies.
p.000145: (3) For purposes of paragraph (c)(1) of
p.000145: this section, if FDA concludes that the applicant submitting the first applica- tion is not actively pursuing
p.000145: approval of its abbreviated application, FDA will make the approval of subsequent abbreviated
p.000145: applications immediately effective if they are otherwise eligible for an immediately effective approval.
p.000145: (4) For purposes of paragraph (c)(1)(i) of this section, the applicant submit- ting the first application
p.000145: shall notify FDA of the date that it commences commercial marketing of its drug product.
p.000145: Commercial marketing com- mences with the first date of introduc- tion or delivery for introduction into
p.000145: interstate commerce outside the con- trol of the manufacturer of a drug product, except for
p.000145: investigational use under part 312 of this chapter, but does not include transfer of the drug prod- uct for
p.000145: reasons other than sale within the control of the manufacturer or ap- plication holder. If an applicant
p.000145: does not promptly notify FDA of such date, the effective date of approval shall be deemed to be the
p.000145: date of the com- mencement of first commercial mar- keting.
p.000145: (d) Delay due to exclusivity. The agen-
p.000145: cy will also delay the effective date of the approval of an abbreviated new drug application under
p.000145: section 505(j) of the act or a 505(b)(2) application if delay is required by the exclusivity
p.000145: provisions in § 314.108. When the effec- tive date of an application is delayed under both this
p.000145: section and § 314.108, the effective date will be the later of the 2 days specified under this section
p.000145: and § 314.108.
p.000145: (e) Notification of court actions. The applicant shall submit a copy of the entry of the order or
p.000145: judgment to the
p.000146: 146
p.000146:
p.000146:
p.000146:
p.000146:
p.000146:
p.000146:
p.000146:
p.000146: Food and Drug Administration, HHS § 314.108
p.000146:
p.000146:
p.000146: Office of Generic Drugs (HFD–600), or to the appropriate division in the Of- fice of New Drugs within
p.000146: 10 working days of a final judgment.
p.000146: (f) Computation of 45-day time clock. (1) The 45-day clock described in para- graph (b)(3) of this
p.000146: section begins on the day after the date of receipt of the applicant’s notice of certification by the patent
p.000146: owner or its representative, and by the approved application holder. When the 45th day falls on Saturday,
p.000146: Sunday, or a Federal holiday, the 45th day will be the next day that is not a Saturday, Sunday, or a
p.000146: Federal holi- day.
p.000146: (2) The abbreviated new drug appli- cant or the 505(b)(2) applicant shall no- tify FDA immediately of the
p.000146: filing of any legal action filed within 45 days of receipt of the notice of certification. If the applicant
p.000146: submitting the abbre- viated new drug application or the 505(b)(2) application or patent owner or its
p.000146: representative does not notify FDA in writing before the expiration of the 45-day time period or the
p.000146: completion of the agency’s review of the application, whichever occurs later, that a legal ac- tion for patent
p.000146: infringement was filed within 45 days of receipt of the notice of certification, approval of the abbre-
p.000146: viated new drug application or the 505(b)(2) application will be made effec- tive immediately upon
p.000146: expiration of the 45 days or upon completion of the agency’s review and approval of the ap- plication,
p.000146: whichever is later. The noti- fication to FDA of the legal action shall include:
p.000146: (i) The abbreviated new drug applica-
p.000146: tion or 505(b)(2) application number.
p.000146: (ii) The name of the abbreviated new drug or 505(b)(2) application applicant.
p.000146: (iii) The established name of the drug product or, if no established name ex- ists, the name(s) of the
p.000146: active ingre- dient(s), the drug product’s strength, and dosage form.
p.000146: (iv) A certification that an action for patent infringement identified by num- ber, has been filed in an
p.000146: appropriate court on a specified date.
p.000146: The applicant of an abbreviated new drug application shall send the notifi- cation to FDA’s Office
p.000146: of Generic Drugs (HFD–600). A 505(b)(2) applicant shall send the notification to the ap- propriate
p.000146: division in the Office of New
p.000146:
p.000146: Drugs reviewing the application. A pat- ent owner or its representative may also notify FDA of the
p.000146: filing of any legal action for patent infringement. The notice should contain the informa- tion and be
p.000146: sent to the offices or divi- sions described in this paragraph.
p.000146: (3) If the patent owner or approved application holder who is an exclusive patent licensee waives its
p.000146: opportunity to file a legal action for patent in- fringement within 45 days of a receipt of the
p.000146: notice of certification and the patent owner or approved application holder who is an exclusive patent
p.000146: li- censee submits to FDA a valid waiver before the 45 days elapse, approval of the abbreviated new drug
p.000146: application or the 505(b)(2) application will be made effective upon completion of the agency’s review
p.000146: and approval of the ap- plication. FDA will only accept a waiv- er in the following form:
p.000146: (Name of patent o ner or exclusive patent li- censee) has received notice from (name of ap- plicant)
p.000146: under (section 505(b)(3) or 505(j)(2)(B) of the act) and does not intend to file an ac- tion for patent
p.000146: infringement against (name of applicant) concerning the drug (name of drug) before (date on hich 45 days elapses.
p.000146: (Name of patent o ner or exclusive patent licensee) waives the opportunity provided by (section
p.000146: 505(c)(3)(C) or 505(j)(B)(iii) of the act) and does not object to FDA’s approval of (name of ap-
p.000146: plicant)’s (505(b)(2) or abbreviated ne drug ap- plication) for (name of drug) with an imme- diate effective
p.000146: date on or after the date of this letter.
p.000146: [59 FR 50367, Oct. 3, 1994, as amended at 63 FR
p.000146: 59712, Nov. 5, 1998; 65 FR 43235, July 13, 2000;
p.000146: 73 FR 39609, July 10, 2008; 74 FR 9766, Mar. 6,
p.000146: 2009]
p.000146:
p.000146: § 314.108 New drug product exclu- sivity.
p.000146: (a) Definitions. The following defini- tions of terms apply to this section:
p.000146: Active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the
p.000146: drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent
p.000146: derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physio- logical
p.000146: or pharmacological action of the drug substance.
p.000146: Approved under section 505(b) means an application submitted under section 505(b) and approved on or after
p.000146: October
p.000147: 147
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147: § 314.108
p.000147: 10, 1962, or an application that was ‘‘deemed approved’’ under section 107(c)(2) of Pub. L.
p.000147: 87–781.
p.000147: Clinical investigation means any ex- periment other than a bioavailability study in which a drug is
p.000147: administered or dispensed to, or used on, human sub- jects.
p.000147: Conducted or sponsored by the appli- cant with regard to an investigation means that before or
p.000147: during the inves- tigation, the applicant was named in Form FDA–1571 filed with FDA as the sponsor of the
p.000147: investigational new drug application under which the investiga- tion was conducted, or the applicant or the
p.000147: applicant’s predecessor in interest, provided substantial support for the in- vestigation. To demonstrate ‘‘substan-
p.000147: tial support,’’ an applicant must either provide a certified statement from a certified public accountant that the
p.000147: ap- plicant provided 50 percent or more of the cost of conducting the study or provide an
p.000147: explanation why FDA should consider the applicant to have conducted or sponsored the study if the
p.000147: applicant’s financial contribution to the study is less than 50 percent or the applicant did not sponsor
p.000147: the inves- tigational new drug. A predecessor in interest is an entity, e.g., a corpora- tion, that the
p.000147: applicant has taken over, merged with, or purchased, or from which the applicant has purchased all
p.000147: rights to the drug. Purchase of non- exclusive rights to a clinical investiga- tion after it is completed is
p.000147: not suffi- cient to satisfy this definition.
p.000147: Date of approval means the date on
p.000147: the letter from FDA stating that the new drug application is approved, whether or not final printed
p.000147: labeling or other materials must yet be submitted as long as approval of such labeling or materials is
p.000147: not expressly required. ‘‘Date of approval’’ refers only to a final approval and not to a
p.000147: tentative approval that may become effective at a later date.
p.000147: Essential to approval means, with re- gard to an investigation, that there are no other data available that could
p.000147: sup- port approval of the application.
p.000147: FDA means the Food and Drug Ad- ministration.
p.000147: Ne chemical entity means a drug that contains no active moiety that has been approved by FDA in any other
p.000147: ap-
p.000147: 21 CFR Ch. I (4–1–12 Edition)
p.000147: plication submitted under section 505(b) of the act.
p.000147: Ne clinical investigation means an in- vestigation in humans the results of which have not been relied on
p.000147: by FDA to demonstrate substantial evidence of effectiveness of a previously approved drug product for any
p.000147: indication or of safety for a new patient population and do not duplicate the results of another investigation
p.000147: that was relied on by the agency to demonstrate the effective- ness or safety in a new patient popu-
p.000147: lation of a previously approved drug product. For purposes of this section, data from a clinical
p.000147: investigation pre- viously submitted for use in the com- prehensive evaluation of the safety of a drug product
p.000147: but not to support the ef- fectiveness of the drug product would be considered new.
p.000147: (b) Submission of and effective date of
p.000147: approval of an abbreviated ne drug ap- plication submitted under section 505(j) of the act or a
p.000147: 505(b)(2) application. (1) [Re- served]
p.000147: (2) If a drug product that contains a new chemical entity was approved after September 24, 1984,
p.000147: in an applica- tion submitted under section 505(b) of the act, no person may submit a
p.000147: 505(b)(2) application or abbreviated new drug application under section 505(j) of the act for a drug product
p.000147: that con- tains the same active moiety as in the new chemical entity for a period of 5 years from the
p.000147: date of approval of the first approved new drug application, except that the 505(b)(2) application or
p.000147: abbreviated application may be sub- mitted after 4 years if it contains a cer- tification of patent
p.000147: invalidity or non- infringement described in
p.000147: § 314.50(i)(1)(i)(A)(4) or
p.000147: § 314.94(a)(12)(i)(A)(4).
p.000147: (3) The approval of a 505(b)(2) applica- tion or abbreviated application de- scribed in paragraph (b)(2)
p.000147: of this sec- tion will become effective as provided in § 314.107(b)(1) or (b)(2), unless the owner of
p.000147: a patent that claims the drug, the patent owner’s representative, or exclusive licensee brings suit for pat-
p.000147: ent infringement against the applicant during the 1-year period beginning 48 months after the date of
p.000147: approval of the new drug application for the new chemical entity and within 45 days after receipt of
p.000147: the notice described at
p.000148: 148
p.000148:
p.000148:
p.000148:
p.000148:
p.000148:
p.000148:
p.000148:
p.000148: Food and Drug Administration, HHS § 314.110
p.000148:
p.000148:
p.000148: § 314.52 or § 314.95, in which case, ap- proval of the 505(b)(2) application or abbreviated
p.000148: application will be made effective as provided in § 314.107(b)(3).
p.000148: (4) If an application:
p.000148: (i) Was submitted under section 505(b) of the act;
p.000148: (ii) Was approved after September 24, 1984;
p.000148: (iii) Was for a drug product that con- tains an active moiety that has been previously approved in another
p.000148: appli- cation under section 505(b) of the act; and
p.000148: (iv) Contained reports of new clinical investigations (other than bio- availability studies)
p.000148: conducted or spon- sored by the applicant that were essen- tial to approval of the application, the agency will
p.000148: not make effective for a pe- riod of 3 years after the date of ap- proval of the application the approval
p.000148: of a 505(b)(2) application or an abbre- viated new drug application for the conditions of approval
p.000148: of the original application, or an abbreviated new drug application submitted pursuant to an approved
p.000148: petition under section 505(j)(2)(C) of the act that relies on the information supporting the conditions of
p.000148: approval of an original new drug ap- plication.
p.000148: (5) If a supplemental application:
p.000148: (i) Was approved after September 24, 1984; and
p.000148: (ii) Contained reports of new clinical investigations (other than bio- availability studies)
p.000148: that were con- ducted or sponsored by the applicant that were essential to approval of the supplemental
p.000148: application, the agency will not make effective for a period of 3 years after the date of approval of the
p.000148: supplemental application the approval of a 505(b)(2) application or an abbre- viated new drug
p.000148: application for a change, or an abbreviated new drug ap- plication submitted pursuant to an ap- proved
p.000148: petition under section 505(j)(2)(C) of the act that relies on the information supporting a change
p.000148: ap- proved in the supplemental new drug application.
p.000148: [59 FR 50368, Oct. 3, 1994]
p.000148:
p.000148: § 314.110 Complete response letter to the applicant.
p.000148: (a) Complete response letter. FDA will send the applicant a complete response
p.000148:
p.000148: letter if the agency determines that we will not approve the application or ab- breviated application in
p.000148: its present form for one or more of the reasons given in § 314.125 or § 314.127, respec- tively.
p.000148: (1) Description of specific deficiencies. A complete response letter will describe all of the specific
p.000148: deficiencies that the agency has identified in an application or abbreviated application, except as
p.000148: stated in paragraph (a)(3) of this sec- tion.
p.000148: (2) Complete revie of data. A com- plete response letter reflects FDA’s complete review of the
p.000148: data submitted in an original application or abbre- viated application (or, where appro- priate, a
p.000148: resubmission) and any amend- ments that the agency has reviewed. The complete response letter will iden- tify any
p.000148: amendments that the agency has not yet reviewed.
p.000148: (3) Inadequate data. If FDA deter- mines, after an application is filed or an abbreviated application
p.000148: is received, that the data submitted are inadequate to support approval, the agency might issue a complete
p.000148: response letter with- out first conducting required inspec- tions and/or reviewing proposed prod- uct
p.000148: labeling.
p.000148: (4) Recommendation of actions for ap- proval. When possible, a complete re- sponse letter will recommend
p.000148: actions that the applicant might take to place the application or abbreviated applica- tion in condition for
p.000148: approval.
...
p.000149: 149
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149: § 314.120
p.000149: to start a new 6-month review cycle be- ginning on the date FDA receives the resubmission.
p.000149: (iii) A resubmission of an NDA sup- plement other than an efficacy supple- ment constitutes an agreement
p.000149: by the applicant to start a new review cycle the same length as the initial review cycle for the
p.000149: supplement (excluding any extension due to a major amend- ment of the initial supplement), begin- ning on the
p.000149: date FDA receives the re- submission.
p.000149: (iv) A major resubmission of an ab- breviated application constitutes an agreement by the applicant to
p.000149: start a new 6-month review cycle beginning on the date FDA receives the resubmis- sion.
p.000149: (v) A minor resubmission of an abbre- viated application constitutes an agreement by the applicant to
p.000149: start a new review cycle beginning on the date FDA receives the resubmission.
p.000149: (2) Withdra al. Withdraw the applica- tion or abbreviated application. A deci- sion to withdraw an application
p.000149: or ab- breviated application is without preju- dice to a subsequent submission.
p.000149: (3) Request opportunity for hearing. Ask the agency to provide the appli- cant an opportunity for a
p.000149: hearing on the question of whether there are grounds for denying approval of the ap- plication or
p.000149: abbreviated application under section 505(d) or (j)(4) of the act, respectively. The applicant must sub-
p.000149: mit the request to the Associate Direc- tor for Policy, Center for Drug Evalua- tion and Research, Food and Drug
p.000149: Ad- ministration, 10903 New Hampshire Ave., Silver Spring, MD 20993. Within 60 days of the date of the
p.000149: request for an opportunity for a hearing, or within a different time period to which FDA and the applicant agree,
p.000149: the agency will ei- ther approve the application or abbre- viated application under § 314.105, or refuse
p.000149: to approve the application under
p.000149: § 314.125 or abbreviated application
p.000149: under § 314.127 and give the applicant written notice of an opportunity for a hearing under § 314.200
p.000149: and section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether there are grounds for denying
p.000149: approval of the application or abbreviated application under sec- tion 505(d) or (j)(4) of the act, respec-
p.000149: tively.
p.000149: 21 CFR Ch. I (4–1–12 Edition)
p.000149: (c) Failure to take action. (1) An appli- cant agrees to extend the review period under section 505(c)(1) or
p.000149: (j)(5)(A) of the act until it takes any of the actions listed in paragraph (b) of this section. For an
p.000149: application or abbreviated ap- plication, FDA may consider an appli- cant’s failure to take any of such
p.000149: ac- tions within 1 year after issuance of a complete response letter to be a re- quest by the
p.000149: applicant to withdraw the application, unless the applicant has requested an extension of time
p.000149: in which to resubmit the application. FDA will grant any reasonable request for such an extension.
p.000149: FDA may con- sider an applicant’s failure to resubmit the application within the extended time period or to
p.000149: request an additional extension to be a request by the appli- cant to withdraw the application.
p.000149: (2) If FDA considers an applicant’s failure to take action in accordance with paragraph (c)(1) of
p.000149: this section to be a request to withdraw the applica- tion, the agency will notify the appli- cant in
p.000149: writing. The applicant will have 30 days from the date of the noti- fication to explain why the application
p.000149: should not be withdrawn and to request an extension of time in which to resub- mit the application. FDA will
p.000149: grant any reasonable request for an exten- sion. If the applicant does not respond to the notification
p.000149: within 30 days, the application will be deemed to be with- drawn.
p.000149: [73 FR 39609, July 10, 2008]
p.000149:
p.000149: § 314.120 [Reserved]
p.000149: § 314.122 Submitting an abbreviated application for, or a 505(j)(2)(C) pe- tition that relies on, a
p.000149: listed drug that is no longer marketed.
p.000149: (a) An abbreviated new drug applica- tion that refers to, or a petition under section 505(j)(2)(C) of
p.000149: the act and
p.000149: § 314.93 that relies on, a listed drug that has been voluntarily withdrawn from sale in the United States must
p.000149: be ac- companied by a petition seeking a de- termination whether the listed drug was withdrawn for
p.000149: safety or effective- ness reasons. The petition must be sub- mitted under §§ 10.25(a) and 10.30 of this chapter and
p.000149: must contain all evidence available to the petitioner concerning
p.000150: 150
p.000150:
p.000150:
p.000150:
p.000150:
p.000150:
p.000150:
p.000150:
p.000150: Food and Drug Administration, HHS § 314.125
p.000150:
p.000150:
p.000150: the reasons for the withdrawal from sale.
p.000150: (b) When a petition described in para- graph (a) of this section is submitted, the agency will consider the
p.000150: evidence in the petition and any other evidence before the agency, and determine whether the listed
p.000150: drug is withdrawn from sale for safety or effectiveness reasons, in accordance with the proce- dures
p.000150: in § 314.161.
p.000150: (c) An abbreviated new drug applica- tion described in paragraph (a) of this section will be
p.000150: disapproved, under
p.000150: § 314.127(a)(11), and a 505(j)(2)(C) peti-
p.000150: tion described in paragraph (a) of this section will be disapproved, under
p.000150: § 314.93(e)(1)(iv), unless the agency de- termines that the withdrawal of the listed drug was not for
p.000150: safety or effec- tiveness reasons.
p.000150: (d) Certain drug products approved for safety and effectiveness that were no longer marketed on
p.000150: September 24, 1984, are not included in the list. Any person who wishes to obtain marketing approval for such a
p.000150: drug product under an abbreviated new drug application must petition FDA for a determination whether the
p.000150: drug product was with- drawn from the market for safety or ef- fectiveness reasons and request that the
p.000150: list be amended to include the drug product. A person seeking such a deter- mination shall use the petition proce-
p.000150: dures established in § 10.30 of this chap- ter. The petitioner shall include in the petition information to
p.000150: show that the drug product was approved for safety and effectiveness and all evidence available to
p.000150: the petitioner concerning the reason that marketing of the drug product ceased.
p.000150: [57 FR 17990, Apr. 28, 1992; 57 FR 29353, July
p.000150: 1, 1992]
p.000150:
p.000150: § 314.125 Refusal to approve an appli- cation.
p.000150: (a) The Food and Drug Administra- tion will refuse to approve the applica- tion and for a new drug give the
p.000150: appli- cant written notice of an opportunity for a hearing under § 314.200 on the question of
p.000150: whether there are grounds for denying approval of the application under section 505(d) of the act, if:
p.000150: (1) FDA sends the applicant a com- plete response letter under § 314.110;
p.000150:
p.000150: (2) The applicant requests an oppor- tunity for hearing for a new drug on the question of whether the
p.000150: application is approvable; and
p.000150: (3) FDA finds that any of the reasons given in paragraph (b) of this section apply.
p.000150: (b) FDA may refuse to approve an ap- plication for any of the following rea- sons:
p.000150: (1) The methods to be used in, and the facilities and controls used for, the manufacture, processing,
p.000150: packing, or holding of the drug substance or the drug product are inadequate to pre- serve its
p.000150: identity, strength, quality, purity, stability, and bioavailability.
p.000150: (2) The investigations required under section 505(b) of the act do not include adequate tests by all
p.000150: methods reason- ably applicable to show whether or not the drug is safe for use under the condi- tions prescribed,
p.000150: recommended, or sug- gested in its proposed labeling.
p.000150: (3) The results of the tests show that the drug is unsafe for use under the conditions prescribed,
p.000150: recommended, or suggested in its proposed labeling or the results do not show that the drug product is safe for
p.000150: use under those con- ditions.
p.000150: (4) There is insufficient information about the drug to determine whether the product is safe for use
p.000150: under the conditions prescribed, recommended, or suggested in its proposed labeling.
p.000150: (5) There is a lack of substantial evi- dence consisting of adequate and well- controlled investigations, as
p.000150: defined in
p.000150: § 314.126, that the drug product will have the effect it purports or is rep- resented to have under
p.000150: the conditions of use prescribed, recommended, or suggested in its proposed labeling.
p.000150: (6) The proposed labeling is false or misleading in any particular.
p.000150: (7) The application contains an un- true statement of a material fact.
p.000150: (8) The drug product’s proposed label- ing does not comply with the require- ments for labels and labeling
p.000150: in part 201.
p.000150: (9) The application does not contain bioavailability or bioequivalence data required under part 320 of this
p.000150: chapter.
p.000150: (10) A reason given in a letter refus- ing to file the application under
p.000150: § 314.101(d), if the deficiency is not cor- rected.
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p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151: § 314.126
p.000151: (11) The drug will be manufactured or processed in whole or in part in an es- tablishment that is not
p.000151: registered and not exempt from registration under section 510 of the act and part 207.
p.000151: (12) The applicant does not permit a properly authorized officer or employee of the Department of
p.000151: Health and Human Services an adequate oppor- tunity to inspect the facilities, con- trols, and
p.000151: any records relevant to the application.
p.000151: (13) The methods to be used in, and the facilities and controls used for, the manufacture, processing,
p.000151: packing, or holding of the drug substance or the drug product do not comply with the current good
p.000151: manufacturing practice regulations in parts 210 and 211.
p.000151: (14) The application does not contain an explanation of the omission of a re- port of any investigation
p.000151: of the drug product sponsored by the applicant, or an explanation of the omission of other information about
p.000151: the drug pertinent to an evaluation of the application that is received or otherwise obtained by the
p.000151: applicant from any source.
p.000151: (15) A nonclinical laboratory study that is described in the application and that is essential to show
p.000151: that the drug is safe for use under the conditions pre- scribed, recommended, or suggested in its proposed
p.000151: labeling was not con- ducted in compliance with the good laboratory practice regulations in part 58
p.000151: of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the
p.000151: practices used in conducting the study and the good laboratory practice regulations do not support the validity
p.000151: of the study.
p.000151: (16) Any clinical investigation in-
p.000151: volving human subjects described in the application, subject to the institu- tional review board
p.000151: regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter, was not
p.000151: conducted in compliance with those regulations such that the rights or safety of human subjects were not
p.000151: adequately protected.
p.000151: (17) The applicant or contract re- search organization that conducted a bioavailability or bioequivalence
p.000151: study described in § 320.38 or § 320.63 of this chapter that is contained in the appli- cation refuses to
p.000151: permit an inspection of facilities or records relevant to the
p.000151: 21 CFR Ch. I (4–1–12 Edition)
p.000151: study by a properly authorized officer or employee of the Department of Health and Human Services or
p.000151: refuses to submit reserve samples of the drug products used in the study when re- quested by FDA.
p.000151: (18) For a new drug, the application failed to contain the patent informa- tion required by section
p.000151: 505(b)(1) of the act.
p.000151: (c) For drugs intended to treat life- threatening or severely-debilitating ill- nesses that are developed in
p.000151: accordance with §§ 312.80 through 312.88 of this chapter, the criteria contained in para- graphs (b) (3),
p.000151: (4), and (5) of this section shall be applied according to the con- siderations contained in § 312.84 of
p.000151: this chapter.
p.000151: [50 FR 7493, Feb. 22, 1985, as amended at 53
p.000151: FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28,
p.000151: 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan.
p.000151: 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766,
p.000151: Mar. 6, 2009]
p.000151:
p.000151: § 314.126 Adequate and well-controlled studies.
p.000151: (a) The purpose of conducting clin- ical investigations of a drug is to dis- tinguish the effect of a drug
p.000151: from other influences, such as spontaneous change in the course of the disease, placebo ef- fect, or biased
p.000151: observation. The charac- teristics described in paragraph (b) of this section have been developed over a period
p.000151: of years and are recognized by the scientific community as the essen- tials of an adequate and
p.000151: well-con- trolled clinical investigation. The Food and Drug Administration considers these characteristics
p.000151: in determining whether an investigation is adequate and well-controlled for purposes of sec- tion 505 of the act.
p.000151: Reports of adequate and well-controlled investigations pro- vide the primary basis for determining whether
p.000151: there is ‘‘substantial evi- dence’’ to support the claims of effec- tiveness for new drugs.
p.000151: Therefore, the study report should provide sufficient details of study design, conduct, and analysis to
p.000151: allow critical evaluation and a determination of whether the characteristics of an adequate
p.000151: and well-controlled study are present.
p.000151: (b) An adequate and well-controlled
p.000151: study has the following characteristics:
p.000151: (1) There is a clear statement of the objectives of the investigation and a
p.000152: 152
p.000152:
p.000152:
p.000152:
p.000152:
p.000152:
p.000152:
p.000152:
p.000152: Food and Drug Administration, HHS § 314.126
p.000152:
p.000152:
p.000152: summary of the proposed or actual methods of analysis in the protocol for the study and in the report
p.000152: of its re- sults. In addition, the protocol should contain a description of the proposed methods of
p.000152: analysis, and the study re- port should contain a description of the methods of analysis ultimately used. If the
p.000152: protocol does not contain a descrip- tion of the proposed methods of anal- ysis, the study report should
p.000152: describe how the methods used were selected.
p.000152: (2) The study uses a design that per- mits a valid comparison with a control to provide a quantitative
p.000152: assessment of drug effect. The protocol for the study and report of results should describe the study design
p.000152: precisely; for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover,
p.000152: and whether the sample size is predetermined or based upon some interim analysis. Generally, the fol-
p.000152: lowing types of control are recognized:
p.000152: (i) Placebo concurrent control. The test drug is compared with an inactive preparation designed to
p.000152: resemble the test drug as far as possible. A placebo- controlled study may include addi- tional
p.000152: treatment groups, such as an ac- tive treatment control or a dose-com- parison control, and usually includes
p.000152: randomization and blinding of patients or investigators, or both.
p.000152: (ii) Dose-comparison concurrent con- trol. At least two doses of the drug are compared. A
p.000152: dose-comparison study may include additional treatment groups, such as placebo control or ac- tive
p.000152: control. Dose-comparison trials usually include randomization and blinding of patients or investigators,
p.000152: or both.
p.000152: (iii) No treatment concurrent control. Where objective measurements of effec- tiveness are available and
p.000152: placebo ef- fect is negligible, the test drug is com- pared with no treatment. No treatment concurrent control
p.000152: trials usually in- clude randomization.
p.000152: (iv) Active treatment concurrent con- trol. The test drug is compared with known effective therapy;
p.000152: for example, where the condition treated is such that administration of placebo or no treatment would
p.000152: be contrary to the in- terest of the patient. An active treat- ment study may include additional
p.000152: treatment groups, however, such as a
p.000152:
p.000152: placebo control or a dose-comparison control. Active treatment trials usu- ally include randomization
p.000152: and blind- ing of patients or investigators, or both. If the intent of the trial is to show
p.000152: similarity of the test and control drugs, the report of the study should assess the ability of the study to
p.000152: have detected a difference between treat- ments. Similarity of test drug and ac- tive control can
p.000152: mean either that both drugs were effective or that neither was effective. The analysis of the study should
p.000152: explain why the drugs should be considered effective in the study, for example, by reference to results in pre-
p.000152: vious placebo-controlled studies of the active control drug.
p.000152: (v) Historical control. The results of treatment with the test drug are com- pared with experience
p.000152: historically de- rived from the adequately documented natural history of the disease or condi- tion, or from
p.000152: the results of active treatment, in comparable patients or populations. Because historical control
p.000152: populations usually cannot be as well assessed with respect to pertinent vari- ables as can concurrent control
p.000152: popu- lations, historical control designs are usually reserved for special cir- cumstances.
p.000152: Examples include studies of diseases with high and predictable mortality (for example, certain malig-
p.000152: nancies) and studies in which the effect of the drug is self-evident (general an- esthetics, drug metabolism).
p.000152: (3) The method of selection of sub- jects provides adequate assurance that they have the disease or
p.000152: condition being studied, or evidence of suscepti- bility and exposure to the condition against which
p.000152: prophylaxis is directed.
p.000152: (4) The method of assigning patients to treatment and control groups mini- mizes bias and is intended to
p.000152: assure comparability of the groups with re- spect to pertinent variables such as age, sex, severity
p.000152: of disease, duration of disease, and use of drugs or therapy other than the test drug. The protocol for
p.000152: the study and the report of its re- sults should describe how subjects were assigned to groups.
p.000152: Ordinarily, in a concurrently controlled study, assign- ment is by randomization, with or without
p.000152: stratification.
p.000153: 153
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153: § 314.127
p.000153: (5) Adequate measures are taken to minimize bias on the part of the sub- jects, observers, and
p.000153: analysts of the data. The protocol and report of the study should describe the procedures used to
p.000153: accomplish this, such as blind- ing.
p.000153: (6) The methods of assessment of sub- jects’ response are well-defined and re- liable. The protocol for the
p.000153: study and the report of results should explain the variables measured, the methods of ob- servation, and criteria
p.000153: used to assess response.
p.000153: (7) There is an analysis of the results of the study adequate to assess the ef- fects of the drug. The
p.000153: report of the study should describe the results and the analytic methods used to evaluate them, including
p.000153: any appropriate statis- tical methods. The analysis should as- sess, among other things, the com-
p.000153: parability of test and control groups with respect to pertinent variables, and the effects of any interim
p.000153: data anal- yses performed.
p.000153: (c) The Director of the Center for Drug Evaluation and Research may, on the Director’s own initiative
p.000153: or on the petition of an interested person, waive in whole or in part any of the criteria in paragraph
p.000153: (b) of this section with re- spect to a specific clinical investiga- tion, either prior to the investigation
p.000153: or in the evaluation of a completed study. A petition for a waiver is re- quired to set forth
p.000153: clearly and con- cisely the specific criteria from which waiver is sought, why the criteria are not
p.000153: reasonably applicable to the par- ticular clinical investigation, what al- ternative procedures, if any,
p.000153: are to be, or have been employed, and what re- sults have been obtained. The petition is also required
p.000153: to state why the clin- ical investigations so conducted will yield, or have yielded, substantial evi-
p.000153: dence of effectiveness, notwithstanding nonconformance with the criteria for which waiver is requested.
p.000153: (d) For an investigation to be consid-
p.000153: ered adequate for approval of a new drug, it is required that the test drug be standardized
p.000153: as to identity, strength, quality, purity, and dosage form to give significance to the results of
p.000153: the investigation.
p.000153: (e) Uncontrolled studies or partially controlled studies are not acceptable as
p.000153: 21 CFR Ch. I (4–1–12 Edition)
p.000153: the sole basis for the approval of claims of effectiveness. Such studies carefully conducted
p.000153: and documented, may provide corroborative support of well-controlled studies regarding effi- cacy and may
p.000153: yield valuable data re- garding safety of the test drug. Such studies will be considered on their mer- its in
p.000153: the light of the principles listed here, with the exception of the require- ment for the comparison of the
p.000153: treated subjects with controls. Isolated case re- ports, random experience, and reports lacking the details
p.000153: which permit sci- entific evaluation will not be consid- ered.
p.000153: [50 FR 7493, Feb. 22, 1985, as amended at 50
p.000153: FR 21238, May 23, 1985; 55 FR 11580, Mar. 29,
p.000153: 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar.
p.000153: 4, 2002]
p.000153:
p.000153: § 314.127 Refusal to approve an abbre- viated new drug application.
p.000153: (a) FDA will refuse to approve an ab- breviated application for a new drug under section 505(j) of the act
p.000153: for any of the following reasons:
p.000153: (1) The methods used in, or the facili- ties and controls used for, the manu- facture, processing, and packing
p.000153: of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity.
p.000153: (2) Information submitted with the abbreviated new drug application is in- sufficient to show that each of the
p.000153: pro- posed conditions of use has been pre- viously approved for the listed drug re- ferred to in the application.
p.000153: (3)(i) If the reference listed drug has only one active ingredient, information submitted with the
p.000153: abbreviated new drug application is insufficient to show that the active ingredient is the same as that of the
p.000153: reference listed drug;
p.000153: (ii) If the reference listed drug has more than one active ingredient, infor- mation submitted with the
p.000153: abbreviated new drug application is insufficient to show that the active ingredients are the same as the
p.000153: active ingredients of the reference listed drug; or
p.000153: (iii) If the reference listed drug has more than one active ingredient and if the abbreviated new drug
p.000153: application is for a drug product that has an active ingredient different from the reference listed drug:
p.000154: 154
p.000154:
p.000154:
p.000154:
p.000154:
p.000154:
p.000154:
p.000154:
p.000154: Food and Drug Administration, HHS § 314.127
p.000154:
p.000154:
p.000154: (A) Information submitted with the abbreviated new drug application is in- sufficient to show:
p.000154: (1) That the other active ingredients are the same as the active ingredients of the reference listed drug;
p.000154: or
p.000154: (2) That the different active ingre- dient is an active ingredient of a listed drug or a drug that does not
p.000154: meet the requirements of section 201(p) of the act; or
p.000154: (B) No petition to submit an abbre- viated application for the drug product with the different active
p.000154: ingredient was approved under § 314.93.
p.000154: (4)(i) If the abbreviated new drug ap- plication is for a drug product whose route of administration,
p.000154: dosage form, or strength purports to be the same as that of the listed drug referred to in the
p.000154: abbreviated new drug application, information submitted in the abbre- viated new drug application is
p.000154: insuffi- cient to show that the route of admin- istration, dosage form, or strength is the same as that of
p.000154: the reference listed drug; or
p.000154: (ii) If the abbreviated new drug appli- cation is for a drug product whose route of administration,
p.000154: dosage form, or strength is different from that of the listed drug referred to in the applica- tion, no
p.000154: petition to submit an abbre- viated new drug application for the drug product with the different
p.000154: route of administration, dosage form, or strength was approved under § 314.93.
p.000154: (5) If the abbreviated new drug appli- cation was submitted under the ap- proval of a petition under §
p.000154: 314.93, the abbreviated new drug application did not contain the information required by FDA with respect
p.000154: to the active in- gredient, route of administration, dos- age form, or strength that is not the same as
p.000154: that of the reference listed drug.
p.000154: (6)(i) Information submitted in the abbreviated new drug application is in- sufficient to show that the
p.000154: drug prod- uct is bioequivalent to the listed drug referred to in the abbreviated new drug application; or
p.000154: (ii) If the abbreviated new drug appli- cation was submitted under a petition approved under § 314.93,
p.000154: information submitted in the abbreviated new drug application is insufficient to show that the active ingredients
p.000154: of the drug prod-
p.000154:
p.000154: uct are of the same pharmacological or therapeutic class as those of the ref- erence listed drug and that
p.000154: the drug product can be expected to have the same therapeutic effect as the ref- erence listed drug
p.000154: when administered to patients for each condition of use approved for the reference listed drug.
p.000154: (7) Information submitted in the ab- breviated new drug application is insuf- ficient to show that the
p.000154: labeling pro- posed for the drug is the same as the labeling approved for the listed drug referred to in
p.000154: the abbreviated new drug application except for changes required because of differences approved in a pe- tition under
p.000154: § 314.93 or because the drug product and the reference listed drug are produced or distributed by different
p.000154: manufacturers or because aspects of the listed drug’s labeling are protected by patent, or by
p.000154: exclusivity, and such differences do not render the proposed drug product less safe or effective than the
p.000154: listed drug for all remaining, non- protected conditions of use.
p.000154: (8)(i) Information submitted in the abbreviated new drug application of any other information
p.000154: available to FDA shows that:
p.000154: (A) The inactive ingredients of the drug product are unsafe for use, as de- scribed in paragraph
p.000154: (a)(8)(ii) of this section, under the conditions pre- scribed, recommended, or suggested in the
p.000154: labeling proposed for the drug prod- uct; or
p.000154: (B) The composition of the drug prod- uct is unsafe, as described in paragraph (a)(8)(ii) of this section, under
p.000154: the con- ditions prescribed, recommended, or suggested in the proposed labeling be- cause of the type
p.000154: or quantity of inac- tive ingredients included or the man- ner in which the inactive ingredients are
p.000154: included.
p.000154: (ii)(A) FDA will consider the inactive ingredients or composition of a drug product unsafe and refuse to
p.000154: approve an abbreviated new drug application under paragraph (a)(8)(i) of this section if, on the basis of
p.000154: information available to the agency, there is a reasonable basis to conclude that one or more of the
p.000154: inactive ingredients of the pro- posed drug or its composition raises se- rious questions of safety or
p.000154: efficacy.
p.000155: 155
p.000155:
p.000155:
p.000155:
p.000155:
p.000155:
p.000155:
p.000155:
p.000155:
p.000155: § 314.127
p.000155: From its experience with reviewing in- active ingredients, and from other in- formation available to
p.000155: it, FDA may identify changes in inactive ingredi- ents or composition that may ad- versely
p.000155: affect a drug product’s safety or efficacy. The inactive ingredients or composition of a proposed drug product will
p.000155: be considered to raise serious ques- tions of safety or efficacy if the prod- uct incorporates one or more
p.000155: of these changes. Examples of the changes that may raise serious questions of safety or efficacy include, but are
p.000155: not limited to, the following:
p.000155: (1) A change in an inactive ingredient
p.000155: so that the product does not comply with an official compendium.
p.000155: (2) A change in composition to in- clude an inactive ingredient that has not been previously approved in a
p.000155: drug product for human use by the same route of administration.
p.000155: (3) A change in the composition of a parenteral drug product to include an inactive ingredient that has
p.000155: not been previously approved in a parenteral drug product.
p.000155: (4) A change in composition of a drug product for ophthalmic use to include an inactive ingredient that
p.000155: has not been previously approved in a drug for ophthalmic use.
p.000155: (5) The use of a delivery or a modified release mechanism never before ap- proved for the drug.
p.000155: (6) A change in composition to in- clude a significantly greater content of one or more inactive ingredients
p.000155: than previously used in the drug product.
p.000155: (7) If the drug product is intended for topical administration, a change in the properties of the vehicle or base
p.000155: that might increase absorption of certain potentially toxic active ingredients thereby affecting the
p.000155: safety of the drug product, or a change in the lipophilic properties of a vehicle or base, e.g., a change
p.000155: from an oleaginous to a water soluble vehicle or base.
p.000155: (B) FDA will consider an inactive in- gredient in, or the composition of, a drug product intended for
p.000155: parenteral use to be unsafe and will refuse to ap- prove the abbreviated new drug appli- cation unless
p.000155: it contains the same in- active ingredients, other than preserv- atives, buffers, and antioxidants, in the same
p.000155: concentration as the listed drug,
p.000155: 21 CFR Ch. I (4–1–12 Edition)
p.000155: and, if it differs from the listed drug in a preservative, buffer, or antioxidant, the application contains
p.000155: sufficient in- formation to demonstrate that the dif- ference does not affect the safety or ef- ficacy of the
p.000155: drug product.
p.000155: (C) FDA will consider an inactive in- gredient in, or the composition of, a drug product intended for
p.000155: ophthalmic or otic use unsafe and will refuse to ap- prove the abbreviated new drug appli- cation unless it
p.000155: contains the same in- active ingredients, other than preserv- atives, buffers, substances to adjust to- nicity,
p.000155: or thickening agents, in the same concentration as the listed drug, and if it differs from the
p.000155: listed drug in a preservative, buffer, substance to ad- just tonicity, or thickening agent, the application
p.000155: contains sufficient infor- mation to demonstrate that the dif- ference does not affect the safety or
p.000155: ef- ficacy of the drug product and the la- beling does not claim any therapeutic advantage over or
p.000155: difference from the listed drug.
p.000155: (9) Approval of the listed drug re- ferred to in the abbreviated new drug application has been
p.000155: withdrawn or sus- pended for grounds described in
p.000155: § 314.150(a) or FDA has published a no- tice of opportunity for hearing to with- draw approval of the
p.000155: reference listed drug under § 314.150(a).
p.000155: (10) Approval of the listed drug re- ferred to in the abbreviated new drug application has been
p.000155: withdrawn under
p.000155: § 314.151 or FDA has proposed to with- draw approval of the reference listed drug under § 314.151(a).
p.000155: (11) FDA has determined that the ref- erence listed drug has been withdrawn from sale for safety or
p.000155: effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily with- drawn from sale
p.000155: and the agency has not determined whether the with- drawal is for safety or effectiveness
p.000155: reasons, or approval of the reference listed drug has been suspended under
p.000155: § 314.153, or the agency has issued an initial decision proposing to suspend the reference listed
p.000155: drug under
p.000155: § 314.153(a)(1).
p.000155: (12) The abbreviated new drug appli- cation does not meet any other re- quirement under section
p.000155: 505(j)(2)(A) of the act.
p.000156: 156
p.000156:
p.000156:
p.000156:
p.000156:
p.000156:
p.000156:
p.000156:
p.000156: Food and Drug Administration, HHS § 314.150
p.000156:
p.000156:
p.000156: (13) The abbreviated new drug appli- cation contains an untrue statement of material fact.
p.000156: (b) FDA may refuse to approve an ab- breviated application for a new drug if the applicant or contract
p.000156: research or- ganization that conducted a bio- availability or bioequivalence study described in
p.000156: § 320.63 of this chapter that is contained in the abbreviated new drug application refuses to permit an
p.000156: inspection of facilities or records rel- evant to the study by a properly au- thorized officer of
p.000156: employee of the De- partment of Health and Human Serv- ices or refuses to submit reserve sam- ples of
p.000156: the drug products used in the study when requested by FDA.
p.000156: [57 FR 17991, Apr. 28, 1992; 57 FR 29353, July
p.000156: 1, 1992, as amended at 58 FR 25927, Apr. 28,
p.000156: 1993; 67 FR 77672, Dec. 19, 2002]
p.000156:
p.000156: § 314.150 Withdrawal of approval of an application or abbreviated applica- tion.
p.000156: (a) The Food and Drug Administra- tion will notify the applicant, and, if appropriate, all other
p.000156: persons who manufacture or distribute identical, re- lated, or similar drug products as de- fined in §§
p.000156: 310.6 and 314.151(a) of this chapter and for a new drug afford an opportunity for a hearing on a
p.000156: proposal to withdraw approval of the applica- tion or abbreviated new drug applica- tion under section 505(e)
p.000156: of the act and under the procedure in § 314.200, if any of the following apply:
p.000156: (1) The Secretary of Health and
p.000156: Human Services has suspended the ap- proval of the application or abbre- viated application for a
p.000156: new drug on a finding that there is an imminent haz- ard to the public health. FDA will promptly
p.000156: afford the applicant an expe- dited hearing following summary sus- pension on a finding of imminent haz-
p.000156: ard to health.
p.000156: (2) FDA finds:
p.000156: (i) That clinical or other experience, tests, or other scientific data show that the drug is unsafe
p.000156: for use under the conditions of use upon the basis of which the application or abbreviated application
p.000156: was approved; or
p.000156: (ii) That new evidence of clinical ex- perience, not contained in the applica- tion or not available to FDA
p.000156: until after the application or abbreviated applica-
p.000156:
p.000156: tion was approved, or tests by new methods, or tests by methods not deemed reasonably
p.000156: applicable when the application or abbreviated application was approved, evaluated together with the evidence
p.000156: available when the appli- cation or abbreviated application was approved, reveal that the drug is not
p.000156: shown to be safe for use under the con- ditions of use upon the basis of which the application or abbreviated
p.000156: applica- tion was approved; or
p.000156: (iii) Upon the basis of new informa- tion before FDA with respect to the drug, evaluated together with
p.000156: the evi- dence available when the application or abbreviated application was ap- proved, that there is
p.000156: a lack of substan- tial evidence from adequate and well- controlled investigations as defined in
p.000156: § 314.126, that the drug will have the ef- fect it is purported or represented to have under the conditions
p.000156: of use pre- scribed, recommended, or suggested in its labeling; or
p.000156: (iv) That the application or abbre- viated application contains any untrue statement of a material fact;
p.000156: or
p.000156: (v) That the patent information pre- scribed by section 505(c) of the act was not submitted within 30
p.000156: days after the receipt of written notice from FDA specifying the failure to submit such information;
p.000156: or
p.000156: (b) FDA may notify the applicant, and, if appropriate, all other persons who manufacture or
p.000156: distribute iden- tical, related, or similar drug products as defined in § 310.6, and for a new drug afford an
p.000156: opportunity for a hearing on a proposal to withdraw approval of the application or abbreviated new
p.000156: drug application under section 505(e) of the act and under the procedure in § 314.200, if the agency finds:
p.000156: (1) That the applicant has failed to establish a system for maintaining re- quired records, or has
p.000156: repeatedly or de- liberately failed to maintain required records or to make required reports under
p.000156: section 505(k) or 507(g) of the act and § 314.80, § 314.81, or § 314.98, or that the applicant has refused to
p.000156: permit ac- cess to, or copying or verification of, its records.
p.000156: (2) That on the basis of new informa- tion before FDA, evaluated together with the evidence available when
p.000156: the application or abbreviated application
p.000157: 157
p.000157:
p.000157:
p.000157:
p.000157:
p.000157:
p.000157:
p.000157:
p.000157:
p.000157: § 314.150
p.000157: was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and
p.000157: packing of the drug are inadequate to ensure and preserve its identity, strength, quality, and purity
p.000157: and were not made adequate within a reasonable time after receipt of written notice from the agency.
p.000157: (3) That on the basis of new informa- tion before FDA, evaluated together with the evidence available when
p.000157: the application or abbreviated application was approved, the labeling of the drug, based on a fair
p.000157: evaluation of all mate- rial facts, is false or misleading in any particular, and the labeling was
p.000157: not corrected by the applicant within a reasonable time after receipt of writ- ten notice from the
p.000157: agency.
p.000157: (4) That the applicant has failed to comply with the notice requirements of section 510(j)(2) of the act.
p.000157: (5) That the applicant has failed to submit bioavailability or bioequiva- lence data required under
p.000157: part 320 of this chapter.
p.000157: (6) The application or abbreviated ap- plication does not contain an expla- nation of the omission of a
p.000157: report of any investigation of the drug product sponsored by the applicant, or an ex- planation of the
p.000157: omission of other in- formation about the drug pertinent to an evaluation of the application or ab-
p.000157: breviated application that is received or otherwise obtained by the applicant from any source.
p.000157: (7) That any nonclinical laboratory study that is described in the applica- tion or abbreviated
p.000157: application and that is essential to show that the drug is safe for use under the conditions pre- scribed,
p.000157: recommended, or suggested in its labeling was not conducted in com- pliance with the good laboratory
p.000157: prac- tice regulations in part 58 of this chap- ter and no reason for the noncompli- ance was provided or, if it
p.000157: was, the dif- ferences between the practices used in conducting the study and the good lab- oratory practice
p.000157: regulations do not support the validity of the study.
p.000157: (8) Any clinical investigation involv-
p.000157: ing human subjects described in the ap- plication or abbreviated application, subject to the
p.000157: institutional review board regulations in part 56 of this chapter or informed consent regula-
p.000157: 21 CFR Ch. I (4–1–12 Edition)
p.000157: tions in part 50 of this chapter, was not conducted in compliance with those regulations such that the
p.000157: rights or safety of human subjects were not ade- quately protected.
p.000157: (9) That the applicant or contract re- search organization that conducted a bioavailability or bioequivalence study
p.000157: described in § 320.38 or § 320.63 of this chapter that is contained in the appli- cation or abbreviated
p.000157: application re- fuses to permit an inspection of facili- ties or records relevant to the study by a
p.000157: properly authorized officer or em- ployee of the Department of Health and Human Services or refuses to
p.000157: submit reserve samples of the drug products used in the study when requested by FDA.
p.000157: (10) That the labeling for the drug
p.000157: product that is the subject of the ab- breviated new drug application is no longer consistent with that for
p.000157: the list- ed drug referred to in the abbreviated new drug application, except for dif- ferences
p.000157: approved in the abbreviated new drug application or those dif- ferences resulting from:
p.000157: (i) A patent on the listed drug issued after approval of the abbreviated new drug application; or
p.000157: (ii) Exclusivity accorded to the listed drug after approval of the abbreviated new drug application that
p.000157: do not render the drug product less safe or ef- fective than the listed drug for any re- maining,
p.000157: nonprotected condition(s) of use.
p.000157: (c) FDA will withdraw approval of an application or abbreviated application if the applicant requests its withdrawal
p.000157: because the drug subject to the appli- cation or abbreviated application is no longer being marketed,
p.000157: provided none of the conditions listed in paragraphs
p.000157: (a) and (b) of this section applies to the drug. FDA will consider a written re- quest for a withdrawal under
p.000157: this para- graph to be a waiver of an opportunity for hearing otherwise provided for in this section. Withdrawal
p.000157: of approval of an application or abbreviated applica- tion under this paragraph is without prejudice to
p.000157: refiling.
p.000157: (d) FDA may notify an applicant that it believes a potential problem associ- ated with a drug is sufficiently
p.000157: serious that the drug should be removed from the market and may ask the applicant
p.000158: 158
p.000158:
p.000158:
p.000158:
p.000158:
p.000158:
p.000158:
p.000158:
p.000158: Food and Drug Administration, HHS § 314.151
p.000158:
p.000158:
p.000158: to waive the opportunity for hearing otherwise provided for under this sec- tion, to permit FDA to
p.000158: withdraw ap- proval of the application or abbre- viated application for the product, and to remove
p.000158: voluntarily the product from the market. If the applicant agrees, the agency will not make a finding under
p.000158: paragraph (b) of this section, but will withdraw approval of the application or abbreviated application in
p.000158: a notice published in the FEDERAL REGISTER that contains a brief summary of the agency’s and the
p.000158: applicant’s views of the reasons for withdrawal.
p.000158: [57 FR 17993, Apr. 28, 1992, as amended at 58
p.000158: FR 25927, Apr. 28, 1993; 64 FR 402, Jan. 5, 1999]
p.000158:
p.000158: § 314.151 Withdrawal of approval of an abbreviated new drug application under section 505(j)(5) of the act.
p.000158: (a) Approval of an abbreviated new drug application approved under
p.000158: § 314.105(d) may be withdrawn when the agency withdraws approval, under
p.000158: § 314.150(a) or under this section, of the approved drug referred to in the abbre- viated new drug
p.000158: application. If the agency proposed to withdraw approval of a listed drug under § 314.150(a), the holder
p.000158: of an approved application for the listed drug has a right to notice and opportunity for hearing. The
p.000158: pub- lished notice of opportunity for hearing will identify all drug products approved under § 314.105(d) whose
p.000158: applications are subject to withdrawal under this section if the listed drug is withdrawn, and will propose
p.000158: to withdraw such drugs. Holders of approved applications for the identified drug products will be provided notice
p.000158: and an opportunity to respond to the proposed withdrawal of their applications as described in para- graphs (b)
p.000158: and (c) of this section.
p.000158: (b)(1) The published notice of oppor-
p.000158: tunity for hearing on the withdrawal of the listed drug will serve as notice to holders of identified
p.000158: abbreviated new drug applications of the grounds for the proposed withdrawal.
p.000158: (2) Holders of applications for drug products identified in the notice of op- portunity for hearing may
p.000158: submit writ- ten comments on the notice of oppor- tunity for hearing issued on the pro- posed withdrawal
p.000158: of the listed drug. If an abbreviated new drug application holder submits comments on the notice
p.000158:
p.000158: of opportunity for hearing and a hear- ing is granted, the abbreviated new drug application holder
p.000158: may partici- pate in the hearing as a nonparty par- ticipant as provided for in § 12.89 of this chapter.
p.000158: (3) Except as provided in paragraphs
p.000158: (c) and (d) of this section, the approval of an abbreviated new drug application for a drug product identified in the
p.000158: no- tice of opportunity for hearing on the withdrawal of a listed drug will be withdrawn when the
p.000158: agency has com- pleted the withdrawal of approval of the listed drug.
p.000158: (c)(1) If the holder of an application for a drug identified in the notice of op- portunity for hearing has
p.000158: submitted timely comments but does not have an opportunity to participate in a hearing because a hearing is not
p.000158: requested or is settled, the submitted comments will be considered by the agency, which will issue an initial
p.000158: decision. The initial de- cision will respond to the comments, and contain the agency’s decision
p.000158: whether there are grounds to withdraw approval of the listed drug and of the abbreviated new drug
p.000158: applications on which timely comments were sub- mitted. The initial decision will be sent to
p.000158: each abbreviated new drug ap- plication holder that has submitted comments.
p.000158: (2) Abbreviated new drug application holders to whom the initial decision was sent may, within 30
p.000158: days of the issuance of the initial decision, submit written objections.
p.000158: (3) The agency may, at its discretion, hold a limited oral hearing to resolve dispositive factual issues that
p.000158: cannot be resolved on the basis of written sub- missions.
p.000158: (4) If there are no timely objections to the initial decision, it will become final at the expiration of 30
p.000158: days.
p.000158: (5) If timely objections are sub- mitted, they will be reviewed and re- sponded to in a final
p.000158: decision.
p.000158: (6) The written comments received, the initial decision, the evidence relied on in the comments and in the
p.000158: initial decision, the objections to the initial decision, and, if a limited oral hearing has been held,
p.000158: the transcript of that hearing and any documents submitted therein, shall form the record upon
p.000159: 159
p.000159:
p.000159:
p.000159:
p.000159:
p.000159:
p.000159:
p.000159:
p.000159:
p.000159: § 314.152
p.000159: which the agency shall make a final decision.
p.000159: (7) Except as provided in paragraph
p.000159: (d) of this section, any abbreviated new drug application whose holder sub- mitted comments on the
p.000159: notice of op- portunity for hearing shall be with- drawn upon the issuance of a final deci- sion
p.000159: concluding that the listed drug should be withdrawn for grounds as de- scribed in § 314.150(a). The final
p.000159: decision shall be in writing and shall constitute final agency action, reviewable in a ju- dicial proceeding.
p.000159: (8) Documents in the record will be publicly available in accordance with
p.000159: § 10.20(j) of this chapter. Documents available for examination or copying will be placed on public
p.000159: display in the Division of Dockets Management (HFA–305), Food and Drug Administra- tion, room.
p.000159: 1–23, 12420 Parklawn Dr., Rockville, MD 20857, promptly upon re- ceipt in that office.
p.000159: (d) If the agency determines, based upon information submitted by the holder of an abbreviated new
p.000159: drug ap- plication, that the grounds for with- drawal of the listed drug are not appli- cable to a drug
p.000159: identified in the notice of opportunity for hearing, the final de- cision will state that the approval of the
p.000159: abbreviated new drug application for such drug is not withdrawn.
p.000159: [57 FR 17994, Apr. 28, 1992]
p.000159:
p.000159: § 314.152 Notice of withdrawal of ap- proval of an application or abbre- viated application for a new drug.
p.000159: If the Food and Drug Administration withdraws approval of an application or abbreviated application for a
p.000159: new drug, FDA will publish a notice in the FEDERAL REGISTER announcing the withdrawal of approval.
p.000159: If the applica- tion or abbreviated application was withdrawn for grounds described in
p.000159: § 314.150(a) or § 314.151, the notice will announce the removal of the drug from the list of approved
p.000159: drugs published under section 505(j)(6) of the act and shall satisfy the requirement of
p.000159: § 314.162(b).
p.000159: [57 FR 17994, Apr. 28, 1992]
p.000159: 21 CFR Ch. I (4–1–12 Edition)
p.000159:
p.000159: § 314.153 Suspension of approval of an abbreviated new drug application.
p.000159: (a) Suspension of approval. The ap- proval of an abbreviated new drug ap- plication approved
p.000159: under § 314.105(d) shall be suspended for the period stated when:
p.000159: (1) The Secretary of the Department of Health and Human Services, under the imminent hazard authority of
p.000159: sec- tion 505(e) of the act or the authority of this paragraph, suspends approval of a listed drug referred
p.000159: to in the abbre- viated new drug application, for the pe- riod of the suspension;
p.000159: (2) The agency, in the notice de- scribed in paragraph (b) of this section, or in any subsequent
p.000159: written notice given an abbreviated new drug applica- tion holder by the agency, concludes that the risk of
p.000159: continued marketing and use of the drug is inappropriate, pending completion of proceedings to withdraw or
p.000159: suspend approval under
p.000159: § 314.151 or paragraph (b) of this sec- tion; or
p.000159: (3) The agency, under the procedures set forth in paragraph (b) of this sec- tion, issues a final decision
p.000159: stating the determination that the abbreviated ap- plication is suspended because the list- ed drug on which the
p.000159: approval of the abbreviated new drug application de- pends has been withdrawn from sale for reasons of safety or
p.000159: effectiveness or has been suspended under paragraph (b) of this section. The suspension will take effect on
p.000159: the date stated in the decision and will remain in effect until the agency determines that the
p.000159: marketing of the drug has resumed or that the withdrawal is not for safety or effec- tiveness reasons.
p.000159: (b) Procedures for suspension of abbre-
p.000159: viated ne drug applications hen a list- ed drug is voluntarily ithdra n for safe- ty or effectiveness
p.000159: reasons. (1) If a listed drug is voluntarily withdrawn from sale, and the agency determines that the
p.000159: withdrawal from sale was for rea- sons of safety or effectiveness, the agency will send each holder
p.000159: of an ap- proved abbreviated new drug applica- tion that is subject to suspension as a result of this
p.000159: determination a copy of the agency’s initial decision setting forth the reasons for the determina-
p.000159: tion. The initial decision will also be placed on file with the Division of
p.000160: 160
p.000160:
p.000160:
p.000160:
p.000160:
p.000160:
p.000160:
p.000160:
p.000160: Food and Drug Administration, HHS § 314.161
p.000160:
p.000160:
p.000160: Dockets Management (HFA–305), Food and Drug Administration, room 1–23, 12420 Parklawn Dr.,
p.000160: Rockville, MD 20857.
p.000160: (2) Each abbreviated new drug appli- cation holder will have 30 days from the issuance of the initial
p.000160: decision to present, in writing, comments and in- formation bearing on the initial deci- sion. If no
p.000160: comments or information is received, the initial decision will be- come final at the expiration of 30 days.
p.000160: (3) Comments and information re- ceived within 30 days of the issuance of the initial decision will be
p.000160: considered by the agency and responded to in a final decision.
p.000160: (4) The agency may, in its discretion, hold a limited oral hearing to resolve dispositive factual issues that
p.000160: cannot be resolved on the basis of written sub- missions.
p.000160: (5) If the final decision affirms the agency’s initial decision that the listed drug was withdrawn for reasons of
p.000160: safe- ty or effectiveness, the decision will be published in the FEDERAL REGISTER in compliance with § 314.152,
p.000160: and will, ex- cept as provided in paragraph (b)(6) of this section, suspend approval of all ab- breviated new
p.000160: drug applications identi- fied under paragraph (b)(1) of this sec- tion and remove from the list the listed drug
p.000160: and any drug whose approval was suspended under this paragraph. The notice will satisfy the
p.000160: requirement of
p.000160: § 314.162(b). The agency’s final decision
p.000160: and copies of materials on which it re- lies will also be filed with the Division of Dockets Management
p.000160: (address in paragraph (b)(1) of this section).
p.000160: (6) If the agency determines in its final decision that the listed drug was withdrawn for reasons of
p.000160: safety or ef- fectiveness but, based upon informa- tion submitted by the holder of an ab- breviated
p.000160: new drug application, also determines that the reasons for the withdrawal of the listed drug are
p.000160: not relevant to the safety and effectiveness of the drug subject to such abbreviated new drug application, the final
p.000160: decision will state that the approval of such ab- breviated new drug application is not suspended.
p.000160: (7) Documents in the record will be
p.000160: publicly available in accordance with
p.000160: § 10.20(j) of this chapter. Documents available for examination or copying
p.000160:
p.000160: will be placed on public display in the Division of Dockets Management (ad- dress in paragraph (b)(1) of
p.000160: this sec- tion) promptly upon receipt in that of- fice.
p.000160: [57 FR 17995, Apr. 28, 1992]
p.000160:
p.000160: § 314.160 Approval of an application or abbreviated application for which approval was previously refused,
p.000160: suspended, or withdrawn.
p.000160: Upon the Food and Drug Administra- tion’s own initiative or upon request of an applicant, FDA may, on the basis of new
p.000160: data, approve an application or ab- breviated application which it had pre- viously refused, suspended, or
p.000160: with- drawn approval. FDA will publish a no- tice in the FEDERAL REGISTER announc- ing the approval.
p.000160: [57 FR 17995, Apr. 28, 1992]
p.000160:
p.000160: § 314.161 Determination of reasons for voluntary withdrawal of a listed drug.
p.000160: (a) A determination whether a listed drug that has been voluntarily with- drawn from sale was
p.000160: withdrawn for safety or effectiveness reasons may be made by the agency at any time after the drug
p.000160: has been voluntarily with- drawn from sale, but must be made:
p.000160: (1) Prior to approving an abbreviated new drug application that refers to the listed drug;
p.000160: (2) Whenever a listed drug is volun- tarily withdrawn from sale and abbre- viated new drug applications
p.000160: that re- ferred to the listed drug have been ap- proved; and
p.000160: (3) When a person petitions for such a determination under §§ 10.25(a) and 10.30 of this chapter.
p.000160: (b) Any person may petition under
p.000160: §§ 10.25(a) and 10.30 of this chapter for a determination whether a listed drug has been voluntarily
p.000160: withdrawn for safety or effectiveness reasons. Any such petition must contain all evidence available to the
p.000160: petitioner concerning the reason that the drug is withdrawn from sale.
p.000160: (c) If the agency determines that a
p.000160: listed drug is withdrawn from sale for safety or effectiveness reasons, the agency will, except as
p.000160: provided in para- graph (d) of this section, publish a no- tice of the determination in the FED- ERAL
p.000160: REGISTER.
p.000161: 161
p.000161:
p.000161:
p.000161:
p.000161:
p.000161:
p.000161:
p.000161:
p.000161:
p.000161: § 314.162
p.000161: (d) If the agency determines under paragraph (a) of this section that a listed drug is withdrawn
p.000161: from sale for safety and effectiveness reasons and there are approved abbreviated new drug
p.000161: applications that are subject to suspension under section 505(j)(5) of the act, FDA will initiate a proceeding
p.000161: in accordance with § 314.153(b).
p.000161: (e) A drug that the agency deter- mines is withdrawn for safety or effec- tiveness reasons will be
p.000161: removed from the list, under § 314.162. The drug may be relisted if the agency has evidence that
p.000161: marketing of the drug has re- sumed or that the withdrawal is not for safety or effectiveness reasons. A
p.000161: de- termination that the drug is not with- drawn for safety or effectiveness rea- sons may be made at any
p.000161: time after its removal from the list, upon the agen- cy’s initiative, or upon the submission of a petition
p.000161: under §§ 10.25(a) and 10.30 of this chapter. If the agency deter- mines that the drug is not
p.000161: withdrawn for safety or effectiveness reasons, the agency shall publish a notice of this de- termination in the
p.000161: FEDERAL REGISTER. The notice will also announce that the drug is relisted, under § 314.162(c). The notice
p.000161: will also serve to reinstate ap- proval of all suspended abbreviated new drug applications that referred to
p.000161: the listed drug.
p.000161: [57 FR 17995, Apr. 28, 1992]
p.000161:
p.000161: § 314.162 Removal of a drug product from the list.
p.000161: (a) FDA will remove a previously ap- proved new drug product from the list for the period stated when:
p.000161: (1) The agency withdraws or suspends approval of a new drug application or an abbreviated new drug
p.000161: application under § 314.150(a) or § 314.151 or under the imminent hazard authority of sec- tion 505(e) of
p.000161: the act, for the same pe- riod as the withdrawal or suspension of the application; or
p.000161: (2) The agency, in accordance with the procedures in § 314.153(b) or § 314.161, issues a final decision
p.000161: stating that the listed drug was withdrawn from sale for safety or effectiveness reasons, or suspended
p.000161: under § 314.153(b), until the agency determines that the withdrawal from the market has ceased or is not for
p.000161: safety or effectiveness reasons.
p.000161: 21 CFR Ch. I (4–1–12 Edition)
p.000161: (b) FDA will publish in the FEDERAL REGISTER a notice announcing the re- moval of a drug from the list.
p.000161: (c) At the end of the period specified in paragraph (a)(1) or (a)(2) of this sec- tion, FDA will
p.000161: relist a drug that has been removed from the list. The agency will publish in the FEDERAL REGISTER a notice
p.000161: announcing the relisting of the drug.
p.000161: [57 FR 17996, Apr. 28, 1992]
p.000161:
p.000161: § 314.170 Adulteration and mis- branding of an approved drug.
p.000161: All drugs, including those the Food and Drug Administration approves under section 505 of the act
p.000161: and this part, are subject to the adulteration and misbranding provisions in sections 501, 502, and 503
p.000161: of the act. FDA is au- thorized to regulate approved new drugs by regulations issued through in-
p.000161: formal rulemaking under sections 501, 502, and 503 of the act.
p.000161: [50 FR 7493, Feb. 22, 1985. Redesignated at 57
p.000161: FR 17983, Apr. 28, 1992, and amended at 64 FR
p.000161: 402, Jan. 5, 1999]
p.000161:
p.000161: Subpart E—Hearing Procedures for New Drugs
p.000161: SOURCE: 50 FR 7493, Feb. 22, 1985, unless
p.000161: otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992.
p.000161:
p.000161: § 314.200 Notice of opportunity for hearing; notice of participation and request for hearing; grant or
p.000161: denial of hearing.
p.000161: (a) Notice of opportunity for hearing. The Director of the Center for Drug Evaluation and Research,
p.000161: Food and Drug Administration, will give the ap- plicant, and all other persons who man- ufacture or
p.000161: distribute identical, re- lated, or similar drug products as de- fined in § 310.6 of this chapter,
p.000161: notice and an opportunity for a hearing on the Center’s proposal to refuse to approve an application or to
p.000161: withdraw the ap- proval of an application or abbreviated application under section 505(e) of the act. The
p.000161: notice will state the reasons for the action and the proposed grounds for the order.
p.000161: (1) The notice may be general (that is, simply summarizing in a general way the information
p.000161: resulting in the
p.000162: 162
p.000162:
p.000162:
p.000162:
p.000162:
p.000162:
p.000162:
p.000162:
p.000162: Food and Drug Administration, HHS § 314.200
p.000162:
p.000162:
p.000162: notice) or specific (that is, either refer- ring to specific requirements in the statute and regulations
p.000162: with which there is a lack of compliance, or pro- viding a detailed description and anal- ysis of the
p.000162: specific facts resulting in the notice).
p.000162: (2) FDA will publish the notice in the FEDERAL REGISTER and will state that the applicant, and other persons
p.000162: sub- ject to the notice under § 310.6, who wishes to participate in a hearing, has 30 days after
p.000162: the date of publication of the notice to file a written notice of participation and request for hearing.
p.000162: The applicant, or other persons subject to the notice under § 310.6, who fails to file a written notice of
p.000162: participation and request for hearing within 30 days, waives the opportunity for a hearing.
p.000162: (3) It is the responsibility of every manufacturer and distributor of a drug product to review every notice
p.000162: of op- portunity for a hearing published in the FEDERAL REGISTER to determine whether it covers
p.000162: any drug product that person manufactures or distrib- utes. Any person may request an opin- ion of
p.000162: the applicability of a notice to a specific product that may be identical, related, or similar to a product
p.000162: listed in a notice by writing to the Division of New Drugs and Labeling Compli- ance, Office of
p.000162: Compliance, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New
p.000162: Hampshire Ave., Silver Spring, MD 20993–0002. A person shall request an opinion within 30 days of
p.000162: the date of publication of the notice to be eligible for an opportunity for a hearing under the notice.
p.000162: If a person requests an opin- ion, that person’s time for filing an ap- pearance and request for a hearing and
p.000162: supporting studies and analyses begins on the date the person receives the opinion from FDA.
p.000162: (b) FDA will provide the notice of op- portunity for a hearing to applicants and to other persons subject to the
p.000162: no- tice under § 310.6, as follows:
p.000162: (1) To any person who has submitted an application or abbreviated applica- tion, by delivering the notice in
p.000162: person or by sending it by registered or cer- tified mail to the last address shown in the application or
p.000162: abbreviated applica- tion.
p.000162:
p.000162: (2) To any person who has not sub- mitted an application or abbreviated application but who is
p.000162: subject to the notice under § 310.6 of this chapter, by publication of the notice in the FED- ERAL
p.000162: REGISTER.
p.000162: (c)(1) Notice of participation and re-
p.000162: quest for a hearing, and submission of studies and comments. The applicant, or any other person
p.000162: subject to the notice under § 310.6, who wishes to participate in a hearing, shall file with the Divi-
p.000162: sion of Dockets Management (HFA– 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
p.000162: Rockville, MD 20852, (i) within 30 days after the date of the publication of the notice (or of the date of
p.000162: receipt of an opinion re- quested under paragraph (a)(3) of this section) a written notice of participa-
p.000162: tion and request for a hearing and (ii) within 60 days after the date of publi- cation of the notice,
p.000162: unless a different period of time is specified in the notice of opportunity for a hearing, the stud- ies on
p.000162: which the person relies to justify a hearing as specified in paragraph (d) of this section. The applicant,
p.000162: or other person, may incorporate by reference the raw data underlying a study if the data were previously
p.000162: submitted to FDA as part of an application, abbreviated application, or other report.
p.000162: (2) FDA will not consider data or
p.000162: analyses submitted after 60 days in de- termining whether a hearing is war- ranted unless they
p.000162: are derived from well-controlled studies begun before the date of the notice of opportunity for hearing
p.000162: and the results of the stud- ies were not available within 60 days after the date of publication of the
p.000162: no- tice. Nevertheless, FDA may consider other studies on the basis of a showing by the person requesting a
p.000162: hearing of inadvertent omission and hardship. The person requesting a hearing shall list in the request
p.000162: for hearing all stud- ies in progress, the results of which the person intends later to submit in sup- port of
p.000162: the request for a hearing. The person shall submit under paragraph (c)(1)(ii) of this section a copy
p.000162: of the complete protocol, a list of the partici- pating investigators, and a brief status report of the studies.
p.000162: (3) Any other interested person who
p.000162: is not subject to the notice of oppor- tunity for a hearing may also submit
p.000163: 163
p.000163:
p.000163:
p.000163:
p.000163:
p.000163:
p.000163:
p.000163:
p.000163:
p.000163: § 314.200
p.000163: comments on the proposal to withdraw approval of the application or abbre- viated application. The comments
p.000163: are requested to be submitted within the time and under the conditions specified in this section.
p.000163: (d) The person requesting a hearing is required to submit under paragraph (c)(1)(ii) of this section the
p.000163: studies (in- cluding all protocols and underlying raw data) on which the person relies to justify a hearing
p.000163: with respect to the drug product. Except, a person who re- quests a hearing on the refusal to ap- prove
p.000163: an application is not required to submit additional studies and analyses if the studies upon which the person
p.000163: re- lies have been submitted in the appli- cation and in the format and con- taining the summaries
p.000163: required under
p.000163: § 314.50.
p.000163: (1) If the grounds for FDA’s proposed action concern the effectiveness of the drug, each request for
p.000163: hearing is re- quired to be supported only by ade- quate and well-controlled clinical stud- ies meeting
p.000163: all of the precise require- ments of § 314.126 and, for combination drug products, § 300.50, or by other stud-
p.000163: ies not meeting those requirements for which a waiver has been previously granted by FDA under § 314.126.
p.000163: Each person requesting a hearing shall sub- mit all adequate and well-controlled clinical studies on the
p.000163: drug product, in- cluding any unfavorable analyses, views, or judgments with respect to the studies. No
p.000163: other data, information, or studies may be submitted.
p.000163: (2) The submission is required to in-
p.000163: clude a factual analysis of all the stud- ies submitted. If the grounds for FDA’s proposed action concern the
p.000163: effective- ness of the drug, the analysis is re- quired to specify how each study ac- cords, on a
p.000163: point-by-point basis, with each criterion required for an adequate well-controlled clinical investigation
p.000163: established under § 314.126 and, if the product is a combination drug product, with each of the
p.000163: requirements for a combination drug established in
p.000163: § 300.50, or the study is required to be accompanied by an appropriate waiver previously granted by FDA.
p.000163: If a study concerns a drug or dosage form or con- dition of use or mode of administration other than the one in
p.000163: question, that fact is required to be clearly stated.
p.000163: 21 CFR Ch. I (4–1–12 Edition)
p.000163: Any study conducted on the final mar- keted form of the drug product is re- quired to be clearly
p.000163: identified.
p.000163: (3) Each person requesting a hearing shall submit an analysis of the data upon which the person relies,
p.000163: except that the required information relating either to safety or to effectiveness may be omitted if the notice of
p.000163: opportunity for hearing does not raise any issue with respect to that aspect of the drug; information on
p.000163: compliance with § 300.50 may be omitted if the drug product is not a combination drug product. A fi-
p.000163: nancial certification or disclosure statement or both as required by part 54 of this chapter must
p.000163: accompany all clinical data submitted. FDA can most efficiently consider submissions made in the following format.
p.000163: I. Safety data.
p.000163: A. Animal safety data.
p.000163: 1. Individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: 2. Combinations of the individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: B. Human safety data.
p.000163: 1. Individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: c. Documented case reports.
p.000163: d. Pertinent marketing experiences that may influence a determination about the safety of each
p.000163: individual active component.
p.000163: 2. Combinations of the individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: c. Documented case reports.
p.000163: d. Pertinent marketing experiences that may influence a determination about the safety of each
p.000163: individual active component.
p.000163: II. Effectiveness data.
p.000163: A. Individual active components: Con- trolled studies, with an analysis showing clearly how
p.000163: each study satisfies, on a point- by-point basis, each of the criteria required by § 314.126.
p.000163: B. Combinations of individual active com- ponents.
p.000163: 1. Controlled studies with an analysis showing clearly how each study satisfies on a point-by-point
p.000163: basis, each of the criteria required by § 314.126.
p.000163: 2. An analysis showing clearly how each re- quirement of § 300.50 has been satisfied.
p.000164: 164
p.000164:
p.000164:
p.000164:
p.000164:
p.000164:
p.000164:
p.000164:
p.000164: Food and Drug Administration, HHS § 314.200
p.000164:
p.000164:
p.000164: III. A summary of the data and views set- ting forth the medical rationale and purpose for the drug and its
p.000164: ingredients and the sci- entific basis for the conclusion that the drug and its ingredients have been
p.000164: proven safe and/or effective for the intended use. If there is an absence of controlled studies in the ma- terial
p.000164: submitted or the requirements of any element of § 300.50 or § 314.126 have not been fully met, that fact
p.000164: is required to be stated clearly and a waiver obtained under § 314.126 is required to be submitted.
p.000164: IV. A statement signed by the person re- sponsible for such submission that it in- cludes in full
p.000164: (or incorporates by reference as permitted in § 314.200(c)(2)) all studies and in- formation specified in § 314.200(d).
p.000164: (WARNING: A willfully false statement is a criminal offense, 18 U.S.C. 1001.)
p.000164: (e) Contentions that a drug product is not subject to the ne drug requirements. A notice of opportunity
p.000164: for a hearing encompasses all issues relating to the legal status of each drug product sub- ject to it,
p.000164: including identical, related, and similar drug products as defined in
p.000164: § 310.6. A notice of appearance and re- quest for a hearing under paragraph (c)(1)(i) of this
p.000164: section is required to contain any contention that the prod- uct is not a new drug because it is gen- erally
p.000164: recognized as safe and effective within the meaning of section 201(p) of the act, or because it is
p.000164: exempt from part or all of the new drug provisions of the act under the exemption for products
p.000164: marketed before June 25, 1938, contained in section 201(p) of the act or under section 107(c) of the
p.000164: Drug Amendments of 1962, or for any other reason. Each contention is required to be supported by a
p.000164: submission under paragraph (c)(1)(ii) of this section and the Commissioner of Food and Drugs will make
p.000164: an administrative deter- mination on each contention. The fail- ure of any person subject to a notice of
p.000164: opportunity for a hearing, including any person who manufactures or dis- tributes an identical,
p.000164: related, or simi- lar drug product as defined in § 310.6, to submit a notice of participation and re- quest for
p.000164: hearing or to raise all such contentions constitutes a waiver of any contentions not raised.
p.000164: (1) A contention that a drug product
p.000164: is generally recognized as safe and ef- fective within the meaning of section 201(p) of the act is
p.000164: required to be sup- ported by submission of the same quan- tity and quality of scientific evidence
p.000164:
p.000164: that is required to obtain approval of an application for the product, unless FDA has waived a
p.000164: requirement for ef- fectiveness (under § 314.126) or safety, or both. The submission should be in the
p.000164: format and with the analyses re- quired under paragraph (d) of this sec- tion. A person who fails to
p.000164: submit the required scientific evidence required under paragraph (d) waives the conten- tion. General
p.000164: recognition of safety and effectiveness shall ordinarily be based upon published studies which may be
p.000164: corroborated by unpublished studies and other data and information.
p.000164: (2) A contention that a drug product is exempt from part or all of the new drug provisions of the act
p.000164: under the ex- emption for products marketed before June 25, 1938, contained in section 201(p) of the act,
p.000164: or under section 107(c) of the Drug Amendments of 1962, is re- quired to be supported by evidence of past
p.000164: and present quantitative for- mulas, labeling, and evidence of mar- keting. A person who makes
p.000164: such a contention should submit the formulas, labeling, and evidence of marketing in the following format.
p.000164: I. Formulation.
p.000164: A. A copy of each pertinent document or record to establish the exact quantitative formulation of
p.000164: the drug (both active and in- active ingredients) on the date of initial marketing of the drug.
p.000164: B. A statement whether such formulation has at any subsequent time been changed in any manner. If any
p.000164: such change has been made, the exact date, nature, and rationale for each change in formulation,
p.000164: including any deletion or change in the concentration of any active ingredient and/or inactive in-
p.000164: gredient, should be stated, together with a copy of each pertinent document or record to establish the date
p.000164: and nature of each such change, including, but not limited to, the formula which resulted from
p.000164: each such change. If no such change has been made, a copy of representative documents or records
p.000164: showing the formula at representative points in time should be submitted to support the statement.
p.000164: II. Labeling.
p.000164: A. A copy of each pertinent document or record to establish the identity of each item of written, printed, or
p.000164: graphic matter used as labeling on the date the drug was initially marketed.
p.000164: B. A statement whether such labeling has at any subsequent time been discontinued or changed in any manner.
p.000164: If such discontinu- ance or change has been made, the exact
p.000165: 165
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165: § 314.200
p.000165: date, nature, and rationale for each dis- continuance or change and a copy of each pertinent
p.000165: document or record to establish each such discontinuance or change should be submitted, including, but
p.000165: not limited to, the labeling which resulted from each such discontinuance or change. If no such
p.000165: dis- continuance or change has been made, a copy of representative documents or records show- ing labeling at
p.000165: representative points in time should be submitted to support the state- ment.
p.000165: III. Marketing.
p.000165: A. A copy of each pertinent document or record to establish the exact date the drug was initially
p.000165: marketed.
p.000165: B. A statement whether such marketing has at any subsequent time been discon- tinued. If such
p.000165: marketing has been discon- tinued, the exact date of each such dis- continuance should be
p.000165: submitted, together with a copy of each pertinent document or record to establish each such date.
p.000165: IV. Verification.
p.000165: A statement signed by the person respon- sible for such submission, that all appro- priate records
p.000165: have been searched and to the best of that person’s knowledge and belief it includes a true and accurate
p.000165: presentation of the facts.
p.000165: (WARNING: A willfully false statement is a criminal offense, 18 U.S.C. 1001.)
p.000165: (3) The Food and Drug Administra- tion will not find a drug product, in- cluding any active ingredient,
p.000165: which is identical, related, or similar, as de- scribed in § 310.6, to a drug product, in- cluding any active
p.000165: ingredient for which an application is or at any time has been effective or deemed approved, or approved
p.000165: under section 505 of the act, to be exempt from part or all of the new drug provisions of the act.
p.000165: (4) A contention that a drug product
p.000165: is not a new drug for any other reason is required to be supported by submis- sion of the factual
p.000165: records, data, and information that are necessary and ap- propriate to support the contention.
p.000165: (5) It is the responsibility of every person who manufactures or distrib- utes a drug product in
p.000165: reliance upon a ‘‘grandfather’’ provision of the act to maintain files that contain the data and
p.000165: information necessary fully to doc- ument and support that status.
p.000165: (f) Separation of functions. Separation of functions commences upon receipt of a request for hearing. The
p.000165: Director of the Center for Drug Evaluation and Re- search, Food and Drug Administration, will prepare an analysis
p.000165: of the request
p.000165: 21 CFR Ch. I (4–1–12 Edition)
p.000165: and a proposed order ruling on the matter. The analysis and proposed order, the request for
p.000165: hearing, and any proposed order denying a hearing and response under paragraph (g) (2) or (3) of this
p.000165: section will be submitted to the Office of the Commissioner of Food and Drugs for review and decision. When the
p.000165: Center for Drug Evaluation and Re- search recommends denial of a hearing on all issues on which a hearing
p.000165: is re- quested, no representative of the Cen- ter will participate or advise in the re- view and decision
p.000165: by the Commis- sioner. When the Center for Drug Eval- uation and Research recommends that a hearing be
p.000165: granted on one or more issues on which a hearing is requested, separation of functions terminates as to
p.000165: those issues, and representatives of the Center may participate or advise in the review and decision by the
p.000165: Com- missioner on those issues. The Com- missioner may modify the text of the issues, but may not
p.000165: deny a hearing on those issues. Separation of functions continues with respect to issues on which
p.000165: the Center for Drug Evaluation and Research has recommended denial of a hearing. The Commissioner
p.000165: will neither evaluate nor rule on the Cen- ter’s recommendation on such issues and such issues will
p.000165: not be included in the notice of hearing. Participants in the hearing may make a motion to the presiding
p.000165: officer for the inclusion of any such issue in the hearing. The rul- ing on such a motion is subject to
p.000165: re- view in accordance with § 12.35(b). Fail- ure to so move constitutes a waiver of the right to a hearing on
p.000165: such an issue. Separation of functions on all issues resumes upon issuance of a notice of hearing. The
p.000165: Office of the General Counsel, Department of Health and Human Services, will observe the same separation
p.000165: of functions.
p.000165: (g) Summary judgment. A person who
p.000165: requests a hearing may not rely upon allegations or denials but is required to set forth specific facts
p.000165: showing that there is a genuine and substantial issue of fact that requires a hearing with re- spect to a particular
p.000165: drug product spec- ified in the request for hearing.
p.000165: (1) Where a specific notice of oppor- tunity for hearing (as defined in para- graph (a)(1) of this section)
p.000165: is used, the Commissioner will enter summary
p.000166: 166
p.000166:
p.000166:
p.000166:
p.000166:
p.000166:
p.000166:
p.000166:
p.000166: Food and Drug Administration, HHS § 314.200
p.000166:
p.000166:
p.000166: judgment against a person who re- quests a hearing, making findings and conclusions, denying a
p.000166: hearing, if it conclusively appears from the face of the data, information, and factual analyses
p.000166: in the request for the hearing that there is no genuine and substan- tial issue of fact which precludes
p.000166: the refusal to approve the application or abbreviated application or the with- drawal of approval of the
p.000166: application or abbreviated application; for example, no adequate and well-controlled clin- ical
p.000166: investigations meeting each of the precise elements of § 314.126 and, for a combination drug product, §
p.000166: 300.50 of this chapter, showing effectiveness have been identified. Any order enter- ing summary
p.000166: judgment is required to set forth the Commissioner’s findings and conclusions in detail and is re-
p.000166: quired to specify why each study sub- mitted fails to meet the requirements of the statute and
p.000166: regulations or why the request for hearing does not raise a genuine and substantial issue of fact.
p.000166: (2) When following a general notice of
p.000166: opportunity for a hearing (as defined in paragraph (a)(1) of this section) the Di- rector of the Center for Drug
p.000166: Evalua- tion and Research concludes that sum- mary judgment against a person re- questing a hearing
p.000166: should be consid- ered, the Director will serve upon the person requesting a hearing by reg- istered
p.000166: mail a proposed order denying a hearing. This person has 60 days after receipt of the proposed order to
p.000166: re- spond with sufficient data, informa- tion, and analyses to demonstrate that there is a genuine and
p.000166: substantial issue of fact which justifies a hearing.
p.000166: (3) When following a general or spe-
p.000166: cific notice of opportunity for a hear- ing a person requesting a hearing sub- mits data or information
p.000166: of a type re- quired by the statute and regulations, and the Director of the Center for Drug Evaluation and
p.000166: Research concludes that summary judgment against the person should be considered, the Direc- tor will
p.000166: serve upon the person by reg- istered mail a proposed order denying a hearing. The person has 60 days after
p.000166: receipt of the proposed order to re- spond with sufficient data, informa- tion, and analyses to
p.000166: demonstrate that there is a genuine and substantial issue of fact which justifies a hearing.
p.000166:
p.000166: (4) If review of the data, information, and analyses submitted show that the grounds cited in the notice
p.000166: are not valid, for example, that substantial evidence of effectiveness exists, the Commissioner
p.000166: will enter summary judgment for the person requesting the hearing, and rescind the notice of op- portunity
p.000166: for hearing.
p.000166: (5) If the Commissioner grants a hearing, it will begin within 90 days after the expiration of the
p.000166: time for re- questing the hearing unless the parties otherwise agree in the case of denial of approval, and as
p.000166: soon as practicable in the case of withdrawal of approval.
p.000166: (6) The Commissioner will grant a hearing if there exists a genuine and substantial issue of fact
p.000166: or if the Com- missioner concludes that a hearing would otherwise be in the public inter- est.
p.000166: (7) If the manufacturer or distributor of an identical, related, or similar drug product requests and is granted a
p.000166: hear- ing, the hearing may consider whether the product is in fact identical, related, or similar to the drug
p.000166: product named in the notice of opportunity for a hear- ing.
p.000166: (8) A request for a hearing, and any subsequent grant or denial of a hear- ing, applies only to the
p.000166: drug products named in such documents.
p.000166: (h) FDA will issue a notice with- drawing approval and declaring all products unlawful for
p.000166: drug products subject to a notice of opportunity for a hearing, including any identical, re- lated, or
p.000166: similar drug product under
p.000166: § 310.6, for which an opportunity for a hearing is waived or for which a hear- ing is denied. The
p.000166: Commissioner may defer or stay the action pending a rul- ing on any related request for a hear- ing or
p.000166: pending any related hearing or other administrative or judicial pro- ceeding.
p.000166: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000166: 1985, as amended at 50 FR 21238, May 23, 1985;
p.000166: 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28,
p.000166: 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252,
p.000166: Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 68 FR
p.000166: 24879, May 9, 2003; 69 FR 48775, Aug. 11, 2004;
p.000166: 74 FR 13113, Mar. 26, 2009]
p.000167: 167
p.000167:
p.000167:
p.000167:
p.000167:
p.000167:
p.000167:
p.000167:
p.000167:
p.000167: § 314.201
p.000167: § 314.201 Procedure for hearings.
p.000167: Parts 10 through 16 apply to hearings relating to new drugs under section 505
p.000167: (d) and (e) of the act.
p.000167: § 314.235 Judicial review.
p.000167: (a) The Commissioner of Food and Drugs will certify the transcript and record. In any case in which
p.000167: the Com- missioner enters an order without a hearing under § 314.200(g), the record certified by
p.000167: the Commissioner is re- quired to include the requests for hear- ing together with the data and infor-
p.000167: mation submitted and the Commis- sioner’s findings and conclusion.
p.000167: (b) A manufacturer or distributor of
p.000167: an identical, related, or similar drug product under § 310.6 may seek judicial review of an order
p.000167: withdrawing ap- proval of a new drug application, whether or not a hearing has been held, in a
p.000167: United States court of appeals under section 505(h) of the act.
p.000167: Subpart F [Reserved]
p.000167: Subpart G—Miscellaneous Provisions
p.000167: SOURCE: 50 FR 7493, Feb. 22, 1985, unless
p.000167: otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992.
p.000167:
p.000167: § 314.410 Imports and exports of new drugs.
p.000167: (a) Imports. (1) A new drug may be im- ported into the United States if: (i) It is the subject of an
p.000167: approved applica- tion under this part; or (ii) it complies with the regulations pertaining to in-
p.000167: vestigational new drugs under part 312; and it complies with the general regu- lations pertaining to
p.000167: imports under subpart E of part 1.
p.000167: (2) A drug substance intended for use in the manufacture, processing, or re- packing of a new drug may be imported
p.000167: into the United States if it complies with the labeling exemption in § 201.122 pertaining to shipments of
p.000167: drug sub- stances in domestic commerce.
p.000167: (b) Exports. (1) A new drug may be ex- ported if it is the subject of an ap- proved application under
p.000167: this part or it complies with the regulations per- taining to investigational new drugs under part
p.000167: 312.
p.000167: 21 CFR Ch. I (4–1–12 Edition)
p.000167: (2) A new drug substance that is cov- ered by an application approved under this part for use in the manufacture
p.000167: of an approved drug product may be ex- ported by the applicant or any person listed as a supplier in the
p.000167: approved ap- plication, provided the drug substance intended for export meets the speci- fication of,
p.000167: and is shipped with a copy of the labeling required for, the ap- proved drug product.
p.000167: (3) Insulin or an antibiotic drug may be exported without regard to the re- quirements in section 802
p.000167: of the act if the insulin or antibiotic drug meets the requirements of section 801(e)(1) of the act.
p.000167: [50 FR 7493, Feb. 22, 1985, unless otherwise
p.000167: noted. Redesignated at 57 FR 17983, Apr. 28,
p.000167: 1992, and amended at 64 FR 402, Jan. 5, 1999;
p.000167: 69 FR 18766, Apr. 8, 2004]
p.000167: § 314.420 Drug master files.
p.000167: (a) A drug master file is a submission of information to the Food and Drug Administration by a person (the
p.000167: drug master file holder) who intends it to be used for one of the following purposes: To permit the holder
p.000167: to incorporate the information by reference when the holder submits an investigational new drug
p.000167: application under part 312 or sub- mits an application or an abbreviated application or an amendment or
p.000167: sup- plement to them under this part, or to permit the holder to authorize other persons to rely on the
p.000167: information to support a submission to FDA without the holder having to disclose the infor- mation to the
p.000167: person. FDA ordinarily neither independently reviews drug master files nor approves or dis-
p.000167: approves submissions to a drug master file. Instead, the agency customarily reviews the information
p.000167: only in the context of an application under part 312 or this part. A drug master file may contain
p.000167: information of the kind re- quired for any submission to the agen- cy, including information about
p.000167: the following:
p.000167: (1) [Reserved]
p.000167: (2) Drug substance, drug substance intermediate, and materials used in their preparation, or drug
p.000167: product;
p.000167: (3) Packaging materials;
p.000167: (4) Excipient, colorant, flavor, es- sence, or materials used in their prepa- ration;
p.000168: 168
p.000168:
p.000168:
p.000168:
p.000168:
p.000168:
p.000168:
p.000168:
p.000168: Food and Drug Administration, HHS § 314.430
p.000168:
p.000168:
p.000168: (5) FDA-accepted reference informa- tion. (A person wishing to submit in- formation and supporting data
p.000168: in a drug master file (DMF) that is not cov- ered by Types II through IV DMF’s must first submit a
p.000168: letter of intent to the Drug Master File Staff, Food and Drug Administration, 5901–B
p.000168: Ammendale Rd., Beltsville, MD 20705– 1266.) FDA will then contact the person to discuss the proposed submission.
p.000168: (b) An investigational new drug ap- plication or an application, abbre- viated application, amendment,
p.000168: or sup- plement may incorporate by reference all or part of the contents of any drug master file in
p.000168: support of the submis- sion if the holder authorizes the incor- poration in writing. Each incorpora-
p.000168: tion by reference is required to de- scribe the incorporated material by name, reference number,
p.000168: volume, and page number of the drug master file.
p.000168: (c) A drug master file is required to be submitted in two copies. The agency has prepared guidance that provides
p.000168: in- formation about how to prepare a well- organized drug master file. If the drug master file holder adds,
p.000168: changes, or de- letes any information in the file, the holder shall notify in writing, each per- son authorized
p.000168: to reference that infor- mation. Any addition, change, or dele- tion of information in a drug master file
p.000168: (except the list required under paragraph (d) of this section) is re- quired to be submitted
p.000168: in two copies and to describe by name, reference number, volume, and page number the information
p.000168: affected in the drug mas- ter file.
p.000168: (d) The drug master file is required to contain a complete list of each person currently authorized to
p.000168: incorporate by reference any information in the file, identifying by name, reference number, volume, and page
p.000168: number the informa- tion that each person is authorized to incorporate. If the holder restricts the
p.000168: authorization to particular drug prod- ucts, the list is required to include the name of each drug product and
p.000168: the ap- plication number, if known, to which the authorization applies.
p.000168: (e) The public availability of data and information in a drug master file, including the availability
p.000168: of data and information in the file to a person au-
p.000168:
p.000168: thorized to reference the file, is deter- mined under part 20 and § 314.430.
p.000168: [50 FR 7493, Feb. 22, 1985, as amended at 50
p.000168: FR 21238, May 23, 1985; 53 FR 33122, Aug. 30,
p.000168: 1988; 55 FR 28380, July 11, 1990; 65 FR 1780,
p.000168: Jan. 12, 2000; 65 FR 56479, Sept. 19, 2000; 67 FR
p.000168: 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004]
p.000168:
p.000168: § 314.430 Availability for public disclo- sure of data and information in an application or abbreviated
p.000168: applica- tion.
p.000168: (a) The Food and Drug Administra- tion will determine the public avail- ability of any part of an application
p.000168: or abbreviated application under this sec- tion and part 20 of this chapter. For purposes of this
p.000168: section, the applica- tion or abbreviated application in- cludes all data and information sub-
p.000168: mitted with or incorporated by ref- erence in the application or abbre- viated application,
p.000168: including investiga- tional new drug applications, drug master files under § 314.420, supple-
p.000168: ments submitted under § 314.70 or
p.000168: § 314.97, reports under § 314.80 or § 314.98,
p.000168: and other submissions. For purposes of this section, safety and effectiveness data include all studies and
p.000168: tests of a drug on animals and humans and all studies and tests of the drug for iden- tity, stability,
p.000168: purity, potency, and bioavailability.
p.000168: (b) FDA will not publicly disclose the existence of an application or abbre- viated application before an
p.000168: approval letter is sent to the applicant under
p.000168: § 314.105 or tentative approval letter is sent to the applicant under § 314.107, unless the existence
p.000168: of the application or abbreviated application has been previously publicly disclosed or ac-
p.000168: knowledged.
p.000168: (c) If the existence of an unapproved application or abbreviated application has not been publicly
p.000168: disclosed or ac- knowledged, no data or information in the application or abbreviated applica- tion is
p.000168: available for public disclosure.
p.000168: (d)(1) If the existence of an applica- tion or abbreviated application has been publicly disclosed
p.000168: or acknowl- edged before the agency sends an ap- proval letter to the applicant, no data or information
p.000168: contained in the appli- cation or abbreviated application is available for public disclosure before
p.000168: the agency sends an approval letter,
p.000169: 169
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169: § 314.430
p.000169: but the Commissioner may, in his or her discretion, disclose a summary of selected portions of the
p.000169: safety and ef- fectiveness data that are appropriate for public consideration of a specific pending issue;
p.000169: for example, for consid- eration of an open session of an FDA advisory committee.
p.000169: (2) Notwithstanding paragraph (d)(1) of this section, FDA will make avail- able to the public upon
p.000169: request the in- formation in the investigational new drug application that was required to be filed in
p.000169: Docket Number 95S–0158 in the Division of Dockets Management (HFA–305), Food and Drug Administra- tion, 5630
p.000169: Fishers Lane, rm. 1061, Rock- ville, MD 20852, for investigations in- volving an exception from informed
p.000169: consent under § 50.24 of this chapter. Persons wishing to request this infor- mation shall submit a
p.000169: request under the Freedom of Information Act.
p.000169: (e) After FDA sends an approval let- ter to the applicant, the following data and information in the
p.000169: application or abbreviated application are imme- diately available for public disclosure, unless the
p.000169: applicant shows that ex- traordinary circumstances exist. A list of approved applications and abbre-
p.000169: viated applications, entitled ‘‘Approved Drug Products with Therapeutic Equivalence Evaluations,’’ is
p.000169: available from the Government Printing Office, Washington, DC 20402. This list is up- dated monthly.
p.000169: (1) [Reserved]
p.000169: (2) If the application applies to a new drug, all safety and effectiveness data previously disclosed to the
p.000169: public as set forth in § 20.81 and a summary or summaries of the safety and effective- ness data and
p.000169: information submitted with or incorporated by reference in the application. The summaries do not
p.000169: constitute the full reports of investiga- tions under section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) on which
p.000169: the safety or effectiveness of the drug may be ap- proved. The summaries consist of the following:
p.000169: (i) For an application approved be- fore July 1, 1975, internal agency records that describe
p.000169: safety and effec- tiveness data and information, for ex- ample, a summary of the basis for ap- proval or
p.000169: internal reviews of the data
p.000169: 21 CFR Ch. I (4–1–12 Edition)
p.000169: and information, after deletion of the following:
p.000169: (a) Names and any information that would identify patients or test subjects or investigators.
p.000169: (b) Any inappropriate gratuitous comments unnecessary to an objective analysis of the data and
p.000169: information.
p.000169: (ii) For an application approved on or after July 1, 1975, a Summary Basis of Approval (SBA) document that
p.000169: con- tains a summary of the safety and ef- fectiveness data and information eval- uated by FDA during the
p.000169: drug approval process. The SBA is prepared in one of the following ways:
p.000169: (a) Before approval of the applica- tion, the applicant may prepare a draft SBA which the Center for Drug
p.000169: Evalua- tion and Research will review and may revise. The draft may be submitted with the application or
p.000169: as an amend- ment.
p.000169: (b) The Center for Drug Evaluation and Research may prepare the SBA.
p.000169: (3) A protocol for a test or study, un- less it is shown to fall within the ex- emption established for
p.000169: trade secrets and confidential commercial informa- tion in § 20.61.
p.000169: (4) Adverse reaction reports, product experience reports, consumer com- plaints, and other similar
p.000169: data and in- formation after deletion of the fol- lowing:
p.000169: (i) Names and any information that would identify the person using the product.
p.000169: (ii) Names and any information that would identify any third party involved with the report, such as a
p.000169: physician or hospital or other institution.
p.000169: (5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as
p.000169: set forth in
p.000169: § 20.81.
p.000169: (6) An assay procedure or other ana- lytical procedure, unless it serves no regulatory or compliance
p.000169: purpose and is shown to fall within the exemption established for trade secrets and con- fidential
p.000169: commercial information in
p.000169: § 20.61.
p.000169: (7) All correspondence and written summaries of oral discussions between FDA and the applicant relating
p.000169: to the application, under the provisions of part 20.
p.000170: 170
p.000170:
p.000170:
p.000170:
p.000170:
p.000170:
p.000170:
p.000170:
p.000170: Food and Drug Administration, HHS § 314.440
p.000170:
p.000170:
p.000170: (f) All safety and effectiveness data and information which have been sub- mitted in an application
p.000170: and which have not previously been disclosed to the public are available to the public, upon request, at
p.000170: the time any one of the following events occurs unless ex- traordinary circumstances are shown:
p.000170: (1) No work is being or will be under- taken to have the application ap- proved.
p.000170: (2) A final determination is made that the application is not approvable and all legal appeals
p.000170: have been ex- hausted.
p.000170: (3) Approval of the application is withdrawn and all legal appeals have been exhausted.
p.000170: (4) A final determination has been made that the drug is not a new drug.
p.000170: (5) For applications submitted under section 505(b) of the act, the effective date of the approval of
p.000170: the first abbre- viated application submitted under section 505(j) of the act which refers to such drug, or
p.000170: the date on which the ap- proval of an abbreviated application under section 505(j) of the act which re- fers
p.000170: to such drug could be made effec- tive if such an abbreviated application had been submitted.
p.000170: (6) For abbreviated applications sub- mitted under section 505(j) of the act, when FDA sends an approval
p.000170: letter to the applicant.
p.000170: (g) The following data and informa- tion in an application or abbreviated application are not available for
p.000170: public disclosure unless they have been pre- viously disclosed to the public as set forth in § 20.81 of
p.000170: this chapter or they relate to a product or ingredient that has been abandoned and they do not represent
p.000170: a trade secret or confidential commercial or financial information under § 20.61 of this chapter:
p.000170: (1) Manufacturing methods or proc- esses, including quality control proce- dures.
p.000170: (2) Production, sales distribution, and similar data and information, ex- cept that any compilation
p.000170: of that data and information aggregated and pre- pared in a way that does not reveal data or
p.000170: information which is not avail- able for public disclosure under this provision is available for public
p.000170: disclo- sure.
p.000170:
p.000170: (3) Quantitative or semiquantitative formulas.
p.000170: (h) The compilations of information specified in § 20.117 are available for public disclosure.
p.000170: [50 FR 7493, Feb. 22, 1985, as amended at 50
p.000170: FR 21238, May 23, 1985; 55 FR 11580, Mar. 29,
p.000170: 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530,
p.000170: Oct. 2, 1996; 64 FR 26698, May 13, 1998; 64 FR
p.000170: 402, Jan. 5, 1999; 66 FR 1832, Jan. 10, 2001; 68
p.000170: FR 24879, May 9, 2003; 69 FR 18766, Apr. 8,
p.000170: 2004; 73 FR 39610, July 10, 2008]
p.000170:
p.000170: § 314.440 Addresses for applications and abbreviated applications.
p.000170: (a) Applicants shall send applica- tions, abbreviated applications, and other correspondence
p.000170: relating to mat- ters covered by this part, except for products listed in paragraph (b) of this section,
p.000170: to the appropriate office iden- tified below:
p.000170: (1) Except as provided in paragraph (a)(4) of this section, an application under § 314.50 or § 314.54
p.000170: submitted for filing should be directed to the Central Document Room, 5901–B Ammendale Rd., Beltsville, MD
p.000170: 20705–1266. Appli- cants may obtain information about folders for binding applications on the Internet
p.000170: at http:// .fda.gov/cder/ ddms/binders.htm. After FDA has filed the application, the agency will
p.000170: inform the applicant which division is respon- sible for the application. Amendments, supplements,
p.000170: resubmissions, requests for waivers, and other correspondence about an application that has been filed
p.000170: should be addressed to 5901–B Ammendale Rd., Beltsville, MD 20705– 1266, to the attention of the
p.000170: appro- priate division.
p.000170: (2) Except as provided in paragraph (a)(4) of this section, an abbreviated ap- plication under § 314.94, and
p.000170: amend- ments, supplements, and resubmissions should be directed to the Office of Ge- neric Drugs (HFD–600),
p.000170: Center for Drug Evaluation and Research, Food and Drug Administration, Metro Park North VII, 7620
p.000170: Standish Pl., Rockville, MD 20855. This includes items sent by parcel post or overnight courier serv- ice.
p.000170: Correspondence not associated with an abbreviated application should be addressed specifically to the
p.000170: in- tended office or division and to the per- son as follows: Office of Generic Drugs,
p.000171: 171
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171: § 314.445
p.000171: Center for Drug Evaluation and Re- search, Food and Drug Administration, Attn: [insert name of person],
p.000171: Metro Park North II, HFD–[insert mail code of office or division], 7500 Standish Place, rm. 150,
p.000171: Rockville, MD 20855. The mail code for the Office of Generic Drugs is HFD–600, the mail codes for the
p.000171: Divisions of Chemistry I, II, and III are HFD–620, HFD–640, and HFD–630,
p.000171: respectively, and the mail code for the Division of Bioequivalence is HFD–650.
p.000171: (3) A request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds
p.000171: for deny- ing approval of an application, except an application under paragraph (b) of this section,
p.000171: should be directed to the Associate Director for Policy (HFD–5).
p.000171: (4) The field copy of an application, an abbreviated application, amend- ments, supplements,
p.000171: resubmissions, re- quests for waivers, and other cor- respondence about an application and an
p.000171: abbreviated application shall be sent to the applicant’s home FDA dis- trict office, except that a foreign
p.000171: appli- cant shall send the field copy to the ap- propriate address identified in para- graphs (a)(1) and (a)(2)
p.000171: of this section.
p.000171: (b) Applicants shall send applications and other correspondence relating to matters covered by this part
p.000171: for the drug products listed below to the Docu- ment Control Center (HFM–99), Center for Biologics Evaluation
p.000171: and Research, 1401 Rockville Pike, suite 200N, Rock- ville, MD 20852–1448, except applicants shall send a
p.000171: request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds
p.000171: for denying approval of an application to the Director, Center for Biologics Evaluation and Research
p.000171: (HFM–1), at the same address.
p.000171: (1) Ingredients packaged together with containers intended for the collec- tion, processing, or storage
p.000171: of blood and blood components;
p.000171: (2) Plasma volume expanders and hy- droxyethyl starch for leukapheresis;
p.000171: (3) Blood component processing solu- tions and shelf life extenders; and
p.000171: 21 CFR Ch. I (4–1–12 Edition)
p.000171: (4) Oxygen carriers.
p.000171: [50 FR 7493, Feb. 22, 1985, as amended at 50
p.000171: FR 21238, May 23, 1985; 55 FR 11581, Mar. 29,
p.000171: 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352,
p.000171: Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR
p.000171: 13473, Mar. 23, 2004; 70 FR 14981, Mar. 24, 2005;
p.000171: 73 FR 39610, July 10, 2008; 74 FR 13113, Mar.
p.000171: 26, 2009; 75 FR 37295, June 29, 2010]
p.000171: § 314.445 Guidance documents.
p.000171: (a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain
p.000171: re- quirements of this part.
p.000171: (b) The Center for Drug Evaluation and Research (CDER) maintains a list of guidance documents that apply
p.000171: to CDER’s regulations. The list is main- tained on the Internet and is published annually in the FEDERAL
p.000171: REGISTER. A request for a copy of the CDER list should be directed to the Office of Training and
p.000171: Communications, Divi- sion of Drug Information, Center for Drug Evaluation and Research, Food and
p.000171: Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993–0002.
p.000171: [65 FR 56480, Sept. 19, 2000, as amended at 74
p.000171: FR 13113, Mar. 26, 2009]
p.000171:
p.000171: Subpart H—Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses
p.000171: SOURCE: 57 FR 58958, Dec. 11, 1992, unless
p.000171: otherwise noted.
p.000171: § 314.500 Scope.
p.000171: This subpart applies to certain new drug products that have been studied for their safety and
p.000171: effectiveness in treating serious or life-threatening ill- nesses and that provide meaningful therapeutic
p.000171: benefit to patients over ex- isting treatments (e.g., ability to treat patients unresponsive to, or intolerant of,
p.000171: available therapy, or improved pa- tient response over available therapy).
p.000171: [57 FR 58958, Dec. 11, 1992, as amended at 64
p.000171: FR 402, Jan. 5, 1999]
p.000171:
p.000171: § 314.510 Approval based on a surro- gate endpoint or on an effect on a clinical endpoint other than
p.000171: sur- vival or irreversible morbidity.
p.000171: FDA may grant marketing approval for a new drug product on the basis of
p.000172: 172
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172: Food and Drug Administration, HHS § 314.530
p.000172:
p.000172:
p.000172: adequate and well-controlled clinical trials establishing that the drug prod- uct has an effect on a
p.000172: surrogate end- point that is reasonably likely, based on epidemiologic, therapeutic, patho- physiologic,
p.000172: or other evidence, to pre- dict clinical benefit or on the basis of an effect on a clinical endpoint
p.000172: other than survival or irreversible morbidity. Approval under this section will be subject to the requirement
p.000172: that the ap- plicant study the drug further, to verify and describe its clinical benefit, where
p.000172: there is uncertainty as to the re- lation of the surrogate endpoint to clinical benefit, or of the observed
p.000172: clin- ical benefit to ultimate outcome. Post- marketing studies would usually be studies already underway.
p.000172: When re- quired to be conducted, such studies must also be adequate and well-con- trolled. The
p.000172: applicant shall carry out any such studies with due diligence.
p.000172: § 314.520 Approval with restrictions to assure safe use.
p.000172: (a) If FDA concludes that a drug product shown to be effective can be safely used only if
p.000172: distribution or use is restricted, FDA will require such postmarketing restrictions as are need- ed to
p.000172: assure safe use of the drug prod- uct, such as:
p.000172: (1) Distribution restricted to certain facilities or physicians with special training or experience; or
p.000172: (2) Distribution conditioned on the performance of specified medical proce- dures.
p.000172: (b) The limitations imposed will be commensurate with the specific safety concerns presented by the drug
p.000172: prod- uct.
p.000172: § 314.530 Withdrawal procedures.
p.000172: (a) For new drugs approved under
p.000172: §§ 314.510 and 314.520, FDA may with- draw approval, following a hearing as provided in part 15 of
p.000172: this chapter, as modified by this section, if:
p.000172: (1) A postmarketing clinical study fails to verify clinical benefit;
p.000172: (2) The applicant fails to perform the required postmarketing study with due diligence;
p.000172: (3) Use after marketing demonstrates that postmarketing restrictions are in- adequate to assure safe use of the drug
p.000172: product;
p.000172:
p.000172: (4) The applicant fails to adhere to the postmarketing restrictions agreed upon;
p.000172: (5) The promotional materials are false or misleading; or
p.000172: (6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its
p.000172: conditions of use.
p.000172: (b) Notice of opportunity for a hearing. The Director of the Center for Drug Evaluation and Research
p.000172: will give the applicant notice of an opportunity for a hearing on the Center’s proposal to withdraw the
p.000172: approval of an applica- tion approved under § 314.510 or § 314.520. The notice, which will ordinarily be a
p.000172: letter, will state generally the reasons for the action and the proposed grounds for the order.
p.000172: (c) Submission of data and information.
p.000172: (1) If the applicant fails to file a writ- ten request for a hearing within 15 days of receipt of the
p.000172: notice, the applicant waives the opportunity for a hearing.
p.000172: (2) If the applicant files a timely re- quest for a hearing, the agency will publish a notice of
p.000172: hearing in the FED- ERAL REGISTER in accordance with
p.000172: §§ 12.32(e) and 15.20 of this chapter.
p.000172: (3) An applicant who requests a hear- ing under this section must, within 30 days of receipt of the notice
p.000172: of oppor- tunity for a hearing, submit the data and information upon which the appli- cant intends to rely
p.000172: at the hearing.
p.000172: (d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not
p.000172: apply at any point in withdrawal proceedings under this section.
p.000172: (e) Procedures for hearings. Hearings held under this section will be con- ducted in accordance
p.000172: with the provi- sions of part 15 of this chapter, with the following modifications:
p.000172: (1) An advisory committee duly con- stituted under part 14 of this chapter will be present at the
p.000172: hearing. The committee will be asked to review the issues involved and to provide advice and
p.000172: recommendations to the Commis- sioner of Food and Drugs.
p.000172: (2) The presiding officer, the advisory committee members, up to three rep- resentatives of the applicant, and up
p.000172: to three representatives of the Center may question any person during or at
p.000173: 173
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173: § 314.540
p.000173: the conclusion of the person’s presen- tation. No other person attending the hearing may question a person
p.000173: making a presentation. The presiding officer may, as a matter of discretion, permit questions to be
p.000173: submitted to the pre- siding officer for response by a person making a presentation.
p.000173: (f) Judicial revie . The Commis- sioner’s decision constitutes final agency action from
p.000173: which the appli- cant may petition for judicial review. Before requesting an order from a court
p.000173: for a stay of action pending re- view, an applicant must first submit a petition for a stay of
p.000173: action under
p.000173: § 10.35 of this chapter.
p.000173: [57 FR 58958, Dec. 11, 1992, as amended at 64
p.000173: FR 402, Jan. 5, 1999]
p.000173:
p.000173: § 314.540 Postmarketing safety report- ing.
p.000173: Drug products approved under this program are subject to the post- marketing recordkeeping
p.000173: and safety reporting applicable to all approved drug products, as provided in §§ 314.80 and 314.81.
p.000173: § 314.550 Promotional materials.
p.000173: For drug products being considered for approval under this subpart, unless otherwise informed by the
p.000173: agency, ap- plicants must submit to the agency for consideration during the preapproval review period copies of
p.000173: all promotional materials, including promotional label- ing as well as advertisements, intended for dissemination or
p.000173: publication within 120 days following marketing approval. After 120 days following marketing ap- proval, unless
p.000173: otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior
p.000173: to the intended time of initial dissemination of the labeling or initial publication of the advertisement.
p.000173: § 314.560 Termination of requirements.
p.000173: If FDA determines after approval that the requirements established in
p.000173: § 314.520, § 314.530, or § 314.550 are no longer necessary for the safe and effec- tive use of a drug
p.000173: product, it will so no- tify the applicant. Ordinarily, for drug products approved under § 314.510, these
p.000173: requirements will no longer apply when FDA determines that the required postmarketing study verifies
p.000173: and de-
p.000173: 21 CFR Ch. I (4–1–12 Edition)
p.000173: scribes the drug product’s clinical ben- efit and the drug product would be ap- propriate for
p.000173: approval under tradi- tional procedures. For drug products approved under § 314.520, the restric-
p.000173: tions would no longer apply when FDA determines that safe use of the drug product can be assured through
p.000173: appro- priate labeling. FDA also retains the discretion to remove specific post- approval requirements
p.000173: upon review of a petition submitted by the sponsor in accordance with § 10.30.
p.000173:
p.000173: Subpart I—Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible
p.000173:
p.000173: SOURCE: 67 FR 37995, May 31, 2002, unless
p.000173: otherwise noted.
p.000173:
p.000173: § 314.600 Scope.
p.000173: This subpart applies to certain new drug products that have been studied for their safety and efficacy
p.000173: in amelio- rating or preventing serious or life- threatening conditions caused by expo- sure to lethal or
p.000173: permanently disabling toxic biological, chemical, radio- logical, or nuclear substances. This
p.000173: subpart applies only to those new drug products for which: Definitive human efficacy studies cannot be
p.000173: conducted because it would be unethical to delib- erately expose healthy human volun- teers to a lethal
p.000173: or permanently dis- abling toxic biological, chemical, radi- ological, or nuclear substance; and
p.000173: field trials to study the product’s effec- tiveness after an accidental or hostile exposure have not been
p.000173: feasible. This subpart does not apply to products that can be approved based on efficacy standards
p.000173: described elsewhere in FDA’s regulations (e.g., accelerated approval based on surrogate markers or clinical
p.000173: endpoints other than survival or irre- versible morbidity), nor does it address the safety evaluation for the
p.000173: products to which it does apply.
p.000173: § 314.610 Approval based on evidence of effectiveness from studies in ani- mals.
p.000173: (a) FDA may grant marketing ap- proval for a new drug product for which safety has been established
p.000173: and for which the requirements of § 314.600 are
p.000174: 174
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174: Food and Drug Administration, HHS § 314.620
p.000174:
p.000174:
p.000174: met based on adequate and well-con- trolled animal studies when the results of those animal studies establish
p.000174: that the drug product is reasonably likely to produce clinical benefit in humans. In assessing the
p.000174: sufficiency of animal data, the agency may take into ac- count other data, including human data,
p.000174: available to the agency. FDA will rely on the evidence from studies in animals to provide substantial
p.000174: evi- dence of the effectiveness of these products only when:
p.000174: (1) There is a reasonably well-under-
p.000174: stood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial
p.000174: reduction by the product;
p.000174: (2) The effect is demonstrated in more than one animal species expected to react with a response
p.000174: predictive for humans, unless the effect is dem- onstrated in a single animal species that
p.000174: represents a sufficiently well- characterized animal model for pre- dicting the response in humans;
p.000174: (3) The animal study endpoint is clearly related to the desired benefit in humans, generally the
p.000174: enhancement of survival or prevention of major mor- bidity; and
p.000174: (4) The data or information on the ki- netics and pharmacodynamics of the product or other relevant data or
p.000174: infor- mation, in animals and humans, allows selection of an effective dose in hu- mans.
p.000174: (b) Approval under this subpart will be subject to three requirements:
p.000174: (1) Postmarketing studies. The appli- cant must conduct postmarketing studies, such as field
p.000174: studies, to verify and describe the drug’s clinical benefit and to assess its safety when used as
p.000174: indicated when such studies are fea- sible and ethical. Such postmarketing studies would not be
p.000174: feasible until an exigency arises. When such studies are feasible, the applicant must conduct such
p.000174: studies with due diligence. Appli- cants must include as part of their ap- plication a plan or approach
p.000174: to post- marketing study commitments in the event such studies become ethical and feasible.
p.000174: (2) Approval ith restrictions to ensure
p.000174: safe use. If FDA concludes that a drug product shown to be effective under this subpart can be
p.000174: safely used only if
p.000174:
p.000174: distribution or use is restricted, FDA will require such postmarketing re- strictions as are needed to
p.000174: ensure safe use of the drug product, commensurate with the specific safety concerns pre- sented by the drug
p.000174: product, such as:
p.000174: (i) Distribution restricted to certain facilities or health care practitioners with special training or
p.000174: experience;
p.000174: (ii) Distribution conditioned on the performance of specified medical proce- dures, including medical followup;
p.000174: and
p.000174: (iii) Distribution conditioned on specified recordkeeping requirements.
p.000174: (3) Information to be provided to patient recipients. For drug products or specific indications approved under
p.000174: this sub- part, applicants must prepare, as part of their proposed labeling, labeling to be provided to
p.000174: patient recipients. The patient labeling must explain that, for ethical or feasibility reasons, the
p.000174: drug’s approval was based on efficacy studies conducted in animals alone and must give the drug’s
p.000174: indication(s), di- rections for use (dosage and adminis- tration), contraindications, a descrip- tion of
p.000174: any reasonably foreseeable risks, adverse reactions, anticipated benefits, drug interactions, and
p.000174: any other relevant information required by FDA at the time of approval. The pa- tient labeling must be
p.000174: available with the product to be provided to patients prior to administration or dispensing of the drug
p.000174: product for the use ap- proved under this subpart, if possible.
p.000174: § 314.620 Withdrawal procedures.
p.000174: (a) Reasons to ithdra approval. For new drugs approved under this subpart, FDA may withdraw approval,
p.000174: following a hearing as provided in part 15 of this chapter, as modified by this section, if:
p.000174: (1) A postmarketing clinical study fails to verify clinical benefit;
p.000174: (2) The applicant fails to perform the postmarketing study with due dili- gence;
p.000174: (3) Use after marketing demonstrates that postmarketing restrictions are in- adequate to ensure safe use of the drug
p.000174: product;
p.000174: (4) The applicant fails to adhere to the postmarketing restrictions applied at the time of approval under this
p.000174: sub- part;
p.000174: (5) The promotional materials are false or misleading; or
p.000175: 175
p.000175:
p.000175:
p.000175:
p.000175:
p.000175:
p.000175:
p.000175:
p.000175:
p.000175: § 314.630
p.000175: (6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its
p.000175: conditions of use.
p.000175: (b) Notice of opportunity for a hearing. The Director of the Center for Drug Evaluation and Research
p.000175: (CDER) will give the applicant notice of an oppor- tunity for a hearing on CDER’s pro- posal to withdraw
p.000175: the approval of an application approved under this sub- part. The notice, which will ordinarily be a
p.000175: letter, will state generally the rea- sons for the action and the proposed grounds for the order.
p.000175: (c) Submission of data and information.
p.000175: (1) If the applicant fails to file a writ- ten request for a hearing within 15 days of receipt of the
p.000175: notice, the applicant waives the opportunity for a hearing.
p.000175: (2) If the applicant files a timely re- quest for a hearing, the agency will publish a notice of
p.000175: hearing in the FED- ERAL REGISTER in accordance with
p.000175: §§ 12.32(e) and 15.20 of this chapter.
p.000175: (3) An applicant who requests a hear- ing under this section must, within 30 days of receipt of the notice
p.000175: of oppor- tunity for a hearing, submit the data and information upon which the appli- cant intends to rely
p.000175: at the hearing.
p.000175: (d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not
p.000175: apply at any point in withdrawal proceedings under this section.
p.000175: (e) Procedures for hearings. Hearings held under this section will be con- ducted in accordance
p.000175: with the provi- sions of part 15 of this chapter, with the following modifications:
p.000175: (1) An advisory committee duly con- stituted under part 14 of this chapter will be present at the
p.000175: hearing. The committee will be asked to review the issues involved and to provide advice and
p.000175: recommendations to the Commis- sioner of Food and Drugs.
p.000175: (2) The presiding officer, the advisory committee members, up to three rep- resentatives of the applicant, and up
p.000175: to three representatives of CDER may question any person during or at the conclusion of the
p.000175: person’s presen- tation. No other person attending the hearing may question a person making a presentation.
p.000175: The presiding officer may, as a matter of discretion, permit questions to be submitted to the pre-
p.000175: 21 CFR Ch. I (4–1–12 Edition)
p.000175: siding officer for response by a person making a presentation.
p.000175: (f) Judicial revie . The Commissioner of Food and Drugs’ decision constitutes final agency action from which the
p.000175: ap- plicant may petition for judicial re- view. Before requesting an order from a court for a stay of
p.000175: action pending re- view, an applicant must first submit a petition for a stay of action under
p.000175: § 10.35 of this chapter.
p.000175:
p.000175: § 314.630 Postmarketing safety report- ing.
p.000175: Drug products approved under this subpart are subject to the post- marketing recordkeeping
p.000175: and safety reporting requirements applicable to all approved drug products, as provided in §§ 314.80 and
p.000175: 314.81.
p.000175: § 314.640 Promotional materials.
p.000175: For drug products being considered for approval under this subpart, unless otherwise informed by the
p.000175: agency, ap- plicants must submit to the agency for consideration during the preapproval review period copies of
p.000175: all promotional materials, including promotional label- ing as well as advertisements, intended for dissemination or
p.000175: publication within 120 days following marketing approval. After 120 days following marketing ap- proval, unless
p.000175: otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior
p.000175: to the intended time of initial dissemination of the labeling or initial publication of the advertisement.
p.000175: § 314.650 Termination of requirements.
p.000175: If FDA determines after approval under this subpart that the require- ments established in
p.000175: §§ 314.610(b)(2), 314.620, and 314.630 are no longer nec- essary for the safe and effective use of a drug
p.000175: product, FDA will so notify the applicant. Ordinarily, for drug products approved under § 314.610, these
p.000175: require- ments will no longer apply when FDA determines that the postmarketing study verifies and
p.000175: describes the drug product’s clinical benefit. For drug products approved under § 314.610, the
p.000175: restrictions would no longer apply when FDA determines that safe use of the drug product can
p.000175: be ensured through appropriate labeling. FDA also
p.000176: 176
p.000176:
p.000176:
p.000176:
p.000176:
p.000176:
p.000176:
p.000176:
p.000176: Food and Drug Administration, HHS § 315.5
p.000176:
p.000176:
p.000176: retains the discretion to remove spe- cific postapproval requirements upon review of a petition
p.000176: submitted by the sponsor in accordance with § 10.30 of this chapter.
p.000176:
p.000176: PART 315—DIAGNOSTIC RADIOPHARMACEUTICALS
p.000176: Sec.
p.000176: 315.1 Scope.
p.000176: 315.2 Definition.
p.000176: 315.3 General factors relevant to safety and effectiveness.
p.000176: 315.4 Indications.
p.000176: 315.5 Evaluation of effectiveness.
p.000176: 315.6 Evaluation of safety.
p.000176: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000176: 355, 371, 374, 379e; sec. 122, Pub. L. 105–115, 111
p.000176: Stat. 2322 (21 U.S.C. 355 note).
p.000176: SOURCE: 64 FR 26667, May 17, 1999, unless
p.000176: otherwise noted.
p.000176: § 315.1 Scope.
p.000176: The regulations in this part apply to radiopharmaceuticals intended for in vivo administration for
p.000176: diagnostic and monitoring use. They do not apply to radiopharmaceuticals intended for therapeutic
p.000176: purposes. In situations where a particular radiopharma- ceutical is proposed for both diagnostic
p.000176: and therapeutic uses, the radiopharma- ceutical must be evaluated taking into account each intended use.
p.000176: § 315.2 Definition.
p.000176: For purposes of this part, diagnostic radiopharmaceutical means:
p.000176: (a) An article that is intended for use in the diagnosis or monitoring of a dis- ease or a manifestation of a
p.000176: disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of
p.000176: nuclear particles or photons; or
...
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p.000163: identified.
p.000163: (3) Each person requesting a hearing shall submit an analysis of the data upon which the person relies,
p.000163: except that the required information relating either to safety or to effectiveness may be omitted if the notice of
p.000163: opportunity for hearing does not raise any issue with respect to that aspect of the drug; information on
p.000163: compliance with § 300.50 may be omitted if the drug product is not a combination drug product. A fi-
p.000163: nancial certification or disclosure statement or both as required by part 54 of this chapter must
p.000163: accompany all clinical data submitted. FDA can most efficiently consider submissions made in the following format.
p.000163: I. Safety data.
p.000163: A. Animal safety data.
p.000163: 1. Individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: 2. Combinations of the individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: B. Human safety data.
p.000163: 1. Individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: c. Documented case reports.
p.000163: d. Pertinent marketing experiences that may influence a determination about the safety of each
p.000163: individual active component.
p.000163: 2. Combinations of the individual active components.
p.000163: a. Controlled studies.
p.000163: b. Partially controlled or uncontrolled studies.
p.000163: c. Documented case reports.
p.000163: d. Pertinent marketing experiences that may influence a determination about the safety of each
p.000163: individual active component.
p.000163: II. Effectiveness data.
p.000163: A. Individual active components: Con- trolled studies, with an analysis showing clearly how
p.000163: each study satisfies, on a point- by-point basis, each of the criteria required by § 314.126.
p.000163: B. Combinations of individual active com- ponents.
p.000163: 1. Controlled studies with an analysis showing clearly how each study satisfies on a point-by-point
p.000163: basis, each of the criteria required by § 314.126.
p.000163: 2. An analysis showing clearly how each re- quirement of § 300.50 has been satisfied.
p.000164: 164
p.000164:
p.000164:
p.000164:
p.000164:
p.000164:
p.000164:
p.000164:
p.000164: Food and Drug Administration, HHS § 314.200
p.000164:
p.000164:
p.000164: III. A summary of the data and views set- ting forth the medical rationale and purpose for the drug and its
p.000164: ingredients and the sci- entific basis for the conclusion that the drug and its ingredients have been
p.000164: proven safe and/or effective for the intended use. If there is an absence of controlled studies in the ma- terial
p.000164: submitted or the requirements of any element of § 300.50 or § 314.126 have not been fully met, that fact
p.000164: is required to be stated clearly and a waiver obtained under § 314.126 is required to be submitted.
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p.000093: commitments to perform post- marketing studies (including proposals for such studies),
p.000093: assay validation data, final release testing on the last lots used to support approval, minor reanalyses
p.000093: of previously submitted data, and other comparatively minor information.
p.000093: Class 2 resubmission means the resub- mission of an application or efficacy supplement, following receipt of
p.000093: a com- plete response letter, that includes any item not specified in the definition of ‘‘Class 1
p.000093: resubmission,’’ including any item that would require presentation to an advisory committee.
p.000093: Complete response letter means a writ- ten communication to an applicant from FDA usually describing
p.000093: all of the deficiencies that the agency has identi- fied in an application or abbreviated application that
p.000093: must be satisfactorily addressed before it can be approved.
p.000093: Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a
p.000093: drug sub- stance, generally, but not necessarily,
p.000093:
p.000094: 94
p.000094: 21 CFR Ch. I (4–1–12 Edition)
p.000094: in association with one or more other ingredients.
p.000094: Drug substance means an active ingre- dient that is intended to furnish phar- macological activity or other
p.000094: direct ef- fect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the
p.000094: structure or any function of the human body, but does not in- clude intermediates use in the syn-
p.000094: thesis of such ingredient.
p.000094: Efficacy supplement means a supple- ment to an approved application pro- posing to make one or more
p.000094: related changes from among the following changes to product labeling:
p.000094: (1) Add or modify an indication or claim;
p.000094: (2) Revise the dose or dose regimen;
p.000094: (3) Provide for a new route of admin- istration;
p.000094: (4) Make a comparative efficacy claim naming another drug product;
p.000094: (5) Significantly alter the intended patient population;
p.000094: (6) Change the marketing status from prescription to over-the-counter use;
p.000094: (7) Provide for, or provide evidence of effectiveness necessary for, the tradi- tional approval of a product
p.000094: originally approved under subpart H of part 314; or
p.000094: (8) Incorporate other information based on at least one adequate and well-controlled clinical
p.000094: study.
p.000094: FDA means the Food and Drug Ad- ministration.
...
p.000094: applicant relies in seeking approval of its abbreviated application.
p.000094: Resubmission means submission by the applicant of all materials needed to fully address all deficiencies
p.000094: identified in the complete response letter. An ap- plication or abbreviated application for which FDA issued a
p.000094: complete response letter, but which was withdrawn before approval and later submitted again, is not a
p.000094: resubmission.
p.000094: Right of reference or use means the au- thority to rely upon, and otherwise use, an investigation for the
p.000094: purpose of obtaining approval of an application, including the ability to make available the underlying raw data
p.000094: from the in- vestigation for FDA audit, if necessary. Specification means the quality stand- ard (i.e., tests,
p.000094: analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of
p.000094: drug substances, drug prod- ucts, intermediates, raw materials, re- agents, components, in-process mate-
p.000094: rials, container closure systems, and other materials used in the production of a drug substance or
p.000094: drug product. For the purpose of this definition, ac- ceptance criteriameans numerical lim- its, ranges,
p.000094: or other criteria for the
p.000094: tests described.
p.000094: The list means the list of drug prod- ucts with effective approvals published in the current edition of
p.000094: FDA’s publi- cation ‘‘Approved Drug Products with Therapeutic Equivalence Evaluations’’
p.000095: 95
p.000095:
p.000095: and any current supplement to the publication.
p.000095: [50 FR 7493, Feb. 22, 1985, as amended at 57
p.000095: FR 17981, Apr. 28, 1992; 69 FR 18763, Apr. 8,
p.000095: 2004; 73 FR 39607, July 10, 2008; 73 FR 49609,
p.000095: Aug. 22, 2008; 74 FR 37167, July 28, 2009]
p.000095:
p.000095: Subpart B—Applications
p.000095: § 314.50 Content and format of an ap- plication.
p.000095: Applications and supplements to ap- proved applications are required to be submitted in the form and
p.000095: contain the information, as appropriate for the par- ticular submission, required under this section. Three copies
p.000095: of the application are required: An archival copy, a re- view copy, and a field copy. An applica- tion for a new
p.000095: chemical entity will gen- erally contain an application form, an index, a summary, five or six technical sections,
...
p.000096:
p.000096:
p.000096: (v) A summary of the nonclinical pharmacology and toxicology section of the application.
p.000096: (vi) A summary of the human phar- macokinetics and bioavailability sec- tion of the application.
p.000096: (vii) A summary of the microbiology section of the application (for anti-in- fective drugs only).
p.000096: (viii) A summary of the clinical data section of the application, including the results of
p.000096: statistical analyses of the clinical trials.
p.000096: (ix) A concluding discussion that pre- sents the benefit and risk consider- ations related to the drug,
p.000096: including a discussion of any proposed additional studies or surveillance the applicant intends to conduct
p.000096: postmarketing.
p.000096: (d) Technical sections. The application is required to contain the technical sections described below.
p.000096: Each tech- nical section is required to contain data and information in sufficient de- tail to
p.000096: permit the agency to make a knowledgeable judgment about wheth- er to approve the application or wheth- er
p.000096: grounds exist under section 505(d) of the act to refuse to approve the appli- cation. The required technical
p.000096: sections are as follows:
p.000096: (1) Chemistry, manufacturing, and con- trols section. A section describing the composition, manufacture,
p.000096: and speci- fication of the drug substance and the drug product, including the following:
p.000096: (i) Drug substance. A full description of the drug substance including its physical and chemical
p.000096: characteristics and stability; the name and address of its manufacturer; the method of syn- thesis (or
p.000096: isolation) and purification of the drug substance; the process con- trols used during manufacture
p.000096: and packaging; and the specifications nec- essary to ensure the identity, strength, quality, and purity of
p.000096: the drug sub- stance and the bioavailability of the drug products made from the sub- stance,
p.000096: including, for example, tests, analytical procedures, and acceptance criteria relating to stability,
p.000096: sterility, particle size, and crystalline form. The application may provide additionally for the use of
p.000096: alternatives to meet any of these requirements, including alter- native sources, process controls, and
p.000096: analytical procedures. Reference to the current edition of the U.S. Pharma-
p.000097: 97
p.000097:
p.000097: copeia and the National Formulary may satisfy relevant requirements in this paragraph.
p.000097: (ii)(a) Drug product. A list of all com- ponents used in the manufacture of the drug product (regardless of
p.000097: whether they appear in the drug product) and a statement of the composition of the drug product; the
...
p.000098: 98
p.000098: 21 CFR Ch. I (4–1–12 Edition)
p.000098: ance with those regulations, a brief statement of the reason for the non- compliance.
p.000098: (3) Human pharmacokinetics and bio- availability section. A section describing the human pharmacokinetic
p.000098: data and human bioavailability data, or infor- mation supporting a waiver of the sub- mission of in vivo
p.000098: bioavailability data under subpart B of part 320, including the following:
p.000098: (i) A description of each of the bio- availability and pharmacokinetic stud- ies of the drug in humans performed
p.000098: by or on behalf of the applicant that in- cludes a description of the analytical procedures and
p.000098: statistical methods used in each study and a statement with respect to each study that it ei-
p.000098: ther was conducted in compliance with the institutional review board regula- tions in part 56, or was not
p.000098: subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compli- ance with the
p.000098: informed consent regula- tions in part 50.
p.000098: (ii) If the application describes in the
p.000098: chemistry, manufacturing, and con- trols section tests, analytical proce- dures, and acceptance
p.000098: criteria needed to assure the bioavailability of the drug product or drug substance, or both, a
p.000098: statement in this section of the rationale for establishing the tests, an- alytical procedures, and acceptance
p.000098: criteria, including data and informa- tion supporting the rationale.
p.000098: (iii) A summarizing discussion and analysis of the pharmacokinetics and metabolism of the active
p.000098: ingredients and the bioavailability or bioequiva- lence, or both, of the drug product.
p.000098: (4) Microbiology section. If the drug is an anti-infective drug, a section de- scribing the
p.000098: microbiology data, includ- ing the following:
p.000098: (i) A description of the biochemical basis of the drug’s action on microbial physiology.
p.000098: (ii) A description of the anti- microbial spectra of the drug, includ- ing results of in
p.000098: vitro preclinical stud- ies to demonstrate concentrations of the drug required for effective use.
p.000098: (iii) A description of any known mechanisms of resistance to the drug, including results of any
...
p.000099: statistical analyses used in evaluating the safety informa- tion.
p.000099: (7) Pediatric use section. A section de- scribing the investigation of the drug for use in pediatric
p.000099: populations, includ- ing an integrated summary of the in- formation (the clinical pharmacology studies,
p.000099: controlled clinical studies, or uncontrolled clinical studies, or other data or information) that is relevant to
p.000099: the safety and effectiveness and bene- fits and risks of the drug in pediatric populations for the
p.000099: claimed indica- tions, a reference to the full descrip- tions of such studies provided under
p.000099: paragraphs (d)(3) and (d)(5) of this sec- tion, and information required to be submitted under §
p.000099: 314.55.
p.000099: (e) Samples and labeling. (1) Upon re-
p.000099: quest from FDA, the applicant shall submit the samples described below to the places identified in the
p.000099: agency’s re- quest. FDA will generally ask appli- cants to submit samples directly to two or more
p.000099: agency laboratories that will perform all necessary tests on the samples and validate the applicant’s
p.000099: analytical procedures.
p.000099: (i) Four representative samples of the following, each sample in sufficient quantity to permit FDA to
p.000099: perform three times each test described in the application to determine whether the drug substance and the
p.000099: drug product meet the specifications given in the ap- plication:
p.000099: (a) The drug product proposed for marketing;
p.000099: (b) The drug substance used in the drug product from which the samples of the drug product were taken; and
p.000099: (c) Reference standards and blanks (except that reference standards recog- nized in an official compendium
p.000099: need not be submitted).
p.000099: (ii) Samples of the finished market package, if requested by FDA.
p.000099: (2) The applicant shall submit the following in the archival copy of the application:
p.000099: (i) Three copies of the analytical pro- cedures and related descriptive infor- mation contained in the
p.000099: chemistry,
p.000100: 100
p.000100:
p.000100:
p.000100:
p.000100:
p.000100:
p.000100:
p.000100:
p.000100: Food and Drug Administration, HHS § 314.50
p.000100:
p.000100:
p.000100: manufacturing, and controls section under paragraph (d)(1) of this section for the drug substance and
p.000100: the drug product that are necessary for FDA’s laboratories to perform all necessary tests on the samples
p.000100: and to validate the applicant’s analytical procedures. The related descriptive information in- cludes a
p.000100: description of each sample; the proposed regulatory specifications for the drug; a detailed description
p.000100: of the methods of analysis; supporting data for accuracy, specificity, precision and ruggedness; and
p.000100: complete results of the applicant’s tests on each sample.
p.000100: (ii) Copies of the label and all label-
p.000100: ing for the drug product (including, if applicable, any Medication Guide re- quired under part 208 of
p.000100: this chapter) for the drug product (4 copies of draft labeling or 12 copies of final printed la- beling).
p.000100: (f) Case report forms and tabulations. The archival copy of the application is required to contain the
p.000100: following case report tabulations and case report forms:
p.000100: (1) Case report tabulations. The appli- cation is required to contain tabula- tions of the data from
p.000100: each adequate and well-controlled study under
p.000100: § 314.126 (Phase 2 and Phase 3 studies as described in §§ 312.21 (b) and (c) of this chapter), tabulations of
...
p.000101: or use,’’ as defined under § 314.3(b), to an investigation described in clause (A) of section 505(b)(1) of the
p.000101: act, the appli- cant shall include in its application a written statement signed by the owner of the data
p.000101: from each such investiga- tion that the applicant may rely on in support of the approval of its
p.000101: applica- tion, and provide FDA access to, the underlying raw data that provide the basis for the report of
p.000101: the investigation submitted in its application.
p.000101: (h) Patent information. The applica- tion is required to contain the patent information described under §
p.000101: 314.53.
p.000101: (i) Patent certification—(1) Contents. A 505(b)(2) application is required to con- tain the following:
p.000101: (i) Patents claiming drug, drug product, or method of use. (A) Except as provided in paragraph (i)(2) of this
p.000101: section, a certification with respect to each pat- ent issued by the United States Patent and Trademark Office
p.000101: that, in the opin- ion of the applicant and to the best of its knowledge, claims a drug (the drug product
p.000101: or drug substance that is a component of the drug product) on which investigations that are
p.000101: relied upon by the applicant for approval of its application were conducted or that claims an approved
p.000101: use for such drug and for which information is required to be filed under section 505(b) and (c) of the
p.000101: act and § 314.53. For each such patent, the applicant shall provide the patent number and certify, in
p.000101: its opin- ion and to the best of its knowledge, one of the following circumstances:
p.000101: (1) That the patent information has not been submitted to FDA. The appli- cant shall entitle such a
p.000101: certification ‘‘Paragraph I Certification’’;
p.000101: 21 CFR Ch. I (4–1–12 Edition)
p.000101: (2) That the patent has expired. The applicant shall entitle such a certifi- cation ‘‘Paragraph II
p.000101: Certification’’;
p.000101: (3) The date on which the patent will expire. The applicant shall entitle such a certification ‘‘Paragraph III
p.000101: Certifi- cation’’; or
p.000101: (4) That the patent is invalid, unen- forceable, or will not be infringed by the manufacture, use, or
p.000101: sale of the drug product for which the application is submitted. The applicant shall enti- tle such a
p.000101: certification ‘‘Paragraph IV Certification’’. This certification shall be submitted in the following form:
...
p.000106: a new drug application or an amendment to it under section 505(b) of the act and
p.000106: § 314.50 or a supplement to an approved application under § 314.70, except as provided in paragraph
p.000106: (d)(2) of this sec- tion.
p.000106: (b) Patents for hich information must
p.000106: be submitted and patents for hich infor- mation must not be submitted—(1) General requirements. An applicant
p.000106: described in paragraph (a) of this section shall sub- mit the required information on the declaration
p.000106: form set forth in paragraph
p.000106: (c) of this section for each patent that claims the drug or a method of using the drug that is the
p.000106: subject of the new drug application or amendment or sup- plement to it and with respect to which a claim of
p.000106: patent infringement could reasonably be asserted if a person not licensed by the owner of the patent en- gaged
p.000106: in the manufacture, use, or sale of the drug product. For purposes of this part, such patents consist
p.000106: of drug substance (active ingredient) patents, drug product (formulation and com- position) patents,
p.000106: and method-of-use patents. For patents that claim the drug substance, the applicant shall submit
p.000106: information only on those pat- ents that claim the drug substance that is the subject of the pending or
p.000106: ap- proved application or that claim a drug substance that is the same as the ac- tive ingredient that is
p.000106: the subject of the approved or pending application. For patents that claim a polymorph that is
p.000106: the same as the active ingre- dient described in the approved or pending application, the
p.000106: applicant shall certify in the declaration forms
p.000106:
p.000106: that the applicant has test data, as set forth in paragraph (b)(2) of this section, demonstrating that a drug
p.000106: product containing the polymorph will perform the same as the drug product described in the new drug application.
p.000106: For pat- ents that claim a drug product, the ap- plicant shall submit information only on those patents that
p.000106: claim a drug product, as is defined in § 314.3, that is described in the pending or approved
p.000106: application. For patents that claim a method of use, the applicant shall sub- mit information only on those
p.000106: patents that claim indications or other condi- tions of use that are described in the pending or approved
p.000106: application. The applicant shall separately identify each pending or approved method of use and
p.000106: related patent claim. For ap- proved applications, the applicant sub- mitting the method-of-use patent shall
p.000106: identify with specificity the section of the approved labeling that corresponds to the method of use
p.000106: claimed by the patent submitted. Process patents, pat- ents claiming packaging, patents claiming
p.000106: metabolites, and patents claiming intermediates are not covered by this section, and information on
p.000106: these patents must not be submitted to FDA.
p.000106: (2) Test Data for Submission of Patent Information for Patents That Claim a Polymorph. The test data,
p.000106: referenced in paragraph (b)(1) of this section, must include the following:
p.000106: (i) A full description of the poly- morphic form of the drug substance, in- cluding its physical and
p.000106: chemical char- acteristics and stability; the method of synthesis (or isolation) and purifi- cation of
p.000106: the drug substance; the proc- ess controls used during manufacture and packaging; and such specifications
p.000106: and analytical methods as are nec- essary to assure the identity, strength, quality, and purity of the
p.000106: polymorphic form of the drug substance;
p.000106: (ii) The executed batch record for a drug product containing the poly- morphic form of the
p.000106: drug substance and documentation that the batch was manufactured under current good man- ufacturing practice
p.000106: requirements;
p.000106: (iii) Demonstration of bioequivalence between the executed batch of the drug product that contains the polymorphic
p.000107: 107
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107:
p.000107: § 314.53
p.000107: form of the drug substance and the drug product as described in the NDA;
p.000107: (iv) A list of all components used in the manufacture of the drug product containing the polymorphic form
p.000107: and a statement of the composition of the drug product; a statement of the speci- fications and
p.000107: analytical methods for each component; a description of the manufacturing and packaging proce- dures
p.000107: and in-process controls for the drug product; such specifications and analytical methods as are necessary to
p.000107: assure the identity, strength, quality, purity, and bioavailability of the drug product, including release and
p.000107: stability data complying with the approved product specifications to demonstrate pharmaceutical
p.000107: equivalence and com- parable product stability; and
p.000107: (v) Comparative in vitro dissolution
p.000107: testing on 12 dosage units each of the executed test batch and the new drug application product.
p.000107: (c) Reporting requirements—(1) General requirements. An applicant described in paragraph (a) of this section
p.000107: shall sub- mit the required patent information described in paragraph (c)(2) of this section for
p.000107: each patent that meets the requirements described in paragraph
p.000107: (b) of this section. We will not accept the patent information unless it is complete and submitted
p.000107: on the appro- priate forms, FDA Forms 3542 or 3542a. These forms may be obtained on the Internet at
p.000107: http:// .fda.gov by searching for ‘‘forms’’.
p.000107: (2) Drug substance (active ingredient),
p.000107: drug product (formulation or composi- tion), and method-of-use patents—(i) Original Declaration.
p.000107: For each patent that claims a drug substance (active ingredient), drug product (formulation and
p.000107: composition), or method of use, the applicant shall submit FDA Form 3542a. The following information
p.000107: and verification is required:
p.000107: (A) New drug application number;
p.000107: (B) Name of new drug application sponsor;
p.000107: (C) Trade name (or proposed trade name) of new drug;
p.000107: (D) Active ingredient(s) of new drug;
p.000107: (E) Strength(s) of new drug;
p.000107: (F) Dosage form of new drug;
p.000107: (G) United States patent number, issue date, and expiration date of pat- ent submitted;
p.000107: 21 CFR Ch. I (4–1–12 Edition)
p.000107: (H) The patent owner’s name, full ad- dress, phone number and, if available, fax number and e-mail address;
p.000107: (I) The name, full address, phone number and, if available, fax number and e-mail address of an
p.000107: agent or rep- resentative who resides or maintains a place of business within the United States
p.000107: authorized to receive notice of patent certification under sections 505(b)(3) and 505(j)(2)(B) of the
p.000107: act and
p.000107: §§ 314.52 and 314.95 (if patent owner or new drug application applicant or hold- er does not reside or have
p.000107: a place of business within the United States);
p.000107: (J) Information on whether the pat- ent has been submitted previously for the new drug application;
p.000107: (K) Information on whether the expi- ration date is a new expiration date if the patent had been
p.000107: submitted pre- viously for listing;
p.000107: (L) Information on whether the pat- ent is a product-by-process patent in which the product claimed is novel;
p.000107: (M) Information on the drug sub- stance (active ingredient) patent in- cluding the following:
p.000107: (1) Whether the patent claims the drug substance that is the active ingre- dient in the drug product
p.000107: described in the new drug application or supple- ment;
p.000107: (2) Whether the patent claims a poly- morph that is the same active ingre- dient that is described in the
p.000107: pending application or supplement;
p.000107: (3) Whether the applicant has test data, described in paragraph (b)(2) of this section, demonstrating
p.000107: that a drug product containing the polymorph will perform the same as the drug product described in the
p.000107: new drug application or supplement, and a description of the polymorphic form(s) claimed by the patent for
p.000107: which such test data exist;
p.000107: (4) Whether the patent claims only a metabolite of the active ingredient; and
p.000107: (5) Whether the patent claims only an intermediate;
p.000107: (N) Information on the drug product (composition/formulation) patent in- cluding the following:
p.000107: (1) Whether the patent claims the drug product for which approval is being sought, as defined in §
p.000107: 314.3; and
p.000107: (2) Whether the patent claims only an intermediate;
p.000108: 108
p.000108:
p.000108:
p.000108:
p.000108:
p.000108:
p.000108:
p.000108:
p.000108: Food and Drug Administration, HHS § 314.53
p.000108:
p.000108:
p.000108: (O) Information on each method-of- use patent including the following:
p.000108: (1) Whether the patent claims one or more methods of using the drug prod- uct for which use
p.000108: approval is being sought and a description of each pend- ing method of use or related indication and related
p.000108: patent claim of the patent being submitted; and
p.000108: (2) Identification of the specific sec- tion of the proposed labeling for the drug product that
p.000108: corresponds to the method of use claimed by the patent submitted;
p.000108: (P) Whether there are no relevant patents that claim the drug substance (active ingredient), drug
p.000108: product (for- mulation or composition) or method(s) of use, for which the applicant is seek- ing approval
p.000108: and with respect to which a claim of patent infringement could reasonably be asserted if a person not
p.000108: licensed by the owner of the patent en- gaged in the manufacture, use, or sale of the drug product;
p.000108: (Q) A signed verification which
p.000108: states:
p.000108: ‘‘The undersigned declares that this is an accurate and complete submission of patent information for the
p.000108: NDA, amendment or sup- plement pending under section 505 of the Federal Food, Drug, and Cosmetic Act.
p.000108: This time-sensitive patent information is sub- mitted pursuant to 21 CFR 314.53. I attest that I am
p.000108: familiar with 21 CFR 314.53 and this submission complies with the require- ments of the regulation. I
p.000108: verify under pen- alty of perjury that the foregoing is true and correct.’’; and
p.000108: (R) Information on whether the ap- plicant, patent owner or attorney, agent, representative or
p.000108: other author- ized official signed the form; the name of the person; and the full address, phone
p.000108: number and, if available, the fax number and e-mail address.
p.000108: (ii) Submission of patent information upon and after approval. Within 30 days after the date of
p.000108: approval of its appli- cation or supplement, the applicant shall submit FDA Form 3542 for each patent
p.000108: that claims the drug substance (active ingredient), drug product (for- mulation and composition), or
p.000108: ap- proved method of use. FDA will rely only on the information submitted on this form and will not
p.000108: list or publish patent information if the patent dec- laration is incomplete or indicates the patent is not
p.000108: eligible for listing. Patent
p.000108:
p.000108: information must also be submitted for patents issued after the date of ap- proval of the new drug
p.000108: application as required in paragraph (c)(2)(ii) of this section. As described in paragraph (d)(4) of
p.000108: this section, patent informa- tion must be submitted to FDA within
p.000108: 30 days of the date of issuance of the patent. If the applicant submits the re- quired patent information
p.000108: within the 30 days, but we notify an applicant that a declaration form is incomplete or shows that the
p.000108: patent is not eligible for listing, the applicant must submit an acceptable declaration form within 15
p.000108: days of FDA notification to be con- sidered timely filed. The following in- formation and verification
p.000108: statement is required:
p.000108: (A) New drug application number;
p.000108: (B) Name of new drug application sponsor;
p.000108: (C) Trade name of new drug;
...
p.000108: (I) The patent owner’s name, full ad- dress, phone number and, if available, fax number and e-mail address;
p.000108: (J) The name, full address, phone number and, if available, fax number and e-mail address of an
p.000108: agent or rep- resentative who resides or maintains a place of business within the United States
p.000108: authorized to receive notice of patent certification under sections 505(b)(3) and 505(j)(2)(B) of the
p.000108: act and
p.000108: §§ 314.52 and 314.95 (if patent owner or new drug application applicant or hold- er does not reside or have
p.000108: a place of business within the United States);
p.000108: (K) Information on whether the pat- ent has been submitted previously for the new drug application;
p.000108: (L) Information on whether the expi- ration date is a new expiration date if the patent had been
p.000108: submitted pre- viously for listing;
p.000108: (M) Information on whether the pat- ent is a product-by-process patent in which the product claimed is novel;
p.000108: (N) Information on the drug sub- stance (active ingredient) patent in- cluding the following:
p.000109: 109
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109:
p.000109: § 314.53
p.000109: (1) Whether the patent claims the drug substance that is the active ingre- dient in the drug product
p.000109: described in the approved application;
p.000109: (2) Whether the patent claims a poly- morph that is the same as the active ingredient that is described in
p.000109: the ap- proved application;
p.000109: (3) Whether the applicant has test data, described at paragraph (b)(2) of this section, demonstrating
p.000109: that a drug product containing the polymorph will perform the same as the drug product described in the
p.000109: approved application and a description of the polymorphic form(s) claimed by the patent for which
p.000109: such test data exist;
p.000109: (4) Whether the patent claims only a metabolite of the active ingredient; and
p.000109: (5) Whether the patent claims only an intermediate;
p.000109: (O) Information on the drug product (composition/formulation) patent in- cluding the following:
p.000109: (1) Whether the patent claims the ap- proved drug product as defined in
p.000109: § 314.3; and
p.000109: (2) Whether the patent claims only an intermediate;
p.000109: (P) Information on each method-of- use patent including the following:
p.000109: (1) Whether the patent claims one or more approved methods of using the approved drug product and a
p.000109: descrip- tion of each approved method of use or indication and related patent claim of the patent being
p.000109: submitted;
p.000109: (2) Identification of the specific sec- tion of the approved labeling for the drug product that
p.000109: corresponds to the method of use claimed by the patent submitted; and
p.000109: (3) The description of the patented method of use as required for publica- tion;
p.000109: (Q) Whether there are no relevant patents that claim the approved drug substance (active ingredient),
p.000109: the ap- proved drug product (formulation or composition) or approved method(s) of use and with respect
p.000109: to which a claim of patent infringement could reason- ably be asserted if a person not li-
p.000109: censed by the owner of the patent en- gaged in the manufacture, use, or sale of the drug product;
p.000109: (R) A signed verification which states: ‘‘The undersigned declares that
p.000109: 21 CFR Ch. I (4–1–12 Edition)
p.000109: this is an accurate and complete sub- mission of patent information for the NDA, amendment or
p.000109: supplement ap- proved under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-sensitive
p.000109: patent information is submitted pursuant to 21 CFR 314.53. I attest that I am familiar with 21 CFR
p.000109: 314.53 and this submission complies with the requirements of the regula- tion. I verify under penalty
p.000109: of perjury that the foregoing is true and cor- rect.’’; and
p.000109: (S) Information on whether the appli- cant, patent owner or attorney, agent, representative or other authorized
p.000109: offi- cial signed the form; the name of the person; and the full address, phone number and, if
p.000109: available, the fax num- ber and e-mail address.
p.000109: (3) No relevant patents. If the appli- cant believes that there are no relevant patents that claim the
p.000109: drug substance (active ingredient), drug product (for- mulation or composition), or the meth- od(s) of use for
p.000109: which the applicant has received approval, and with respect to which a claim of patent infringement could
p.000109: reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use,
p.000109: or sale of the drug product, the applicant will verify this information in the ap- propriate forms, FDA
p.000109: Forms 3542 or 3542a.
p.000109: (4) Authorized signature. The declara- tions required by this section shall be signed by the
p.000109: applicant or patent owner, or the applicant’s or patent owner’s attorney, agent (representa-
p.000109: tive), or other authorized official.
p.000109: (d) When and here to submit patent information—(1) Original application. An applicant shall submit with
p.000109: its original application submitted under this part, including an application described in section 505(b)(2)
p.000109: of the act, the infor- mation described in paragraph (c) of this section on each drug (ingredient),
p.000109: drug product (formulation and com- position), and method of use patent issued before the
p.000109: application is filed with FDA and for which patent infor- mation is required to be submitted under
...
p.000115: (3) Notwithstanding the requirements of paragraphs (b) and (c) of this sec- tion, an applicant must make a
p.000115: change provided for in those paragraphs in ac- cordance with a regulation or guidance that provides for a less
p.000115: burdensome no- tification of the change (for example, by submission of a supplement that does not
p.000115: require approval prior to dis- tribution of the product or in an an- nual report).
p.000115: (4) The applicant must promptly re- vise all promotional labeling and ad- vertising to make it consistent
p.000115: with any labeling change implemented in accordance with paragraphs (b) and (c) of this section.
p.000115: (5) Except for a supplement providing for a change in the labeling, the appli- cant must include in each
p.000115: supplement and amendment to a supplement pro- viding for a change under paragraph (b) or (c) of this section a
p.000115: statement certi- fying that a field copy has been pro- vided in accordance with § 314.440(a)(4).
p.000115: (6) A supplement or annual report must include a list of all changes con- tained in the supplement
p.000115: or annual re- port. For supplements, this list must be provided in the cover letter.
p.000115: (b) Changes requiring supplement sub- mission and approval prior to distribution of the product made
p.000115: using the change (major changes). (1) A supplement must be submitted for any change in the drug
p.000115: substance, drug product, produc- tion process, quality controls, equip- ment, or facilities that has a
p.000115: substan- tial potential to have an adverse effect on the identity, strength, quality, pu- rity, or potency of
p.000115: the drug product as these factors may relate to the safety or effectiveness of the drug product.
p.000115: (2) These changes include, but are not limited to:
p.000115: (i) Except those described in para- graphs (c) and (d) of this section,
p.000116: 116
p.000116:
p.000116:
p.000116:
p.000116:
p.000116:
p.000116:
p.000116:
p.000116: Food and Drug Administration, HHS § 314.70
p.000116:
p.000116:
p.000116: changes in the qualitative or quan- titative formulation of the drug prod- uct, including inactive
p.000116: ingredients, or in the specifications provided in the approved application;
p.000116: (ii) Changes requiring completion of studies in accordance with part 320 of this chapter to
p.000116: demonstrate the equivalence of the drug product to the drug product as manufactured without the change
p.000116: or to the reference listed drug;
p.000116: (iii) Changes that may affect drug substance or drug product sterility as- surance, such as changes
p.000116: in drug sub- stance, drug product, or component sterilization method(s) or an addition, deletion, or
p.000116: substitution of steps in an aseptic processing operation;
p.000116: (iv) Changes in the synthesis or man- ufacture of the drug substance that may affect the impurity profile
p.000116: and/or the physical, chemical, or biological properties of the drug substance;
p.000116: (v) The following labeling changes:
p.000116: (A) Changes in labeling, except those described in paragraphs (c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of
p.000116: this section;
p.000116: (B) If applicable, any change to a Medication Guide required under part 208 of this chapter, except
p.000116: for changes in the information specified in
p.000116: § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and
p.000116: (C) Any change to the information required by § 201.57(a) of this chapter, with the following exceptions that
p.000116: may be reported in an annual report under paragraph (d)(2)(x) of this section:
p.000116: (1) Removal of a listed section(s) specified in § 201.57(a)(5) of this chapter; and
p.000116: (2) Changes to the most recent revi- sion date of the labeling as specified in
p.000116: § 201.57(a)(15) of this chapter.
p.000116: (vi) Changes in a drug product con- tainer closure system that controls the drug product delivered to a
p.000116: patient or changes in the type (e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl chloride,
p.000116: vial to syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a packaging component
p.000116: that may affect the impu- rity profile of the drug product.
p.000116: (vii) Changes solely affecting a nat- ural product, a recombinant DNA-de- rived protein/polypeptide, or a
p.000116: complex
p.000116:
p.000116: or conjugate of a drug substance with a monoclonal antibody for the following:
p.000116: (A) Changes in the virus or adven- titious agent removal or inactivation method(s);
p.000116: (B) Changes in the source material or cell line; and
p.000116: (C) Establishment of a new master cell bank or seed.
p.000116: (viii) Changes to a drug product under an application that is subject to a validity assessment
p.000116: because of sig- nificant questions regarding the integ- rity of the data supporting that appli- cation.
p.000116: (3) The applicant must obtain ap- proval of a supplement from FDA prior to distribution of a drug
p.000116: product made using a change under paragraph (b) of this section. Except for submissions under paragraph
p.000116: (e) of this section, the following information must be con- tained in the supplement:
p.000116: (i) A detailed description of the pro- posed change;
p.000116: (ii) The drug product(s) involved;
p.000116: (iii) The manufacturing site(s) or area(s) affected;
p.000116: (iv) A description of the methods used and studies performed to assess the effects of the change;
p.000116: (v) The data derived from such stud- ies;
p.000116: (vi) For a natural product, a recom- binant DNA-derived protein/ polypeptide, or a
p.000116: complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and a list
p.000116: of relevant standard oper- ating procedures must be provided in addition to the requirements in para-
p.000116: graphs (b)(3)(iv) and (b)(3)(v) of this section; and
p.000116: (vii) For sterilization process and test methodologies related to steriliza- tion process validation,
p.000116: relevant vali- dation protocols and a list of relevant standard operating procedures must be provided in
p.000116: addition to the require- ments in paragraphs (b)(3)(iv) and (b)(3)(v) of this section.
p.000116: (4) An applicant may ask FDA to ex- pedite its review of a supplement for public health reasons or if
p.000116: a delay in making the change described in it would impose an extraordinary hard- ship on the
p.000116: applicant. Such a supple- ment and its mailing cover should be
p.000117: 117
p.000117:
p.000117:
p.000117:
p.000117:
p.000117:
p.000117:
p.000117:
p.000117:
p.000117: § 314.70
p.000117: plainly marked: ‘‘Prior Approval Sup- plement-Expedited Review Requested.’’
p.000117: (c) Changes requiring supplement sub- mission at least 30 days prior to distribu- tion of the drug
p.000117: product made using the change (moderate changes). (1) A supple- ment must be submitted for any
p.000117: change in the drug substance, drug product, production process, quality controls, equipment, or
p.000117: facilities that has a moderate potential to have an adverse effect on the identity,
p.000117: strength, quality, purity, or potency of the drug product as these factors may relate to the safety or
p.000117: effectiveness of the drug product. If the supplement provides for a labeling change under
p.000117: paragraph (c)(6)(iii) of this section, 12 copies of the final printed labeling must be included.
p.000117: (2) These changes include, but are not limited to:
p.000117: (i) A change in the container closure system that does not affect the quality of the drug product, except
p.000117: those de- scribed in paragraphs (b) and (d) of this section; and
p.000117: (ii) Changes solely affecting a nat- ural protein, a recombinant DNA-de- rived protein/polypeptide or a
p.000117: complex or conjugate of a drug substance with a monoclonal antibody, including:
p.000117: (A) An increase or decrease in pro- duction scale during finishing steps that involves different
p.000117: equipment; and
p.000117: (B) Replacement of equipment with that of a different design that does not affect the process methodology or proc-
p.000117: ess operating parameters.
p.000117: (iii) Relaxation of an acceptance cri- terion or deletion of a test to comply with an official
p.000117: compendium that is consistent with FDA statutory and reg- ulatory requirements.
p.000117: (3) A supplement submitted under paragraph (c)(1) of this section is re- quired to give a full
p.000117: explanation of the basis for the change and identify the date on which the change is to be made.
p.000117: The supplement must be labeled ‘‘Supplement—Changes Being Effected in 30 Days’’ or, if applicable
p.000117: under paragraph (c)(6) of this section, ‘‘Sup- plement—Changes Being Effected.’’
p.000117: (4) Pending approval of the supple- ment by FDA, except as provided in paragraph (c)(6) of this
p.000117: section, dis- tribution of the drug product made using the change may begin not less
p.000117: 21 CFR Ch. I (4–1–12 Edition)
p.000117: than 30 days after receipt of the supple- ment by FDA. The information listed in paragraphs (b)(3)(i)
p.000117: through (b)(3)(vii) of this section must be con- tained in the supplement.
p.000117: (5) The applicant must not distribute the drug product made using the change if within 30 days
p.000117: following FDA’s receipt of the supplement, FDA informs the applicant that either:
p.000117: (i) The change requires approval prior to distribution of the drug prod- uct in accordance with
p.000117: paragraph (b) of this section; or
p.000117: (ii) Any of the information required under paragraph (c)(4) of this section is missing; the applicant must
p.000117: not dis- tribute the drug product made using the change until the supplement has been amended to provide
p.000117: the missing information.
p.000117: (6) The agency may designate a cat- egory of changes for the purpose of pro- viding that, in the case of a
p.000117: change in such category, the holder of an ap- proved application may commence dis- tribution of the
p.000117: drug product involved upon receipt by the agency of a supple- ment for the change. These changes in- clude, but are
p.000117: not limited to:
p.000117: (i) Addition to a specification or changes in the methods or controls to provide increased
p.000117: assurance that the drug substance or drug product will have the characteristics of identity,
p.000117: strength, quality, purity, or potency that it purports or is represented to possess;
p.000117: (ii) A change in the size and/or shape of a container for a nonsterile drug product, except for solid
p.000117: dosage forms, without a change in the labeled amount of drug product or from one container
p.000117: closure system to another;
p.000117: (iii) Changes in the labeling to reflect newly acquired information, except for changes to the information
p.000117: required in
p.000117: § 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish
p.000117: any of the following:
p.000117: (A) To add or strengthen a contra- indication, warning, precaution, or ad- verse reaction for which the
p.000117: evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c)
p.000117: of this chapter;
p.000118: 118
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118: Food and Drug Administration, HHS § 314.70
p.000118:
p.000118:
p.000118: (B) To add or strengthen a statement about drug abuse, dependence, psycho- logical effect, or overdosage;
p.000118: (C) To add or strengthen an instruc- tion about dosage and administration that is intended to increase
p.000118: the safe use of the drug product;
p.000118: (D) To delete false, misleading, or un- supported indications for use or claims for effectiveness; or
p.000118: (E) Any labeling change normally re- quiring a supplement submission and approval prior to distribution of
p.000118: the drug product that FDA specifically re- quests be submitted under this provi- sion.
p.000118: (7) If the agency disapproves the sup- plemental application, it may order the manufacturer to cease
p.000118: distribution of the drug product(s) made with the manufacturing change.
p.000118: (d) Changes to be described in an an- nual report (minor changes). (1) Changes in the drug substance,
p.000118: drug product, production process, quality controls, equipment, or facilities that have a minimal
p.000118: potential to have an adverse effect on the identity, strength, qual- ity, purity, or potency of the
p.000118: drug product as these factors may relate to the safety or effectiveness of the drug product must be
p.000118: documented by the ap- plicant in the next annual report in ac- cordance with § 314.81(b)(2).
p.000118: (2) These changes include, but are not
p.000118: limited to:
p.000118: (i) Any change made to comply with a change to an official compendium, except a change described in
p.000118: paragraph (c)(2)(iii) of this section, that is con- sistent with FDA statutory and regu- latory
p.000118: requirements.
p.000118: (ii) The deletion or reduction of an ingredient intended to affect only the color of the drug product;
p.000118: (iii) Replacement of equipment with that of the same design and operating principles except those
p.000118: equipment changes described in paragraph (c) of this section;
p.000118: (iv) A change in the size and/or shape of a container containing the same number of dosage units for a
p.000118: nonsterile solid dosage form drug product, with- out a change from one container clo- sure system to
p.000118: another;
...
p.000118: imprint;
p.000118: (ix) A change in the labeling con- cerning the description of the drug product or in the
p.000118: information about how the drug product is supplied, that does not involve a change in the dosage strength or
p.000118: dosage form; and
p.000118: (x) An editorial or similar minor change in labeling, including a change to the information
p.000118: allowed by para- graphs (b)(2)(v)(C)(1) and (2) of this sec- tion.
p.000118: (3) For changes under this category, the applicant is required to submit in the annual report:
p.000118: (i) A statement by the holder of the approved application that the effects of the change have been assessed;
p.000118: (ii) A full description of the manufac- turing and controls changes, including the manufacturing site(s) or area(s)
p.000118: in- volved;
p.000118: (iii) The date each change was imple- mented;
p.000118: (iv) Data from studies and tests per- formed to assess the effects of the change; and,
p.000118: (v) For a natural product, recom- binant DNA-derived protein/ polypeptide, complex or
p.000118: conjugate of a drug substance with a monoclonal anti- body, sterilization process or test methodology
p.000118: related to sterilization process validation, a cross-reference to relevant validation protocols and/or
p.000118: standard operating procedures.
p.000119: 119
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119: § 314.71
p.000119: (e) Protocols. An applicant may sub- mit one or more protocols describing the specific tests and studies
p.000119: and ac- ceptance criteria to be achieved to demonstrate the lack of adverse effect for specified
p.000119: types of manufacturing changes on the identity, strength, quality, purity, and potency of the
p.000119: drug product as these factors may re- late to the safety or effectiveness of the drug product. Any such
p.000119: protocols, if not included in the approved applica- tion, or changes to an approved pro- tocol, must be
p.000119: submitted as a supple- ment requiring approval from FDA prior to distribution of a drug product
p.000119: produced with the manufacturing change. The supplement, if approved, may subsequently justify a
p.000119: reduced re- porting category for the particular change because the use of the protocol for that type of
p.000119: change reduces the po- tential risk of an adverse effect.
p.000119: (f) Patent information. The applicant
...
p.000133: approval of a drug product that differs from the reference listed drug in preservative, buffer, or
p.000133: antioxidant provided that the applicant identifies and characterizes the differences and provides
p.000133: information demonstrating that the differences do not affect the safety or efficacy of the proposed drug
p.000133: product.
p.000133: (iv) Inactive ingredient changes per-
p.000133: mitted in drug products intended for oph- thalmic or otic use. Generally, a drug product intended
p.000133: for ophthalmic or otic use shall contain the same inac- tive ingredients and in the same con-
p.000133: centration as the reference listed drug identified by the applicant under para- graph (a)(3) of this
p.000133: section. However, an applicant may seek approval of a drug product that differs from the ref- erence
p.000133: listed drug in preservative, buff- er, substance to adjust tonicity, or thickening agent provided that
p.000133: the ap- plicant identifies and characterizes the differences and provides information demonstrating that the
p.000133: differences do not affect the safety or efficacy of the proposed drug product, except that, in a product
p.000133: intended for ophthalmic use, an applicant may not change a buffer or substance to adjust tonicity for
p.000133: the purpose of claiming a therapeutic ad- vantage over or difference from the listed drug, e.g., by
p.000133: using a balanced salt solution as a diluent as opposed to an isotonic saline solution, or by mak- ing a
p.000133: significant change in the pH or other change that may raise questions of irritability.
p.000133: (v) Inactive ingredient changes per-
p.000133: mitted in drug products intended for top- ical use. Generally, a drug product in- tended for topical
p.000133: use, solutions for
p.000134: 134
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134: Food and Drug Administration, HHS § 314.94
p.000134:
p.000134:
p.000134: aerosolization or nebulization, and nasal solutions shall contain the same inactive ingredients as
p.000134: the reference listed drug identified by the applicant under paragraph (a)(3) of this section. However, an
p.000134: abbreviated application may include different inactive ingredi- ents provided that the applicant identi- fies
p.000134: and characterizes the differences and provides information dem- onstrating that the differences
...
p.000146: (Name of patent o ner or exclusive patent licensee) waives the opportunity provided by (section
p.000146: 505(c)(3)(C) or 505(j)(B)(iii) of the act) and does not object to FDA’s approval of (name of ap-
p.000146: plicant)’s (505(b)(2) or abbreviated ne drug ap- plication) for (name of drug) with an imme- diate effective
p.000146: date on or after the date of this letter.
p.000146: [59 FR 50367, Oct. 3, 1994, as amended at 63 FR
p.000146: 59712, Nov. 5, 1998; 65 FR 43235, July 13, 2000;
p.000146: 73 FR 39609, July 10, 2008; 74 FR 9766, Mar. 6,
p.000146: 2009]
p.000146:
p.000146: § 314.108 New drug product exclu- sivity.
p.000146: (a) Definitions. The following defini- tions of terms apply to this section:
p.000146: Active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the
p.000146: drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent
p.000146: derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physio- logical
p.000146: or pharmacological action of the drug substance.
p.000146: Approved under section 505(b) means an application submitted under section 505(b) and approved on or after
p.000146: October
p.000147: 147
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147:
p.000147: § 314.108
p.000147: 10, 1962, or an application that was ‘‘deemed approved’’ under section 107(c)(2) of Pub. L.
p.000147: 87–781.
p.000147: Clinical investigation means any ex- periment other than a bioavailability study in which a drug is
p.000147: administered or dispensed to, or used on, human sub- jects.
p.000147: Conducted or sponsored by the appli- cant with regard to an investigation means that before or
p.000147: during the inves- tigation, the applicant was named in Form FDA–1571 filed with FDA as the sponsor of the
p.000147: investigational new drug application under which the investiga- tion was conducted, or the applicant or the
p.000147: applicant’s predecessor in interest, provided substantial support for the in- vestigation. To demonstrate ‘‘substan-
p.000147: tial support,’’ an applicant must either provide a certified statement from a certified public accountant that the
p.000147: ap- plicant provided 50 percent or more of the cost of conducting the study or provide an
p.000147: explanation why FDA should consider the applicant to have conducted or sponsored the study if the
p.000147: applicant’s financial contribution to the study is less than 50 percent or the applicant did not sponsor
...
p.000150: the petitioner concerning the reason that marketing of the drug product ceased.
p.000150: [57 FR 17990, Apr. 28, 1992; 57 FR 29353, July
p.000150: 1, 1992]
p.000150:
p.000150: § 314.125 Refusal to approve an appli- cation.
p.000150: (a) The Food and Drug Administra- tion will refuse to approve the applica- tion and for a new drug give the
p.000150: appli- cant written notice of an opportunity for a hearing under § 314.200 on the question of
p.000150: whether there are grounds for denying approval of the application under section 505(d) of the act, if:
p.000150: (1) FDA sends the applicant a com- plete response letter under § 314.110;
p.000150:
p.000150: (2) The applicant requests an oppor- tunity for hearing for a new drug on the question of whether the
p.000150: application is approvable; and
p.000150: (3) FDA finds that any of the reasons given in paragraph (b) of this section apply.
p.000150: (b) FDA may refuse to approve an ap- plication for any of the following rea- sons:
p.000150: (1) The methods to be used in, and the facilities and controls used for, the manufacture, processing,
p.000150: packing, or holding of the drug substance or the drug product are inadequate to pre- serve its
p.000150: identity, strength, quality, purity, stability, and bioavailability.
p.000150: (2) The investigations required under section 505(b) of the act do not include adequate tests by all
p.000150: methods reason- ably applicable to show whether or not the drug is safe for use under the condi- tions prescribed,
p.000150: recommended, or sug- gested in its proposed labeling.
p.000150: (3) The results of the tests show that the drug is unsafe for use under the conditions prescribed,
p.000150: recommended, or suggested in its proposed labeling or the results do not show that the drug product is safe for
p.000150: use under those con- ditions.
p.000150: (4) There is insufficient information about the drug to determine whether the product is safe for use
p.000150: under the conditions prescribed, recommended, or suggested in its proposed labeling.
p.000150: (5) There is a lack of substantial evi- dence consisting of adequate and well- controlled investigations, as
p.000150: defined in
p.000150: § 314.126, that the drug product will have the effect it purports or is rep- resented to have under
...
p.000150: (6) The proposed labeling is false or misleading in any particular.
p.000150: (7) The application contains an un- true statement of a material fact.
p.000150: (8) The drug product’s proposed label- ing does not comply with the require- ments for labels and labeling
p.000150: in part 201.
p.000150: (9) The application does not contain bioavailability or bioequivalence data required under part 320 of this
p.000150: chapter.
p.000150: (10) A reason given in a letter refus- ing to file the application under
p.000150: § 314.101(d), if the deficiency is not cor- rected.
p.000151: 151
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151: § 314.126
p.000151: (11) The drug will be manufactured or processed in whole or in part in an es- tablishment that is not
p.000151: registered and not exempt from registration under section 510 of the act and part 207.
p.000151: (12) The applicant does not permit a properly authorized officer or employee of the Department of
p.000151: Health and Human Services an adequate oppor- tunity to inspect the facilities, con- trols, and
p.000151: any records relevant to the application.
p.000151: (13) The methods to be used in, and the facilities and controls used for, the manufacture, processing,
p.000151: packing, or holding of the drug substance or the drug product do not comply with the current good
p.000151: manufacturing practice regulations in parts 210 and 211.
p.000151: (14) The application does not contain an explanation of the omission of a re- port of any investigation
p.000151: of the drug product sponsored by the applicant, or an explanation of the omission of other information about
p.000151: the drug pertinent to an evaluation of the application that is received or otherwise obtained by the
p.000151: applicant from any source.
p.000151: (15) A nonclinical laboratory study that is described in the application and that is essential to show
p.000151: that the drug is safe for use under the conditions pre- scribed, recommended, or suggested in its proposed
p.000151: labeling was not con- ducted in compliance with the good laboratory practice regulations in part 58
p.000151: of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the
p.000151: practices used in conducting the study and the good laboratory practice regulations do not support the validity
p.000151: of the study.
p.000151: (16) Any clinical investigation in-
p.000151: volving human subjects described in the application, subject to the institu- tional review board
...
p.000155: it contains the same in- active ingredients, other than preserv- atives, buffers, and antioxidants, in the same
p.000155: concentration as the listed drug,
p.000155: 21 CFR Ch. I (4–1–12 Edition)
p.000155: and, if it differs from the listed drug in a preservative, buffer, or antioxidant, the application contains
p.000155: sufficient in- formation to demonstrate that the dif- ference does not affect the safety or ef- ficacy of the
p.000155: drug product.
p.000155: (C) FDA will consider an inactive in- gredient in, or the composition of, a drug product intended for
p.000155: ophthalmic or otic use unsafe and will refuse to ap- prove the abbreviated new drug appli- cation unless it
p.000155: contains the same in- active ingredients, other than preserv- atives, buffers, substances to adjust to- nicity,
p.000155: or thickening agents, in the same concentration as the listed drug, and if it differs from the
p.000155: listed drug in a preservative, buffer, substance to ad- just tonicity, or thickening agent, the application
p.000155: contains sufficient infor- mation to demonstrate that the dif- ference does not affect the safety or
p.000155: ef- ficacy of the drug product and the la- beling does not claim any therapeutic advantage over or
p.000155: difference from the listed drug.
p.000155: (9) Approval of the listed drug re- ferred to in the abbreviated new drug application has been
p.000155: withdrawn or sus- pended for grounds described in
p.000155: § 314.150(a) or FDA has published a no- tice of opportunity for hearing to with- draw approval of the
p.000155: reference listed drug under § 314.150(a).
p.000155: (10) Approval of the listed drug re- ferred to in the abbreviated new drug application has been
p.000155: withdrawn under
p.000155: § 314.151 or FDA has proposed to with- draw approval of the reference listed drug under § 314.151(a).
...
p.000167: the Com- missioner enters an order without a hearing under § 314.200(g), the record certified by
p.000167: the Commissioner is re- quired to include the requests for hear- ing together with the data and infor-
p.000167: mation submitted and the Commis- sioner’s findings and conclusion.
p.000167: (b) A manufacturer or distributor of
p.000167: an identical, related, or similar drug product under § 310.6 may seek judicial review of an order
p.000167: withdrawing ap- proval of a new drug application, whether or not a hearing has been held, in a
p.000167: United States court of appeals under section 505(h) of the act.
p.000167: Subpart F [Reserved]
p.000167: Subpart G—Miscellaneous Provisions
p.000167: SOURCE: 50 FR 7493, Feb. 22, 1985, unless
p.000167: otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992.
p.000167:
p.000167: § 314.410 Imports and exports of new drugs.
p.000167: (a) Imports. (1) A new drug may be im- ported into the United States if: (i) It is the subject of an
p.000167: approved applica- tion under this part; or (ii) it complies with the regulations pertaining to in-
p.000167: vestigational new drugs under part 312; and it complies with the general regu- lations pertaining to
p.000167: imports under subpart E of part 1.
p.000167: (2) A drug substance intended for use in the manufacture, processing, or re- packing of a new drug may be imported
p.000167: into the United States if it complies with the labeling exemption in § 201.122 pertaining to shipments of
p.000167: drug sub- stances in domestic commerce.
p.000167: (b) Exports. (1) A new drug may be ex- ported if it is the subject of an ap- proved application under
p.000167: this part or it complies with the regulations per- taining to investigational new drugs under part
p.000167: 312.
p.000167: 21 CFR Ch. I (4–1–12 Edition)
p.000167: (2) A new drug substance that is cov- ered by an application approved under this part for use in the manufacture
p.000167: of an approved drug product may be ex- ported by the applicant or any person listed as a supplier in the
p.000167: approved ap- plication, provided the drug substance intended for export meets the speci- fication of,
p.000167: and is shipped with a copy of the labeling required for, the ap- proved drug product.
p.000167: (3) Insulin or an antibiotic drug may be exported without regard to the re- quirements in section 802
p.000167: of the act if the insulin or antibiotic drug meets the requirements of section 801(e)(1) of the act.
p.000167: [50 FR 7493, Feb. 22, 1985, unless otherwise
p.000167: noted. Redesignated at 57 FR 17983, Apr. 28,
p.000167: 1992, and amended at 64 FR 402, Jan. 5, 1999;
p.000167: 69 FR 18766, Apr. 8, 2004]
p.000167: § 314.420 Drug master files.
p.000167: (a) A drug master file is a submission of information to the Food and Drug Administration by a person (the
p.000167: drug master file holder) who intends it to be used for one of the following purposes: To permit the holder
p.000167: to incorporate the information by reference when the holder submits an investigational new drug
p.000167: application under part 312 or sub- mits an application or an abbreviated application or an amendment or
p.000167: sup- plement to them under this part, or to permit the holder to authorize other persons to rely on the
p.000167: information to support a submission to FDA without the holder having to disclose the infor- mation to the
p.000167: person. FDA ordinarily neither independently reviews drug master files nor approves or dis-
p.000167: approves submissions to a drug master file. Instead, the agency customarily reviews the information
p.000167: only in the context of an application under part 312 or this part. A drug master file may contain
p.000167: information of the kind re- quired for any submission to the agen- cy, including information about
p.000167: the following:
p.000167: (1) [Reserved]
p.000167: (2) Drug substance, drug substance intermediate, and materials used in their preparation, or drug
p.000167: product;
p.000167: (3) Packaging materials;
p.000167: (4) Excipient, colorant, flavor, es- sence, or materials used in their prepa- ration;
p.000168: 168
p.000168:
p.000168:
p.000168:
p.000168:
p.000168:
p.000168:
p.000168:
p.000168: Food and Drug Administration, HHS § 314.430
p.000168:
p.000168:
p.000168: (5) FDA-accepted reference informa- tion. (A person wishing to submit in- formation and supporting data
p.000168: in a drug master file (DMF) that is not cov- ered by Types II through IV DMF’s must first submit a
p.000168: letter of intent to the Drug Master File Staff, Food and Drug Administration, 5901–B
p.000168: Ammendale Rd., Beltsville, MD 20705– 1266.) FDA will then contact the person to discuss the proposed submission.
p.000168: (b) An investigational new drug ap- plication or an application, abbre- viated application, amendment,
...
p.000173: tions would no longer apply when FDA determines that safe use of the drug product can be assured through
p.000173: appro- priate labeling. FDA also retains the discretion to remove specific post- approval requirements
p.000173: upon review of a petition submitted by the sponsor in accordance with § 10.30.
p.000173:
p.000173: Subpart I—Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible
p.000173:
p.000173: SOURCE: 67 FR 37995, May 31, 2002, unless
p.000173: otherwise noted.
p.000173:
p.000173: § 314.600 Scope.
p.000173: This subpart applies to certain new drug products that have been studied for their safety and efficacy
p.000173: in amelio- rating or preventing serious or life- threatening conditions caused by expo- sure to lethal or
p.000173: permanently disabling toxic biological, chemical, radio- logical, or nuclear substances. This
p.000173: subpart applies only to those new drug products for which: Definitive human efficacy studies cannot be
p.000173: conducted because it would be unethical to delib- erately expose healthy human volun- teers to a lethal
p.000173: or permanently dis- abling toxic biological, chemical, radi- ological, or nuclear substance; and
p.000173: field trials to study the product’s effec- tiveness after an accidental or hostile exposure have not been
p.000173: feasible. This subpart does not apply to products that can be approved based on efficacy standards
p.000173: described elsewhere in FDA’s regulations (e.g., accelerated approval based on surrogate markers or clinical
p.000173: endpoints other than survival or irre- versible morbidity), nor does it address the safety evaluation for the
p.000173: products to which it does apply.
p.000173: § 314.610 Approval based on evidence of effectiveness from studies in ani- mals.
p.000173: (a) FDA may grant marketing ap- proval for a new drug product for which safety has been established
p.000173: and for which the requirements of § 314.600 are
p.000174: 174
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174: Food and Drug Administration, HHS § 314.620
p.000174:
p.000174:
p.000174: met based on adequate and well-con- trolled animal studies when the results of those animal studies establish
p.000174: that the drug product is reasonably likely to produce clinical benefit in humans. In assessing the
p.000174: sufficiency of animal data, the agency may take into ac- count other data, including human data,
p.000174: available to the agency. FDA will rely on the evidence from studies in animals to provide substantial
p.000174: evi- dence of the effectiveness of these products only when:
p.000174: (1) There is a reasonably well-under-
p.000174: stood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial
p.000174: reduction by the product;
p.000174: (2) The effect is demonstrated in more than one animal species expected to react with a response
p.000174: predictive for humans, unless the effect is dem- onstrated in a single animal species that
p.000174: represents a sufficiently well- characterized animal model for pre- dicting the response in humans;
p.000174: (3) The animal study endpoint is clearly related to the desired benefit in humans, generally the
p.000174: enhancement of survival or prevention of major mor- bidity; and
p.000174: (4) The data or information on the ki- netics and pharmacodynamics of the product or other relevant data or
p.000174: infor- mation, in animals and humans, allows selection of an effective dose in hu- mans.
p.000174: (b) Approval under this subpart will be subject to three requirements:
p.000174: (1) Postmarketing studies. The appli- cant must conduct postmarketing studies, such as field
p.000174: studies, to verify and describe the drug’s clinical benefit and to assess its safety when used as
p.000174: indicated when such studies are fea- sible and ethical. Such postmarketing studies would not be
p.000174: feasible until an exigency arises. When such studies are feasible, the applicant must conduct such
p.000174: studies with due diligence. Appli- cants must include as part of their ap- plication a plan or approach
p.000174: to post- marketing study commitments in the event such studies become ethical and feasible.
p.000174: (2) Approval ith restrictions to ensure
...
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p.000119: distributor.
p.000119: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000119: 1985, as amended at 50 FR 21238, May 23, 1985;
p.000119: 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12,
p.000119: 2003]
p.000119:
p.000119: § 314.80 Postmarketing reporting of adverse drug experiences.
p.000119: (a) Definitions. The following defini- tions of terms apply to this section:
p.000120: 120
p.000120:
p.000120:
p.000120:
p.000120:
p.000120:
p.000120:
p.000120:
p.000120: Food and Drug Administration, HHS § 314.80
p.000120:
p.000120:
p.000120: Adverse drug experience. Any adverse event associated with the use of a drug in humans, whether or not
p.000120: considered drug related, including the following: An adverse event occurring in the course of the use
p.000120: of a drug product in professional practice; an adverse event occurring from drug overdose whether
p.000120: accidental or intentional; an adverse event occurring from drug abuse; an adverse event
p.000120: occurring from drug withdrawal; and any failure of expected pharmacological action.
p.000120: Disability. A substantial disruption of
p.000120: a person’s ability to conduct normal life functions.
p.000120: Life-threatening adverse drug experi- ence. Any adverse drug experience that places the patient, in the
p.000120: view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred,
p.000120: i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have
p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
p.000120: includes events that may be symptomatically and pathophysiologically related to an event listed
p.000120: in the labeling, but differ from the event because of greater se-
p.000120:
...
Health / ill
Searching for indicator ill:
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p.000092: 314.160 Approval of an application or abbre- viated application for which approval was previously
p.000092: refused, suspended, or withdrawn.
p.000092: 314.161 Determination of reasons for vol- untary withdrawal of a listed drug.
p.000092: 314.162 Removal of a drug product from the list.
p.000092: 314.170 Adulteration and misbranding of an approved drug.
p.000092:
p.000092: Subpart E—Hearing Procedures for New Drugs
p.000092: 314.200 Notice of opportunity for hearing; notice of participation and request for hearing; grant or
p.000092: denial of hearing.
p.000092: 314.201 Procedure for hearings.
p.000092: 314.235 Judicial review.
p.000092:
p.000092: Subpart F [Reserved]
p.000092: Subpart G—Miscellaneous Provisions
p.000092: 314.410 Imports and exports of new drugs.
p.000092: 314.420 Drug master files.
p.000092: 314.430 Availability for public disclosure of data and information in an application or abbreviated
p.000092: application.
p.000092: 314.440 Addresses for applications and ab- breviated applications.
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092: Food and Drug Administration, HHS § 314.3
p.000092:
p.000092:
p.000092: 314.445 Guidance documents.
p.000092:
p.000092: Subpart H—Accelerated Approval of New Drugs for Serious or Life-Threatening Ill- nesses
p.000092: 314.500 Scope.
p.000092: 314.510 Approval based on a surrogate end- point or on an effect on a clinical end- point other than
p.000092: survival or irreversible morbidity.
p.000092: 314.520 Approval with restrictions to assure safe use.
p.000092: 314.530 Withdrawal procedures.
p.000092: 314.540 Postmarketing safety reporting.
p.000092: 314.550 Promotional materials.
p.000092: 314.560 Termination of requirements.
p.000092:
p.000092: Subpart I—Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible
p.000092: 314.600 Scope.
p.000092: 314.610 Approval based on evidence of effec- tiveness from studies in animals.
p.000092: 314.620 Withdrawal procedures.
p.000092: 314.630 Postmarketing safety reporting. 314.640 Promotional materials.
p.000092: 314.650 Termination of requirements.
p.000092: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000092: 355, 356, 356a, 356b, 356c, 371, 374, 379e.
p.000092: SOURCE: 50 FR 7493, Feb. 22, 1985, unless
p.000092: otherwise noted.
p.000092: EDITORIAL NOTE: Nomenclature changes to part 314 can be found at 69 FR 13717, Mar. 24,
p.000092: 2004.
p.000092:
p.000092: Subpart A—General Provisions
p.000092: § 314.1 Scope of this part.
p.000092: (a) This part sets forth procedures and requirements for the submission to, and the review by,
p.000092: the Food and Drug Administration of applications and abbreviated applications to market a new drug under
p.000092: section 505 of the Federal Food, Drug, and Cosmetic Act, as well as amendments, supplements, and
...
p.000101: relied upon by the applicant for approval of its application were conducted or that claims an approved
p.000101: use for such drug and for which information is required to be filed under section 505(b) and (c) of the
p.000101: act and § 314.53. For each such patent, the applicant shall provide the patent number and certify, in
p.000101: its opin- ion and to the best of its knowledge, one of the following circumstances:
p.000101: (1) That the patent information has not been submitted to FDA. The appli- cant shall entitle such a
p.000101: certification ‘‘Paragraph I Certification’’;
p.000101: 21 CFR Ch. I (4–1–12 Edition)
p.000101: (2) That the patent has expired. The applicant shall entitle such a certifi- cation ‘‘Paragraph II
p.000101: Certification’’;
p.000101: (3) The date on which the patent will expire. The applicant shall entitle such a certification ‘‘Paragraph III
p.000101: Certifi- cation’’; or
p.000101: (4) That the patent is invalid, unen- forceable, or will not be infringed by the manufacture, use, or
p.000101: sale of the drug product for which the application is submitted. The applicant shall enti- tle such a
p.000101: certification ‘‘Paragraph IV Certification’’. This certification shall be submitted in the following form:
p.000101: I, (name of applicant), certify that Patent No. llllll (is invalid, unenforceable, or ill not be infringed
p.000101: by the manufacture, use, or sale of) (name of proposed drug product) for which this application
p.000101: is submitted.
p.000101: The certification shall be accompanied by a statement that the applicant will comply with the
p.000101: requirements under
p.000101: § 314.52(a) with respect to providing a notice to each owner of the patent or their representatives and
p.000101: to the holder of the approved application for the drug product which is claimed by the patent or a
p.000101: use of which is claimed by the patent and with the requirements under § 314.52(c) with respect to
p.000101: the content of the notice.
p.000101: (B) If the drug on which investiga- tions that are relied upon by the appli- cant were conducted is itself a
p.000101: licensed generic drug of a patented drug first approved under section 505(b) of the act, the
p.000101: appropriate patent certifi- cation under this section with respect to each patent that claims the first-ap-
p.000101: proved patented drug or that claims an approved use for such a drug.
p.000101: (ii) No relevant patents. If, in the opin- ion of the applicant and to the best of its knowledge, there are no
p.000101: patents de- scribed in paragraph (i)(1)(i) of this sec- tion, a certification in the following form:
...
p.000134: issued by the United States Patent and Trademark Office that, in the opinion of the applicant and to the
p.000134: best of its knowledge, claims the reference listed drug or that claims a use of such listed drug for which the
p.000134: applicant is seeking approval under section 505(j) of the act and for which information is required to be filed
p.000134: under section 505(b) and (c) of the act and § 314.53. For each such patent, the applicant shall provide
p.000134: the patent number and certify, in its opin- ion and to the best of its knowledge, one of the following
p.000134: circumstances:
p.000134: (1) That the patent information has not been submitted to FDA. The appli- cant shall entitle such a
p.000134: certification ‘‘Paragraph I Certification’’;
p.000134: (2) That the patent has expired. The applicant shall entitle such a certifi- cation ‘‘Paragraph II
p.000134: Certification’’;
p.000134: (3) The date on which the patent will expire. The applicant shall entitle such a certification ‘‘Paragraph III
p.000134: Certifi- cation’’; or
p.000134: (4) That the patent is invalid, unen- forceable, or will not be infringed by the manufacture, use, or
p.000134: sale of the drug product for which the abbreviated application is submitted. The applicant shall entitle
p.000134: such a certification ‘‘Paragraph IV Certification’’. This cer- tification shall be submitted in the fol- lowing
p.000134: form:
p.000134:
p.000134: I, (name of applicant), certify that Patent No. llllll (is invalid, unenforceable, or ill not be infringed
p.000134: by the manufacture, use, or sale of) (name of proposed drug product) for
p.000134: which this application is submitted.
p.000134: The certification shall be accompanied by a statement that the applicant will comply with the
p.000134: requirements under
p.000134: § 314.95(a) with respect to providing a notice to each owner of the patent or their representatives and
p.000134: to the holder of the approved application for the list- ed drug, and with the requirements under §
p.000134: 314.95(c) with respect to the content of the notice.
p.000134: (B) If the abbreviated new drug appli- cation refers to a listed drug that is itself a licensed generic
p.000134: product of a patented drug first approved under sec- tion 505(b) of the act, the appropriate patent
p.000134: certification under paragraph (a)(12)(i) of this section with respect to each patent that claims the first-ap-
p.000134: proved patented drug or that claims a use for such drug.
p.000134: (ii) No relevant patents. If, in the opin-
p.000134: ion of the applicant and to the best of its knowledge, there are no patents de- scribed in paragraph
p.000134: (a)(12)(i) of this section, a certification in the following form:
...
p.000151: of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the
p.000151: practices used in conducting the study and the good laboratory practice regulations do not support the validity
p.000151: of the study.
p.000151: (16) Any clinical investigation in-
p.000151: volving human subjects described in the application, subject to the institu- tional review board
p.000151: regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter, was not
p.000151: conducted in compliance with those regulations such that the rights or safety of human subjects were not
p.000151: adequately protected.
p.000151: (17) The applicant or contract re- search organization that conducted a bioavailability or bioequivalence
p.000151: study described in § 320.38 or § 320.63 of this chapter that is contained in the appli- cation refuses to
p.000151: permit an inspection of facilities or records relevant to the
p.000151: 21 CFR Ch. I (4–1–12 Edition)
p.000151: study by a properly authorized officer or employee of the Department of Health and Human Services or
p.000151: refuses to submit reserve samples of the drug products used in the study when re- quested by FDA.
p.000151: (18) For a new drug, the application failed to contain the patent informa- tion required by section
p.000151: 505(b)(1) of the act.
p.000151: (c) For drugs intended to treat life- threatening or severely-debilitating ill- nesses that are developed in
p.000151: accordance with §§ 312.80 through 312.88 of this chapter, the criteria contained in para- graphs (b) (3),
p.000151: (4), and (5) of this section shall be applied according to the con- siderations contained in § 312.84 of
p.000151: this chapter.
p.000151: [50 FR 7493, Feb. 22, 1985, as amended at 53
p.000151: FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28,
p.000151: 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan.
p.000151: 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766,
p.000151: Mar. 6, 2009]
p.000151:
p.000151: § 314.126 Adequate and well-controlled studies.
p.000151: (a) The purpose of conducting clin- ical investigations of a drug is to dis- tinguish the effect of a drug
p.000151: from other influences, such as spontaneous change in the course of the disease, placebo ef- fect, or biased
p.000151: observation. The charac- teristics described in paragraph (b) of this section have been developed over a period
p.000151: of years and are recognized by the scientific community as the essen- tials of an adequate and
p.000151: well-con- trolled clinical investigation. The Food and Drug Administration considers these characteristics
p.000151: in determining whether an investigation is adequate and well-controlled for purposes of sec- tion 505 of the act.
p.000151: Reports of adequate and well-controlled investigations pro- vide the primary basis for determining whether
p.000151: there is ‘‘substantial evi- dence’’ to support the claims of effec- tiveness for new drugs.
...
p.000171: Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR
p.000171: 13473, Mar. 23, 2004; 70 FR 14981, Mar. 24, 2005;
p.000171: 73 FR 39610, July 10, 2008; 74 FR 13113, Mar.
p.000171: 26, 2009; 75 FR 37295, June 29, 2010]
p.000171: § 314.445 Guidance documents.
p.000171: (a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain
p.000171: re- quirements of this part.
p.000171: (b) The Center for Drug Evaluation and Research (CDER) maintains a list of guidance documents that apply
p.000171: to CDER’s regulations. The list is main- tained on the Internet and is published annually in the FEDERAL
p.000171: REGISTER. A request for a copy of the CDER list should be directed to the Office of Training and
p.000171: Communications, Divi- sion of Drug Information, Center for Drug Evaluation and Research, Food and
p.000171: Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993–0002.
p.000171: [65 FR 56480, Sept. 19, 2000, as amended at 74
p.000171: FR 13113, Mar. 26, 2009]
p.000171:
p.000171: Subpart H—Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses
p.000171: SOURCE: 57 FR 58958, Dec. 11, 1992, unless
p.000171: otherwise noted.
p.000171: § 314.500 Scope.
p.000171: This subpart applies to certain new drug products that have been studied for their safety and
p.000171: effectiveness in treating serious or life-threatening ill- nesses and that provide meaningful therapeutic
p.000171: benefit to patients over ex- isting treatments (e.g., ability to treat patients unresponsive to, or intolerant of,
p.000171: available therapy, or improved pa- tient response over available therapy).
p.000171: [57 FR 58958, Dec. 11, 1992, as amended at 64
p.000171: FR 402, Jan. 5, 1999]
p.000171:
p.000171: § 314.510 Approval based on a surro- gate endpoint or on an effect on a clinical endpoint other than
p.000171: sur- vival or irreversible morbidity.
p.000171: FDA may grant marketing approval for a new drug product on the basis of
p.000172: 172
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172: Food and Drug Administration, HHS § 314.530
p.000172:
p.000172:
p.000172: adequate and well-controlled clinical trials establishing that the drug prod- uct has an effect on a
p.000172: surrogate end- point that is reasonably likely, based on epidemiologic, therapeutic, patho- physiologic,
p.000172: or other evidence, to pre- dict clinical benefit or on the basis of an effect on a clinical endpoint
p.000172: other than survival or irreversible morbidity. Approval under this section will be subject to the requirement
p.000172: that the ap- plicant study the drug further, to verify and describe its clinical benefit, where
p.000172: there is uncertainty as to the re- lation of the surrogate endpoint to clinical benefit, or of the observed
...
Social / Access to Social Goods
Searching for indicator access:
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p.000100: (d) of this section.
p.000100: (1) The applicant ordinarily is not re- quired to resubmit information pre- viously submitted, but may
p.000100: incor- porate the information by reference. A reference to information submitted previously is
p.000100: required to identify the file by name, reference number, vol- ume, and page number in the agency’s
p.000100: records where the information can be found. A reference to information sub- mitted to the agency by a person
p.000100: other
p.000101: 101
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101:
p.000101: § 314.50
p.000101: than the applicant is required to con- tain a written statement that author- izes the reference and that is
p.000101: signed by the person who submitted the informa- tion.
p.000101: (2) The applicant shall submit an ac- curate and complete English trans- lation of each part of the
p.000101: application that is not in English. The applicant shall submit a copy of each original lit- erature
p.000101: publication for which an English translation is submitted.
p.000101: (3) If an applicant who submits a new drug application under section 505(b) of the act obtains a ‘‘right of reference
p.000101: or use,’’ as defined under § 314.3(b), to an investigation described in clause (A) of section 505(b)(1) of the
p.000101: act, the appli- cant shall include in its application a written statement signed by the owner of the data
p.000101: from each such investiga- tion that the applicant may rely on in support of the approval of its
p.000101: applica- tion, and provide FDA access to, the underlying raw data that provide the basis for the report of
p.000101: the investigation submitted in its application.
p.000101: (h) Patent information. The applica- tion is required to contain the patent information described under §
p.000101: 314.53.
p.000101: (i) Patent certification—(1) Contents. A 505(b)(2) application is required to con- tain the following:
p.000101: (i) Patents claiming drug, drug product, or method of use. (A) Except as provided in paragraph (i)(2) of this
p.000101: section, a certification with respect to each pat- ent issued by the United States Patent and Trademark Office
p.000101: that, in the opin- ion of the applicant and to the best of its knowledge, claims a drug (the drug product
p.000101: or drug substance that is a component of the drug product) on which investigations that are
p.000101: relied upon by the applicant for approval of its application were conducted or that claims an approved
p.000101: use for such drug and for which information is required to be filed under section 505(b) and (c) of the
p.000101: act and § 314.53. For each such patent, the applicant shall provide the patent number and certify, in
p.000101: its opin- ion and to the best of its knowledge, one of the following circumstances:
...
p.000104:
p.000104:
p.000104: either provide a certified statement from a certified public accountant that the applicant provided 50
p.000104: percent or more of the cost of conducting the study or provide an explanation of why FDA should
p.000104: consider the applicant to have conducted or sponsored the study if the applicant’s financial contribu-
p.000104: tion to the study is less than 50 percent or the applicant did not sponsor the in- vestigational new drug. A
p.000104: predecessor in interest is an entity, e.g., a corpora- tion, that the applicant has taken over, merged with, or
p.000104: purchased, or from which the applicant has purchased all rights to the drug. Purchase of non- exclusive
p.000104: rights to a clinical investiga- tion after it is completed is not suffi- cient to satisfy this definition.
p.000104: (k) Financial certification or disclosure
p.000104: statement. The application shall contain a financial certification or disclosure statement or both as required
p.000104: by part 54 of this chapter.
p.000104: (l) Format of an original application—
p.000104: (1) Archival copy. The applicant must submit a complete archival copy of the application that contains the
p.000104: informa- tion required under paragraphs (a) through (f) of this section. FDA will maintain the
p.000104: archival copy during the review of the application to permit in- dividual reviewers to refer to informa-
p.000104: tion that is not contained in their par- ticular technical sections of the appli- cation, to give other agency
p.000104: personnel access to the application for official business, and to maintain in one place a complete
p.000104: copy of the application. Ex- cept as required by paragraph (l)(1)(i) of this section, applicants may submit
p.000104: the archival copy on paper or in elec- tronic format provided that electronic submissions are made in
p.000104: accordance with part 11 of this chapter.
p.000104: (i) Labeling. The content of labeling
p.000104: required under § 201.100(d)(3) of this chapter (commonly referred to as the package insert or
p.000104: professional label- ing), including all text, tables, and fig- ures, must be submitted to the agency in
p.000104: electronic format as described in paragraph (l)(5) of this section. This re- quirement is in addition to the
p.000104: require- ments of paragraph (e)(2)(ii) of this sec- tion that copies of the formatted label and all labeling
p.000104: be submitted. Submis- sions under this paragraph must be made in accordance with part 11 of this
p.000104:
p.000104: chapter, except for the requirements of
p.000104: § 11.10(a), (c) through (h), and (k), and the corresponding requirements of
p.000104: § 11.30.
p.000104: (ii) [Reserved]
p.000104: (2) Revie copy. The applicant must submit a review copy of the applica- tion. Each of the technical
p.000104: sections, de- scribed in paragraphs (d)(1) through (d)(6) of this section, in the review copy is required to be
p.000104: separately bound with a copy of the application form required under paragraph (a) of this section and a copy of the
p.000104: summary required under paragraph (c) of this section.
p.000104: (3) Field copy. The applicant must
p.000104: submit a field copy of the application that contains the technical section de- scribed in paragraph
...
p.000136: (13) Financial certification or disclosure statement. An abbreviated application shall contain a financial
p.000136: certification or disclosure statement as required by part 54 of this chapter.
p.000136: (b) Drug products subject to the Drug Efficacy Study Implementation (DESI) re- vie . If the abbreviated new
p.000136: drug appli- cation is for a duplicate of a drug prod- uct that is subject to FDA’s DESI re- view (a review
p.000136: of drug products ap- proved as safe between 1938 and 1962) or other DESI-like review and the drug product
p.000136: evaluated in the review is a listed drug, the applicant shall comply with the provisions of paragraph
p.000136: (a) of this section.
p.000136: (c) [Reserved]
p.000136: (d) Format of an abbreviated applica- tion. (1) The applicant must submit a complete archival copy of
p.000136: the abbre- viated application as required under paragraphs (a) and (c) of this section. FDA will
p.000136: maintain the archival copy during the review of the application to permit individual reviewers to refer to
p.000136: information that is not contained in their particular technical sections of
p.000136:
p.000136: the application, to give other agency personnel access to the application for official business, and to
p.000136: maintain in one place a complete copy of the appli- cation.
p.000136: (i) Format of submission. An applicant may submit portions of the archival copy of the abbreviated
p.000136: application in any form that the applicant and FDA agree is acceptable, except as provided in paragraph
p.000136: (d)(1)(ii) of this section.
p.000136: (ii) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter (commonly referred
p.000136: to as the package insert or professional label- ing), including all text, tables, and fig- ures, must be
p.000136: submitted to the agency in electronic format as described in paragraph (d)(1)(iii) of this
p.000136: section. This requirement applies to the con- tent of labeling for the proposed drug product only and is
p.000136: in addition to the requirements of paragraph (a)(8)(ii) of this section that copies of the for-
p.000136: matted label and all proposed labeling be submitted. Submissions under this paragraph must be made in
p.000136: accordance with part 11 of this chapter, except for the requirements of § 11.10(a), (c) through
p.000136: (h), and (k), and the cor- responding requirements of § 11.30.
p.000136: (iii) Electronic format submissions.
p.000136: Electronic format submissions must be in a form that FDA can process, re- view, and archive. FDA will
p.000136: periodi- cally issue guidance on how to provide the electronic submission (e.g., method of transmission,
p.000136: media, file formats, preparation and organization of files).
...
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p.000110: (5) Submission date. Patent informa- tion shall be considered to be sub- mitted to FDA as of the date
p.000110: the infor- mation is received by the Central Doc- ument Room.
p.000110: (6) Identification. Each submission of patent information, except information submitted with an original
p.000110: application, and its mailing cover shall bear promi- nent identification as to its contents, i.e., ‘‘Patent
p.000110: Information,’’ or, if sub- mitted after approval of an applica- tion, ‘‘Time Sensitive Patent Informa-
p.000110: tion.’’
p.000110: (e) Public disclosure of patent informa- tion. FDA will publish in the list the patent number and
p.000110: expiration date of each patent that is required to be, and is, submitted to FDA by an applicant, and
p.000110: for each use patent, the approved indications or other conditions of use covered by a patent. FDA will
p.000110: publish such patent information upon approval of the application, or, if the patent in- formation is submitted
p.000110: by the appli- cant after approval of an application as provided under paragraph (d)(2) of this section, as
p.000110: soon as possible after the submission to the agency of the patent information. Patent information sub- mitted
p.000110: by the last working day of a month will be published in that month’s supplement to the list.
p.000110: Patent information received by the Agency be- tween monthly publication of supple- ments to the list will be placed
p.000110: on pub- lic display in FDA’s Division of Free- dom of Information. A request for cop- ies of the file shall
p.000110: be sent in writing to the Division of Freedom of Information (ELEM–1029), Food and Drug Adminis- tration, 12420
p.000110: Parklawn Dr., Element Bldg., Rockville, MD 20857.
p.000110: (f) Correction of patent information er-
p.000110: rors. If any person disputes the accu- racy or relevance of patent information submitted to the agency under this
p.000110: sec- tion and published by FDA in the list, or believes that an applicant has failed to submit required patent
p.000110: information, that person must first notify the agen- cy in writing stating the grounds for disagreement. Such
p.000110: notification should be directed to the Office of Generic Drugs, OGD Document Room, Atten- tion:
p.000110: Orange Book Staff, 7500 Standish Pl., Rockville, MD 20855. The agency
p.000111: 111
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111:
p.000111: § 314.54
p.000111: will then request of the applicable new drug application holder that the cor- rectness of the patent
p.000111: information or omission of patent information be con- firmed. Unless the application holder withdraws or amends
p.000111: its patent infor- mation in response to FDA’s request, the agency will not change the patent information
p.000111: in the list. If the new drug application holder does not change the patent information submitted to FDA, a
p.000111: 505(b)(2) application or an abbre- viated new drug application under sec- tion 505(j) of the act
p.000111: submitted for a drug that is claimed by a patent for which information has been submitted must, despite
...
p.000168: available for public disclosure.
p.000168: (d)(1) If the existence of an applica- tion or abbreviated application has been publicly disclosed
p.000168: or acknowl- edged before the agency sends an ap- proval letter to the applicant, no data or information
p.000168: contained in the appli- cation or abbreviated application is available for public disclosure before
p.000168: the agency sends an approval letter,
p.000169: 169
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169:
p.000169: § 314.430
p.000169: but the Commissioner may, in his or her discretion, disclose a summary of selected portions of the
p.000169: safety and ef- fectiveness data that are appropriate for public consideration of a specific pending issue;
p.000169: for example, for consid- eration of an open session of an FDA advisory committee.
p.000169: (2) Notwithstanding paragraph (d)(1) of this section, FDA will make avail- able to the public upon
p.000169: request the in- formation in the investigational new drug application that was required to be filed in
p.000169: Docket Number 95S–0158 in the Division of Dockets Management (HFA–305), Food and Drug Administra- tion, 5630
p.000169: Fishers Lane, rm. 1061, Rock- ville, MD 20852, for investigations in- volving an exception from informed
p.000169: consent under § 50.24 of this chapter. Persons wishing to request this infor- mation shall submit a
p.000169: request under the Freedom of Information Act.
p.000169: (e) After FDA sends an approval let- ter to the applicant, the following data and information in the
p.000169: application or abbreviated application are imme- diately available for public disclosure, unless the
p.000169: applicant shows that ex- traordinary circumstances exist. A list of approved applications and abbre-
p.000169: viated applications, entitled ‘‘Approved Drug Products with Therapeutic Equivalence Evaluations,’’ is
p.000169: available from the Government Printing Office, Washington, DC 20402. This list is up- dated monthly.
p.000169: (1) [Reserved]
p.000169: (2) If the application applies to a new drug, all safety and effectiveness data previously disclosed to the
p.000169: public as set forth in § 20.81 and a summary or summaries of the safety and effective- ness data and
p.000169: information submitted with or incorporated by reference in the application. The summaries do not
p.000169: constitute the full reports of investiga- tions under section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) on which
p.000169: the safety or effectiveness of the drug may be ap- proved. The summaries consist of the following:
p.000169: (i) For an application approved be- fore July 1, 1975, internal agency records that describe
p.000169: safety and effec- tiveness data and information, for ex- ample, a summary of the basis for ap- proval or
p.000169: internal reviews of the data
p.000169: 21 CFR Ch. I (4–1–12 Edition)
p.000169: and information, after deletion of the following:
...
Social / Age
Searching for indicator age:
(return to top)
p.000098: clinical studies that have not been analyzed in detail for any reason (e.g., because they have been
p.000098: discon- tinued or are incomplete) are to be in- cluded in this section, including a copy of the protocol and
p.000098: a brief description of the results and status of the study.
p.000098: (iii) A description of each uncon-
p.000098: trolled clinical study, a summary of the results, and a brief statement ex- plaining why the study
p.000098: is classified as uncontrolled.
p.000098: (iv) A description and analysis of any other data or information relevant to an evaluation of the safety and
p.000098: effec- tiveness of the drug product obtained or otherwise received by the applicant from any source,
p.000098: foreign or domestic, including information derived from clinical investigations, including con- trolled
p.000098: and uncontrolled studies of uses of the drug other than those proposed in the application, commercial
p.000098: mar- keting experience, reports in the sci- entific literature, and unpublished sci- entific papers.
p.000098: (v) An integrated summary of the
p.000098: data demonstrating substantial evi- dence of effectiveness for the claimed indications. Evidence is
p.000098: also required to support the dosage and administra- tion section of the labeling, including support for
p.000098: the dosage and dose inter- val recommended. The effectiveness data shall be presented by gender,
p.000098: age, and racial subgroups and shall identify any modifications of dose or dose inter- val needed for specific
p.000098: subgroups. Ef-
p.000099: 99
p.000099:
p.000099: fectiveness data from other subgroups of the population of patients treated, when appropriate, such
p.000099: as patients with renal failure or patients with dif- ferent levels of severity of the disease, also
p.000099: shall be presented.
p.000099: (vi) A summary and updates of safety information, as follows:
p.000099: (a) The applicant shall submit an in- tegrated summary of all available in- formation about the safety
p.000099: of the drug product, including pertinent animal data, demonstrated or potential ad- verse effects of
p.000099: the drug, clinically sig- nificant drug/drug interactions, and other safety considerations, such as
p.000099: data from epidemiological studies of related drugs. The safety data shall be presented by gender,
p.000099: age, and racial subgroups. When appropriate, safety data from other subgroups of the popu- lation of
p.000099: patients treated also shall be presented, such as for patients with renal failure or patients with
p.000099: different levels of severity of the disease. A de- scription of any statistical analyses performed in
p.000099: analyzing safety data should also be included, unless already included under paragraph (d)(5)(ii) of
p.000099: this section.
p.000099: (b) The applicant shall, under section
p.000099: 505(i) of the act, update periodically its pending application with new safety in- formation learned about the drug
p.000099: that may reasonably affect the statement of contraindications, warnings, pre- cautions, and adverse
p.000099: reactions in the draft labeling and, if applicable, any Medication Guide required under part
p.000099: 208 of this chapter. These ‘‘safety up- date reports’’ are required to include the same kinds of
p.000099: information (from clinical studies, animal studies, and other sources) and are required to be submitted
p.000099: in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition,
p.000099: the reports are required to include the case report forms for each patient who died during a clinical
p.000099: study or who did not complete the study because of an adverse event (unless this requirement is waived).
p.000099: The applicant shall submit these reports (1) 4 months after the ini- tial submission; (2) in a resubmission
p.000099: following receipt of a complete re- sponse letter; and (3) at other times as requested by FDA. Prior
...
p.000112: (2) The rate at which its active ingre- dient(s) is absorbed or otherwise made available to the site of
p.000112: action is unin- tentionally less than that of the ref- erence listed drug.
p.000112: [57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec.
p.000112: 28, 1992, as amended at 58 FR 47351, Sept. 8,
p.000112: 1993; 59 FR 50364, Oct. 3, 1994]
p.000112: § 314.55 Pediatric use information.
p.000112: (a) Required assessment. Except as pro- vided in paragraphs (b), (c), and (d) of this section, each application
p.000112: for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of
p.000112: administration shall con- tain data that are adequate to assess the safety and effectiveness of the drug
p.000112: product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and
p.000112: administra- tion for each pediatric subpopulation for which the drug is safe and effective. Where the course of the
p.000112: disease and the effects of the drug are sufficiently similar in adults and pediatric pa- tients,
p.000112: FDA may conclude that pedi- atric effectiveness can be extrapolated
p.000112:
p.000112: from adequate and well-controlled studies in adults usually supplemented with other information
p.000112: obtained in pe- diatric patients, such as pharmaco- kinetic studies. Studies may not be needed in
p.000112: each pediatric age group, if data from one age group can be extrap- olated to another. Assessments of safe- ty and
p.000112: effectiveness required under this section for a drug product that rep- resents a meaningful therapeutic
p.000112: ben- efit over existing treatments for pedi- atric patients must be carried out using appropriate
p.000112: formulations for each age group(s) for which the assess- ment is required.
p.000112: (b) Deferred submission. (1) FDA may, on its own initiative or at the request of an applicant, defer
p.000112: submission of some or all assessments of safety and effectiveness described in paragraph (a) of this section
p.000112: until after approval of the drug product for use in adults. De- ferral may be granted if, among other
p.000112: reasons, the drug is ready for approval in adults before studies in pediatric pa- tients are complete, or
p.000112: pediatric stud- ies should be delayed until additional safety or effectiveness data have been collected. If
p.000112: an applicant requests de- ferred submission, the request must provide a certification from the appli-
p.000112: cant of the grounds for delaying pedi- atric studies, a description of the planned or ongoing
p.000112: studies, and evi- dence that the studies are being or will be conducted with due diligence and at the earliest
p.000112: possible time.
p.000112: (2) If FDA determines that there is an adequate justification for tempo- rarily delaying the
p.000112: submission of as- sessments of pediatric safety and effec- tiveness, the drug product may be ap- proved for
p.000112: use in adults subject to the requirement that the applicant submit the required assessments within a spec-
p.000112: ified time.
p.000112: (c) Waivers—(1) General. FDA may grant a full or partial waiver of the re- quirements of paragraph (a) of this
p.000112: sec- tion on its own initiative or at the re- quest of an applicant. A request for a waiver must
p.000112: provide an adequate jus- tification.
p.000112: (2) Full aiver. An applicant may re- quest a waiver of the requirements of paragraph (a) of this
p.000112: section if the ap- plicant certifies that:
p.000113: 113
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113:
p.000113: § 314.60
p.000113: (i) The drug product does not rep- resent a meaningful therapeutic ben- efit over existing
p.000113: treatments for pedi- atric patients and is not likely to be used in a substantial number of pedi- atric
p.000113: patients;
p.000113: (ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so
p.000113: small or geographically dispersed; or
p.000113: (iii) There is evidence strongly sug- gesting that the drug product would be ineffective or unsafe in all
p.000113: pediatric age groups.
p.000113: (3) Partial aiver. An applicant may request a waiver of the requirements of paragraph (a) of this section
p.000113: with re- spect to a specified pediatric age group, if the applicant certifies that:
p.000113: (i) The drug product does not rep- resent a meaningful therapeutic ben- efit over existing
p.000113: treatments for pedi- atric patients in that age group, and is not likely to be used in a substantial number of
p.000113: patients in that age group;
p.000113: (ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group
p.000113: is so small or geographically dispersed;
p.000113: (iii) There is evidence strongly sug- gesting that the drug product would be ineffective or unsafe in that age
p.000113: group; or
p.000113: (iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary
p.000113: for that age group have failed.
p.000113: (4) FDA action on aiver. FDA shall grant a full or partial waiver, as appro- priate, if the agency finds that
p.000113: there is a reasonable basis on which to con- clude that one or more of the grounds for waiver
p.000113: specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the
p.000113: ground that it is not possible to develop a pedi- atric formulation, the waiver will cover only those
p.000113: pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that
p.000113: the product would be ineffective or unsafe in pediatric populations, this information will be included in
p.000113: the product’s labeling.
p.000113: (5) Definition of ‘‘meaningful thera- peutic benefit’’. For purposes of this sec- tion and § 201.23 of this
p.000113: chapter, a drug will be considered to offer a meaningful
p.000113: 21 CFR Ch. I (4–1–12 Edition)
p.000113: therapeutic benefit over existing thera- pies if FDA estimates that:
p.000113: (i) If approved, the drug would rep- resent a significant improvement in the treatment, diagnosis, or
p.000113: prevention of a disease, compared to marketed products adequately labeled for that use in the
p.000113: relevant pediatric popu- lation. Examples of how improvement might be demonstrated include, for ex- ample,
p.000113: evidence of increased effective- ness in treatment, prevention, or diag- nosis of disease, elimination
p.000113: or sub- stantial reduction of a treatment-lim- iting drug reaction, documented en- hancement of
p.000113: compliance, or evidence of safety and effectiveness in a new subpopulation; or
p.000113: (ii) The drug is in a class of drugs or
p.000113: for an indication for which there is a need for additional therapeutic op- tions.
...
p.000118: (iii) Replacement of equipment with that of the same design and operating principles except those
p.000118: equipment changes described in paragraph (c) of this section;
p.000118: (iv) A change in the size and/or shape of a container containing the same number of dosage units for a
p.000118: nonsterile solid dosage form drug product, with- out a change from one container clo- sure system to
p.000118: another;
p.000118: (v) A change within the container closure system for a nonsterile drug product, based upon
p.000118: a showing of
p.000118:
p.000118: equivalency to the approved system under a protocol approved in the appli- cation or published in an
p.000118: official com- pendium;
p.000118: (vi) An extension of an expiration dating period based upon full shelf life data on production
p.000118: batches obtained from a protocol approved in the appli- cation;
p.000118: (vii) The addition or revision of an al- ternative analytical procedure that provides the same or
p.000118: increased assur- ance of the identity, strength, quality, purity, or potency of the material being
p.000118: tested as the analytical proce- dure described in the approved applica- tion, or deletion of an alternative
p.000118: ana- lytical procedure;
p.000118: (viii) The addition by embossing, de- bossing, or engraving of a code imprint to a solid oral dosage form
p.000118: drug prod- uct other than a modified release dos- age form, or a minor change in an ex- isting code
p.000118: imprint;
p.000118: (ix) A change in the labeling con- cerning the description of the drug product or in the
p.000118: information about how the drug product is supplied, that does not involve a change in the dosage strength or
p.000118: dosage form; and
p.000118: (x) An editorial or similar minor change in labeling, including a change to the information
p.000118: allowed by para- graphs (b)(2)(v)(C)(1) and (2) of this sec- tion.
p.000118: (3) For changes under this category, the applicant is required to submit in the annual report:
p.000118: (i) A statement by the holder of the approved application that the effects of the change have been assessed;
p.000118: (ii) A full description of the manufac- turing and controls changes, including the manufacturing site(s) or area(s)
p.000118: in- volved;
p.000118: (iii) The date each change was imple- mented;
p.000118: (iv) Data from studies and tests per- formed to assess the effects of the change; and,
p.000118: (v) For a natural product, recom- binant DNA-derived protein/ polypeptide, complex or
p.000118: conjugate of a drug substance with a monoclonal anti- body, sterilization process or test methodology
p.000118: related to sterilization process validation, a cross-reference to relevant validation protocols and/or
p.000118: standard operating procedures.
p.000119: 119
p.000119:
p.000119:
p.000119:
...
p.000152: explain why the drugs should be considered effective in the study, for example, by reference to results in pre-
p.000152: vious placebo-controlled studies of the active control drug.
p.000152: (v) Historical control. The results of treatment with the test drug are com- pared with experience
p.000152: historically de- rived from the adequately documented natural history of the disease or condi- tion, or from
p.000152: the results of active treatment, in comparable patients or populations. Because historical control
p.000152: populations usually cannot be as well assessed with respect to pertinent vari- ables as can concurrent control
p.000152: popu- lations, historical control designs are usually reserved for special cir- cumstances.
p.000152: Examples include studies of diseases with high and predictable mortality (for example, certain malig-
p.000152: nancies) and studies in which the effect of the drug is self-evident (general an- esthetics, drug metabolism).
p.000152: (3) The method of selection of sub- jects provides adequate assurance that they have the disease or
p.000152: condition being studied, or evidence of suscepti- bility and exposure to the condition against which
p.000152: prophylaxis is directed.
p.000152: (4) The method of assigning patients to treatment and control groups mini- mizes bias and is intended to
p.000152: assure comparability of the groups with re- spect to pertinent variables such as age, sex, severity
p.000152: of disease, duration of disease, and use of drugs or therapy other than the test drug. The protocol for
p.000152: the study and the report of its re- sults should describe how subjects were assigned to groups.
p.000152: Ordinarily, in a concurrently controlled study, assign- ment is by randomization, with or without
p.000152: stratification.
p.000153: 153
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153:
p.000153: § 314.127
p.000153: (5) Adequate measures are taken to minimize bias on the part of the sub- jects, observers, and
p.000153: analysts of the data. The protocol and report of the study should describe the procedures used to
p.000153: accomplish this, such as blind- ing.
p.000153: (6) The methods of assessment of sub- jects’ response are well-defined and re- liable. The protocol for the
p.000153: study and the report of results should explain the variables measured, the methods of ob- servation, and criteria
p.000153: used to assess response.
p.000153: (7) There is an analysis of the results of the study adequate to assess the ef- fects of the drug. The
p.000153: report of the study should describe the results and the analytic methods used to evaluate them, including
p.000153: any appropriate statis- tical methods. The analysis should as- sess, among other things, the com-
p.000153: parability of test and control groups with respect to pertinent variables, and the effects of any interim
p.000153: data anal- yses performed.
...
p.000154: dosage form, or strength purports to be the same as that of the listed drug referred to in the
p.000154: abbreviated new drug application, information submitted in the abbre- viated new drug application is
p.000154: insuffi- cient to show that the route of admin- istration, dosage form, or strength is the same as that of
p.000154: the reference listed drug; or
p.000154: (ii) If the abbreviated new drug appli- cation is for a drug product whose route of administration,
p.000154: dosage form, or strength is different from that of the listed drug referred to in the applica- tion, no
p.000154: petition to submit an abbre- viated new drug application for the drug product with the different
p.000154: route of administration, dosage form, or strength was approved under § 314.93.
p.000154: (5) If the abbreviated new drug appli- cation was submitted under the ap- proval of a petition under §
p.000154: 314.93, the abbreviated new drug application did not contain the information required by FDA with respect
p.000154: to the active in- gredient, route of administration, dos- age form, or strength that is not the same as
p.000154: that of the reference listed drug.
p.000154: (6)(i) Information submitted in the abbreviated new drug application is in- sufficient to show that the
p.000154: drug prod- uct is bioequivalent to the listed drug referred to in the abbreviated new drug application; or
p.000154: (ii) If the abbreviated new drug appli- cation was submitted under a petition approved under § 314.93,
p.000154: information submitted in the abbreviated new drug application is insufficient to show that the active ingredients
p.000154: of the drug prod-
p.000154:
p.000154: uct are of the same pharmacological or therapeutic class as those of the ref- erence listed drug and that
p.000154: the drug product can be expected to have the same therapeutic effect as the ref- erence listed drug
p.000154: when administered to patients for each condition of use approved for the reference listed drug.
p.000154: (7) Information submitted in the ab- breviated new drug application is insuf- ficient to show that the
...
Social / Child
Searching for indicator children:
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p.000123: U.S. approval of the application, two copies of the re- port to the FDA division responsible for
p.000123: reviewing the application. Each an-
p.000123: 21 CFR Ch. I (4–1–12 Edition)
p.000123: nual report is required to be accom- panied by a completed transmittal Form FDA 2252 (Transmittal
p.000123: of Peri- odic Reports for Drugs for Human Use), and must include all the information required under this section
p.000123: that the ap- plicant received or otherwise obtained during the annual reporting interval that ends on the
p.000123: U.S. anniversary date. The report is required to contain in the order listed:
p.000123: (i) Summary. A brief summary of sig- nificant new information from the pre- vious year that might affect the
p.000123: safety, effectiveness, or labeling of the drug product. The report is also required to contain a brief
p.000123: description of actions the applicant has taken or intends to take as a result of this new informa- tion,
p.000123: for example, submit a labeling supplement, add a warning to the label- ing, or initiate a new study.
p.000123: The sum- mary shall briefly state whether label- ing supplements for pediatric use have been submitted and
p.000123: whether new stud- ies in the pediatric population to sup- port appropriate labeling for the pedi- atric
p.000123: population have been initiated. Where possible, an estimate of patient exposure to the drug product, with
p.000123: spe- cial reference to the pediatric popu- lation (neonates, infants, children, and adolescents) shall
p.000123: be provided, includ- ing dosage form.
p.000123: (ii)(a) Distribution data. Information
p.000123: about the quantity of the drug product distributed under the approved applica- tion, including that distributed to
p.000123: dis- tributors. The information is required to include the National Drug Code (NDC) number, the
p.000123: total number of dosage units of each strength or po- tency distributed (e.g., 100,000/5 milli- gram
p.000123: tablets, 50,000/10 milliliter vials), and the quantities distributed for do- mestic use and the quantities
p.000123: distrib- uted for foreign use. Disclosure of fi- nancial or pricing data is not required.
p.000123: (b) Authorized generic drugs. If appli-
p.000123: cable, the date each authorized generic drug (as defined in § 314.3) entered the market, the date each
p.000123: authorized ge- neric drug ceased being distributed, and the corresponding trade or brand name. Each
p.000123: dosage form and/or strength is a different authorized ge- neric drug and should be listed sepa-
p.000123: rately. The first annual report sub- mitted on or after January 25, 2010
p.000124: 124
p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124: Food and Drug Administration, HHS § 314.81
p.000124:
p.000124:
...
Social / Fetus/Neonate
Searching for indicator fetus:
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p.000097: such early submis- sions as resources permit.
p.000097: (v) The applicant shall include a statement certifying that the field copy of the application
p.000097: has been pro- vided to the applicant’s home FDA dis- trict office.
p.000097: (2) Nonclinical pharmacology and toxi- cology section. A section describing, with the aid of graphs
p.000097: and tables, ani- mal and in vitro studies with drug, in- cluding the following:
p.000097: (i) Studies of the pharmacological ac- tions of the drug in relation to its pro- posed therapeutic indication and
p.000097: stud- ies that otherwise define the pharma- cologic properties of the drug or are pertinent to possible
p.000097: adverse effects.
p.000097: (ii) Studies of the toxicological ef- fects of the drug as they relate to the drug’s intended clinical
p.000097: uses, includ- ing, as appropriate, studies assessing the drug’s acute, subacute, and chronic toxicity;
p.000097: carcinogenicity; and studies of toxicities related to the drug’s par- ticular mode of administration or
p.000097: con- ditions of use.
p.000097: (iii) Studies, as appropriate, of the ef- fects of the drug on reproduction and on the developing fetus.
p.000097: (iv) Any studies of the absorption, distribution, metabolism, and excre- tion of the drug in animals.
p.000097: (v) For each nonclinical laboratory study subject to the good laboratory practice regulations under part
p.000097: 58 a statement that it was conducted in compliance with the good laboratory practice regulations in
p.000097: part 58, or, if the study was not conducted in compli-
p.000098: 98
p.000098: 21 CFR Ch. I (4–1–12 Edition)
p.000098: ance with those regulations, a brief statement of the reason for the non- compliance.
p.000098: (3) Human pharmacokinetics and bio- availability section. A section describing the human pharmacokinetic
p.000098: data and human bioavailability data, or infor- mation supporting a waiver of the sub- mission of in vivo
p.000098: bioavailability data under subpart B of part 320, including the following:
p.000098: (i) A description of each of the bio- availability and pharmacokinetic stud- ies of the drug in humans performed
p.000098: by or on behalf of the applicant that in- cludes a description of the analytical procedures and
p.000098: statistical methods used in each study and a statement with respect to each study that it ei-
p.000098: ther was conducted in compliance with the institutional review board regula- tions in part 56, or was not
p.000098: subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compli- ance with the
p.000098: informed consent regula- tions in part 50.
p.000098: (ii) If the application describes in the
...
Searching for indicator neonates:
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p.000123: (2) Annual report. The applicant shall submit each year within 60 days of the anniversary date of
p.000123: U.S. approval of the application, two copies of the re- port to the FDA division responsible for
p.000123: reviewing the application. Each an-
p.000123: 21 CFR Ch. I (4–1–12 Edition)
p.000123: nual report is required to be accom- panied by a completed transmittal Form FDA 2252 (Transmittal
p.000123: of Peri- odic Reports for Drugs for Human Use), and must include all the information required under this section
p.000123: that the ap- plicant received or otherwise obtained during the annual reporting interval that ends on the
p.000123: U.S. anniversary date. The report is required to contain in the order listed:
p.000123: (i) Summary. A brief summary of sig- nificant new information from the pre- vious year that might affect the
p.000123: safety, effectiveness, or labeling of the drug product. The report is also required to contain a brief
p.000123: description of actions the applicant has taken or intends to take as a result of this new informa- tion,
p.000123: for example, submit a labeling supplement, add a warning to the label- ing, or initiate a new study.
p.000123: The sum- mary shall briefly state whether label- ing supplements for pediatric use have been submitted and
p.000123: whether new stud- ies in the pediatric population to sup- port appropriate labeling for the pedi- atric
p.000123: population have been initiated. Where possible, an estimate of patient exposure to the drug product, with
p.000123: spe- cial reference to the pediatric popu- lation (neonates, infants, children, and adolescents) shall
p.000123: be provided, includ- ing dosage form.
p.000123: (ii)(a) Distribution data. Information
p.000123: about the quantity of the drug product distributed under the approved applica- tion, including that distributed to
p.000123: dis- tributors. The information is required to include the National Drug Code (NDC) number, the
p.000123: total number of dosage units of each strength or po- tency distributed (e.g., 100,000/5 milli- gram
p.000123: tablets, 50,000/10 milliliter vials), and the quantities distributed for do- mestic use and the quantities
p.000123: distrib- uted for foreign use. Disclosure of fi- nancial or pricing data is not required.
p.000123: (b) Authorized generic drugs. If appli-
p.000123: cable, the date each authorized generic drug (as defined in § 314.3) entered the market, the date each
p.000123: authorized ge- neric drug ceased being distributed, and the corresponding trade or brand name. Each
p.000123: dosage form and/or strength is a different authorized ge- neric drug and should be listed sepa-
p.000123: rately. The first annual report sub- mitted on or after January 25, 2010
p.000124: 124
p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124:
p.000124: Food and Drug Administration, HHS § 314.81
p.000124:
p.000124:
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Social / Incarcerated
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p.000172: 172
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172:
p.000172: Food and Drug Administration, HHS § 314.530
p.000172:
p.000172:
p.000172: adequate and well-controlled clinical trials establishing that the drug prod- uct has an effect on a
p.000172: surrogate end- point that is reasonably likely, based on epidemiologic, therapeutic, patho- physiologic,
p.000172: or other evidence, to pre- dict clinical benefit or on the basis of an effect on a clinical endpoint
p.000172: other than survival or irreversible morbidity. Approval under this section will be subject to the requirement
p.000172: that the ap- plicant study the drug further, to verify and describe its clinical benefit, where
p.000172: there is uncertainty as to the re- lation of the surrogate endpoint to clinical benefit, or of the observed
p.000172: clin- ical benefit to ultimate outcome. Post- marketing studies would usually be studies already underway.
p.000172: When re- quired to be conducted, such studies must also be adequate and well-con- trolled. The
p.000172: applicant shall carry out any such studies with due diligence.
p.000172: § 314.520 Approval with restrictions to assure safe use.
p.000172: (a) If FDA concludes that a drug product shown to be effective can be safely used only if
p.000172: distribution or use is restricted, FDA will require such postmarketing restrictions as are need- ed to
p.000172: assure safe use of the drug prod- uct, such as:
p.000172: (1) Distribution restricted to certain facilities or physicians with special training or experience; or
p.000172: (2) Distribution conditioned on the performance of specified medical proce- dures.
p.000172: (b) The limitations imposed will be commensurate with the specific safety concerns presented by the drug
p.000172: prod- uct.
p.000172: § 314.530 Withdrawal procedures.
p.000172: (a) For new drugs approved under
p.000172: §§ 314.510 and 314.520, FDA may with- draw approval, following a hearing as provided in part 15 of
p.000172: this chapter, as modified by this section, if:
p.000172: (1) A postmarketing clinical study fails to verify clinical benefit;
p.000172: (2) The applicant fails to perform the required postmarketing study with due diligence;
p.000172: (3) Use after marketing demonstrates that postmarketing restrictions are in- adequate to assure safe use of the drug
p.000172: product;
p.000172:
p.000172: (4) The applicant fails to adhere to the postmarketing restrictions agreed upon;
p.000172: (5) The promotional materials are false or misleading; or
p.000172: (6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its
p.000172: conditions of use.
p.000172: (b) Notice of opportunity for a hearing. The Director of the Center for Drug Evaluation and Research
p.000172: will give the applicant notice of an opportunity for a hearing on the Center’s proposal to withdraw the
p.000172: approval of an applica- tion approved under § 314.510 or § 314.520. The notice, which will ordinarily be a
...
p.000174: represents a sufficiently well- characterized animal model for pre- dicting the response in humans;
p.000174: (3) The animal study endpoint is clearly related to the desired benefit in humans, generally the
p.000174: enhancement of survival or prevention of major mor- bidity; and
p.000174: (4) The data or information on the ki- netics and pharmacodynamics of the product or other relevant data or
p.000174: infor- mation, in animals and humans, allows selection of an effective dose in hu- mans.
p.000174: (b) Approval under this subpart will be subject to three requirements:
p.000174: (1) Postmarketing studies. The appli- cant must conduct postmarketing studies, such as field
p.000174: studies, to verify and describe the drug’s clinical benefit and to assess its safety when used as
p.000174: indicated when such studies are fea- sible and ethical. Such postmarketing studies would not be
p.000174: feasible until an exigency arises. When such studies are feasible, the applicant must conduct such
p.000174: studies with due diligence. Appli- cants must include as part of their ap- plication a plan or approach
p.000174: to post- marketing study commitments in the event such studies become ethical and feasible.
p.000174: (2) Approval ith restrictions to ensure
p.000174: safe use. If FDA concludes that a drug product shown to be effective under this subpart can be
p.000174: safely used only if
p.000174:
p.000174: distribution or use is restricted, FDA will require such postmarketing re- strictions as are needed to
p.000174: ensure safe use of the drug product, commensurate with the specific safety concerns pre- sented by the drug
p.000174: product, such as:
p.000174: (i) Distribution restricted to certain facilities or health care practitioners with special training or
p.000174: experience;
p.000174: (ii) Distribution conditioned on the performance of specified medical proce- dures, including medical followup;
p.000174: and
p.000174: (iii) Distribution conditioned on specified recordkeeping requirements.
p.000174: (3) Information to be provided to patient recipients. For drug products or specific indications approved under
p.000174: this sub- part, applicants must prepare, as part of their proposed labeling, labeling to be provided to
p.000174: patient recipients. The patient labeling must explain that, for ethical or feasibility reasons, the
p.000174: drug’s approval was based on efficacy studies conducted in animals alone and must give the drug’s
p.000174: indication(s), di- rections for use (dosage and adminis- tration), contraindications, a descrip- tion of
p.000174: any reasonably foreseeable risks, adverse reactions, anticipated benefits, drug interactions, and
p.000174: any other relevant information required by FDA at the time of approval. The pa- tient labeling must be
p.000174: available with the product to be provided to patients prior to administration or dispensing of the drug
p.000174: product for the use ap- proved under this subpart, if possible.
p.000174: § 314.620 Withdrawal procedures.
p.000174: (a) Reasons to ithdra approval. For new drugs approved under this subpart, FDA may withdraw approval,
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Social / Marital Status
Searching for indicator single:
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p.000122: paragraph (f) of this sec- tion. In cases where the applicant be- lieves that preparing the FDA
p.000122: Form 3500A constitutes an undue hardship, the applicant may arrange with the Of- fice of Surveillance and
p.000122: Epidemiology for an acceptable alternative reporting format.
p.000122: (e) Postmarketing studies. (1) An appli-
p.000122: cant is not required to submit a 15-day Alert report under paragraph (c) of this section for an adverse drug
p.000122: experience obtained from a postmarketing study (whether or not conducted under an in- vestigational new drug
p.000122: application) un- less the applicant concludes that there is a reasonable possibility that the drug
p.000122: caused the adverse experience.
p.000122: (2) The applicant shall separate and clearly mark reports of adverse drug experiences that occur during a
p.000122: post- marketing study as being distinct from those experiences that are being re- ported spontaneously to
p.000122: the applicant.
p.000122: (f) Reporting FDA Form 3500A. (1) Ex- cept as provided in paragraph (f)(3) of this section, the
p.000122: applicant shall com- plete FDA Form 3500A for each report of an adverse drug experience (foreign events
p.000122: may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form).
p.000122: (2) Each completed FDA Form 3500A should refer only to an individual pa- tient or a single attached
p.000122: publication.
p.000122: (3) Instead of using FDA Form 3500A, an applicant may use a computer-gen- erated FDA Form 3500A or other
p.000122: alter- native format (e.g., a computer-gen- erated tape or tabular listing) provided that:
p.000122: (i) The content of the alternative for- mat is equivalent in all elements of in- formation to those specified
p.000122: in FDA Form 3500A; and
p.000122:
p.000122: (ii) The format is agreed to in ad- vance by the Office of Surveillance and Epidemiology.
p.000122: (4) FDA Form 3500A and instructions for completing the form are available on the Internet at http://
p.000122: .fda.gov/ med atch/index.html.
p.000122: (g) Multiple reports. An applicant should not include in reports under this section any
p.000122: adverse drug experi- ences that occurred in clinical trials if they were previously submitted as part of the
p.000122: approved application. If a report applies to a drug for which an appli- cant holds more than one approved
p.000122: ap- plication, the applicant should submit the report to the application that was first approved. If a
p.000122: report refers to more than one drug marketed by an ap- plicant, the applicant should submit the report
p.000122: to the application for the drug listed first in the report.
p.000122: (h) Patient privacy. An applicant
p.000122: should not include in reports under this section the names and addresses of individual patients; instead,
...
p.000131: approverd peti- tion under § 10.30 of this chapter or
p.000131: § 314.93, the reference listed drug must be the same as the listed drug approved in the petition.
p.000131: (ii) A statement as to whether, ac- cording to the information published in the list, the reference listed drug
p.000131: is en- titled to a period of marketing exclu- sivity under section 505(j)(4)(D) of the act.
p.000131: (iii) For an abbreviated new drug ap- plication based on an approved petition under § 10.30 of this chapter or §
p.000131: 314.93, a reference to FDA-assigned docket num- ber for the petition and a copy of
p.000131: 21 CFR Ch. I (4–1–12 Edition)
p.000131: FDA’s correspondence approving the petition.
p.000131: (4) Conditions of use. (i) A statement that the conditions of use prescribed, recommended, or suggested
p.000131: in the la- beling proposed for the drug product have been previously approved for the reference listed
p.000131: drug.
p.000131: (ii) A reference to the applicant’s an- notated proposed labeling and to the currently approved labeling for the
p.000131: ref- erence listed drug provided under para- graph (a)(8) of this section.
p.000131: (5) Active ingredients. (i) For a single- active-ingredient drug product, infor- mation to show that
p.000131: the active ingre- dient is the same as that of the ref- erence single-active-ingredient listed drug, as
p.000131: follows:
p.000131: (A) A statement that the active in- gredient of the proposed drug product is the same as that of the
p.000131: reference listed drug.
p.000131: (B) A reference to the applicant’s an- notated proposed labeling and to the currently approved labeling for the
p.000131: ref- erence listed drug provided under para- graph (a)(8) of this section.
p.000131: (ii) For a combination drug product, information to show that the active in- gredients are the same as those
p.000131: of the reference listed drug except for any dif- ferent active ingredient that has been the subject of an
p.000131: approved petition, as follows:
p.000131: (A) A statement that the active in- gredients of the proposed drug product are the same as those of
p.000131: the reference listed drug, or if one of the active in- gredients differs from one of the active ingredients of
p.000131: the reference listed drug and the abbreviated application is sub- mitted under the approval of a petition under §
p.000131: 314.93 to vary such active ingre- dient, information to show that the other active ingredients of the
...
p.000173: products to which it does apply.
p.000173: § 314.610 Approval based on evidence of effectiveness from studies in ani- mals.
p.000173: (a) FDA may grant marketing ap- proval for a new drug product for which safety has been established
p.000173: and for which the requirements of § 314.600 are
p.000174: 174
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174:
p.000174: Food and Drug Administration, HHS § 314.620
p.000174:
p.000174:
p.000174: met based on adequate and well-con- trolled animal studies when the results of those animal studies establish
p.000174: that the drug product is reasonably likely to produce clinical benefit in humans. In assessing the
p.000174: sufficiency of animal data, the agency may take into ac- count other data, including human data,
p.000174: available to the agency. FDA will rely on the evidence from studies in animals to provide substantial
p.000174: evi- dence of the effectiveness of these products only when:
p.000174: (1) There is a reasonably well-under-
p.000174: stood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial
p.000174: reduction by the product;
p.000174: (2) The effect is demonstrated in more than one animal species expected to react with a response
p.000174: predictive for humans, unless the effect is dem- onstrated in a single animal species that
p.000174: represents a sufficiently well- characterized animal model for pre- dicting the response in humans;
p.000174: (3) The animal study endpoint is clearly related to the desired benefit in humans, generally the
p.000174: enhancement of survival or prevention of major mor- bidity; and
p.000174: (4) The data or information on the ki- netics and pharmacodynamics of the product or other relevant data or
p.000174: infor- mation, in animals and humans, allows selection of an effective dose in hu- mans.
p.000174: (b) Approval under this subpart will be subject to three requirements:
p.000174: (1) Postmarketing studies. The appli- cant must conduct postmarketing studies, such as field
p.000174: studies, to verify and describe the drug’s clinical benefit and to assess its safety when used as
p.000174: indicated when such studies are fea- sible and ethical. Such postmarketing studies would not be
p.000174: feasible until an exigency arises. When such studies are feasible, the applicant must conduct such
p.000174: studies with due diligence. Appli- cants must include as part of their ap- plication a plan or approach
p.000174: to post- marketing study commitments in the event such studies become ethical and feasible.
p.000174: (2) Approval ith restrictions to ensure
p.000174: safe use. If FDA concludes that a drug product shown to be effective under this subpart can be
p.000174: safely used only if
p.000174:
p.000174: distribution or use is restricted, FDA will require such postmarketing re- strictions as are needed to
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Social / Police Officer
Searching for indicator officer:
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p.000142: the director of the division responsible for reviewing the application.
p.000142: (e) Other meetings. Other meetings be-
p.000142: tween FDA and applicants may be held, with advance notice, to discuss sci- entific, medical, and other
p.000142: issues that arise during the review process. Re- quests for meetings shall be directed to the director of
p.000142: the division responsible for reviewing the application or abbre- viated application. FDA will make
p.000142: every attempt to grant requests for meetings that involve important issues and that can be scheduled at
p.000142: mutually convenient times. However, ‘‘drop-in’’ visits (i.e., an unannounced and un- scheduled visit
p.000142: by a company rep- resentative) are discouraged except for urgent matters, such as to discuss an
p.000142: important new safety issue.
p.000142: [57 FR 17988, Apr. 28, 1992; 57 FR 29353, July
p.000142: 1, 1992, as amended at 73 FR 39609, July 10,
p.000142: 2008]
p.000142: § 314.103 Dispute resolution.
p.000142: (a) General. FDA is committed to re- solving differences between applicants and FDA reviewing divisions
p.000142: with re- spect to technical requirements for ap- plications or abbreviated applications as quickly and
p.000142: amicably as possible through the cooperative exchange of information and views.
p.000142: (b) Administrative and procedural
p.000142: issues. When administrative or proce- dural disputes arise, the applicant should first attempt
p.000142: to resolve the matter with the division responsible for reviewing the application or abbre- viated
p.000142: application, beginning with the consumer safety officer assigned to the application or abbreviated application.
p.000142: If resolution is not achieved, the appli- cant may raise the matter with the
p.000142:
p.000142: person designated as ombudsman, whose function shall be to investigate what has happened and to
p.000142: facilitate a timely and equitable resolution. Appro- priate issues to raise with the ombuds- man include resolving
p.000142: difficulties in scheduling meetings, obtaining timely replies to inquiries, and obtaining timely
p.000142: completion of pending reviews. Further details on this procedure are contained in a staff manual guide
p.000142: that is publicly available under FDA’s pub- lic information regulations in part 20.
p.000142: (c) Scientific and medical disputes. (1)
p.000142: Because major scientific issues are or- dinarily communicated to applicants in a complete response
p.000142: letter pursuant to § 314.110, the ‘‘end-of-review con- ference’’ described in § 314.102(d) will
p.000142: provide a timely forum for discussing and resolving, if possible, scientific and medical issues on which the
p.000142: applicant disagrees with the agency. In addition, the ‘‘ninety-day conference’’ described in § 314.102(c)
p.000142: will provide a timely forum for discussing and resolving, if possible, issues identified by that date.
p.000142: (2) When scientific or medical dis-
p.000142: putes arise at other times during the review process, applicants should dis- cuss the matter directly
p.000142: with the re- sponsible reviewing officials. If nec- essary, applicants may request a meet- ing with the
p.000142: appropriate reviewing offi- cials and management representatives in order to seek a resolution. Ordi-
...
p.000150: under the conditions prescribed, recommended, or suggested in its proposed labeling.
p.000150: (5) There is a lack of substantial evi- dence consisting of adequate and well- controlled investigations, as
p.000150: defined in
p.000150: § 314.126, that the drug product will have the effect it purports or is rep- resented to have under
p.000150: the conditions of use prescribed, recommended, or suggested in its proposed labeling.
p.000150: (6) The proposed labeling is false or misleading in any particular.
p.000150: (7) The application contains an un- true statement of a material fact.
p.000150: (8) The drug product’s proposed label- ing does not comply with the require- ments for labels and labeling
p.000150: in part 201.
p.000150: (9) The application does not contain bioavailability or bioequivalence data required under part 320 of this
p.000150: chapter.
p.000150: (10) A reason given in a letter refus- ing to file the application under
p.000150: § 314.101(d), if the deficiency is not cor- rected.
p.000151: 151
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151:
p.000151: § 314.126
p.000151: (11) The drug will be manufactured or processed in whole or in part in an es- tablishment that is not
p.000151: registered and not exempt from registration under section 510 of the act and part 207.
p.000151: (12) The applicant does not permit a properly authorized officer or employee of the Department of
p.000151: Health and Human Services an adequate oppor- tunity to inspect the facilities, con- trols, and
p.000151: any records relevant to the application.
p.000151: (13) The methods to be used in, and the facilities and controls used for, the manufacture, processing,
p.000151: packing, or holding of the drug substance or the drug product do not comply with the current good
p.000151: manufacturing practice regulations in parts 210 and 211.
p.000151: (14) The application does not contain an explanation of the omission of a re- port of any investigation
p.000151: of the drug product sponsored by the applicant, or an explanation of the omission of other information about
p.000151: the drug pertinent to an evaluation of the application that is received or otherwise obtained by the
p.000151: applicant from any source.
p.000151: (15) A nonclinical laboratory study that is described in the application and that is essential to show
p.000151: that the drug is safe for use under the conditions pre- scribed, recommended, or suggested in its proposed
p.000151: labeling was not con- ducted in compliance with the good laboratory practice regulations in part 58
p.000151: of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the
p.000151: practices used in conducting the study and the good laboratory practice regulations do not support the validity
p.000151: of the study.
p.000151: (16) Any clinical investigation in-
p.000151: volving human subjects described in the application, subject to the institu- tional review board
p.000151: regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter, was not
p.000151: conducted in compliance with those regulations such that the rights or safety of human subjects were not
p.000151: adequately protected.
p.000151: (17) The applicant or contract re- search organization that conducted a bioavailability or bioequivalence
p.000151: study described in § 320.38 or § 320.63 of this chapter that is contained in the appli- cation refuses to
p.000151: permit an inspection of facilities or records relevant to the
p.000151: 21 CFR Ch. I (4–1–12 Edition)
p.000151: study by a properly authorized officer or employee of the Department of Health and Human Services or
p.000151: refuses to submit reserve samples of the drug products used in the study when re- quested by FDA.
p.000151: (18) For a new drug, the application failed to contain the patent informa- tion required by section
p.000151: 505(b)(1) of the act.
p.000151: (c) For drugs intended to treat life- threatening or severely-debilitating ill- nesses that are developed in
p.000151: accordance with §§ 312.80 through 312.88 of this chapter, the criteria contained in para- graphs (b) (3),
p.000151: (4), and (5) of this section shall be applied according to the con- siderations contained in § 312.84 of
p.000151: this chapter.
p.000151: [50 FR 7493, Feb. 22, 1985, as amended at 53
p.000151: FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28,
p.000151: 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan.
p.000151: 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766,
p.000151: Mar. 6, 2009]
p.000151:
p.000151: § 314.126 Adequate and well-controlled studies.
p.000151: (a) The purpose of conducting clin- ical investigations of a drug is to dis- tinguish the effect of a drug
p.000151: from other influences, such as spontaneous change in the course of the disease, placebo ef- fect, or biased
p.000151: observation. The charac- teristics described in paragraph (b) of this section have been developed over a period
p.000151: of years and are recognized by the scientific community as the essen- tials of an adequate and
...
p.000155: and the agency has not determined whether the with- drawal is for safety or effectiveness
p.000155: reasons, or approval of the reference listed drug has been suspended under
p.000155: § 314.153, or the agency has issued an initial decision proposing to suspend the reference listed
p.000155: drug under
p.000155: § 314.153(a)(1).
p.000155: (12) The abbreviated new drug appli- cation does not meet any other re- quirement under section
p.000155: 505(j)(2)(A) of the act.
p.000156: 156
p.000156:
p.000156:
p.000156:
p.000156:
p.000156:
p.000156:
p.000156:
p.000156: Food and Drug Administration, HHS § 314.150
p.000156:
p.000156:
p.000156: (13) The abbreviated new drug appli- cation contains an untrue statement of material fact.
p.000156: (b) FDA may refuse to approve an ab- breviated application for a new drug if the applicant or contract
p.000156: research or- ganization that conducted a bio- availability or bioequivalence study described in
p.000156: § 320.63 of this chapter that is contained in the abbreviated new drug application refuses to permit an
p.000156: inspection of facilities or records rel- evant to the study by a properly au- thorized officer of
p.000156: employee of the De- partment of Health and Human Serv- ices or refuses to submit reserve sam- ples of
p.000156: the drug products used in the study when requested by FDA.
p.000156: [57 FR 17991, Apr. 28, 1992; 57 FR 29353, July
p.000156: 1, 1992, as amended at 58 FR 25927, Apr. 28,
p.000156: 1993; 67 FR 77672, Dec. 19, 2002]
p.000156:
p.000156: § 314.150 Withdrawal of approval of an application or abbreviated applica- tion.
p.000156: (a) The Food and Drug Administra- tion will notify the applicant, and, if appropriate, all other
p.000156: persons who manufacture or distribute identical, re- lated, or similar drug products as de- fined in §§
p.000156: 310.6 and 314.151(a) of this chapter and for a new drug afford an opportunity for a hearing on a
p.000156: proposal to withdraw approval of the applica- tion or abbreviated new drug applica- tion under section 505(e)
p.000156: of the act and under the procedure in § 314.200, if any of the following apply:
p.000156: (1) The Secretary of Health and
p.000156: Human Services has suspended the ap- proval of the application or abbre- viated application for a
p.000156: new drug on a finding that there is an imminent haz- ard to the public health. FDA will promptly
p.000156: afford the applicant an expe- dited hearing following summary sus- pension on a finding of imminent haz-
p.000156: ard to health.
p.000156: (2) FDA finds:
...
p.000157: breviated application that is received or otherwise obtained by the applicant from any source.
p.000157: (7) That any nonclinical laboratory study that is described in the applica- tion or abbreviated
p.000157: application and that is essential to show that the drug is safe for use under the conditions pre- scribed,
p.000157: recommended, or suggested in its labeling was not conducted in com- pliance with the good laboratory
p.000157: prac- tice regulations in part 58 of this chap- ter and no reason for the noncompli- ance was provided or, if it
p.000157: was, the dif- ferences between the practices used in conducting the study and the good lab- oratory practice
p.000157: regulations do not support the validity of the study.
p.000157: (8) Any clinical investigation involv-
p.000157: ing human subjects described in the ap- plication or abbreviated application, subject to the
p.000157: institutional review board regulations in part 56 of this chapter or informed consent regula-
p.000157: 21 CFR Ch. I (4–1–12 Edition)
p.000157: tions in part 50 of this chapter, was not conducted in compliance with those regulations such that the
p.000157: rights or safety of human subjects were not ade- quately protected.
p.000157: (9) That the applicant or contract re- search organization that conducted a bioavailability or bioequivalence study
p.000157: described in § 320.38 or § 320.63 of this chapter that is contained in the appli- cation or abbreviated
p.000157: application re- fuses to permit an inspection of facili- ties or records relevant to the study by a
p.000157: properly authorized officer or em- ployee of the Department of Health and Human Services or refuses to
p.000157: submit reserve samples of the drug products used in the study when requested by FDA.
p.000157: (10) That the labeling for the drug
p.000157: product that is the subject of the ab- breviated new drug application is no longer consistent with that for
p.000157: the list- ed drug referred to in the abbreviated new drug application, except for dif- ferences
p.000157: approved in the abbreviated new drug application or those dif- ferences resulting from:
p.000157: (i) A patent on the listed drug issued after approval of the abbreviated new drug application; or
p.000157: (ii) Exclusivity accorded to the listed drug after approval of the abbreviated new drug application that
p.000157: do not render the drug product less safe or ef- fective than the listed drug for any re- maining,
p.000157: nonprotected condition(s) of use.
p.000157: (c) FDA will withdraw approval of an application or abbreviated application if the applicant requests its withdrawal
...
p.000165: of the request
p.000165: 21 CFR Ch. I (4–1–12 Edition)
p.000165: and a proposed order ruling on the matter. The analysis and proposed order, the request for
p.000165: hearing, and any proposed order denying a hearing and response under paragraph (g) (2) or (3) of this
p.000165: section will be submitted to the Office of the Commissioner of Food and Drugs for review and decision. When the
p.000165: Center for Drug Evaluation and Re- search recommends denial of a hearing on all issues on which a hearing
p.000165: is re- quested, no representative of the Cen- ter will participate or advise in the re- view and decision
p.000165: by the Commis- sioner. When the Center for Drug Eval- uation and Research recommends that a hearing be
p.000165: granted on one or more issues on which a hearing is requested, separation of functions terminates as to
p.000165: those issues, and representatives of the Center may participate or advise in the review and decision by the
p.000165: Com- missioner on those issues. The Com- missioner may modify the text of the issues, but may not
p.000165: deny a hearing on those issues. Separation of functions continues with respect to issues on which
p.000165: the Center for Drug Evaluation and Research has recommended denial of a hearing. The Commissioner
p.000165: will neither evaluate nor rule on the Cen- ter’s recommendation on such issues and such issues will
p.000165: not be included in the notice of hearing. Participants in the hearing may make a motion to the presiding
p.000165: officer for the inclusion of any such issue in the hearing. The rul- ing on such a motion is subject to
p.000165: re- view in accordance with § 12.35(b). Fail- ure to so move constitutes a waiver of the right to a hearing on
p.000165: such an issue. Separation of functions on all issues resumes upon issuance of a notice of hearing. The
p.000165: Office of the General Counsel, Department of Health and Human Services, will observe the same separation
p.000165: of functions.
p.000165: (g) Summary judgment. A person who
p.000165: requests a hearing may not rely upon allegations or denials but is required to set forth specific facts
p.000165: showing that there is a genuine and substantial issue of fact that requires a hearing with re- spect to a particular
p.000165: drug product spec- ified in the request for hearing.
p.000165: (1) Where a specific notice of oppor- tunity for hearing (as defined in para- graph (a)(1) of this section)
p.000165: is used, the Commissioner will enter summary
p.000166: 166
p.000166:
p.000166:
p.000166:
p.000166:
p.000166:
p.000166:
p.000166:
p.000166: Food and Drug Administration, HHS § 314.200
p.000166:
p.000166:
p.000166: judgment against a person who re- quests a hearing, making findings and conclusions, denying a
p.000166: hearing, if it conclusively appears from the face of the data, information, and factual analyses
p.000166: in the request for the hearing that there is no genuine and substan- tial issue of fact which precludes
p.000166: the refusal to approve the application or abbreviated application or the with- drawal of approval of the
...
p.000172: approval of an applica- tion approved under § 314.510 or § 314.520. The notice, which will ordinarily be a
p.000172: letter, will state generally the reasons for the action and the proposed grounds for the order.
p.000172: (c) Submission of data and information.
p.000172: (1) If the applicant fails to file a writ- ten request for a hearing within 15 days of receipt of the
p.000172: notice, the applicant waives the opportunity for a hearing.
p.000172: (2) If the applicant files a timely re- quest for a hearing, the agency will publish a notice of
p.000172: hearing in the FED- ERAL REGISTER in accordance with
p.000172: §§ 12.32(e) and 15.20 of this chapter.
p.000172: (3) An applicant who requests a hear- ing under this section must, within 30 days of receipt of the notice
p.000172: of oppor- tunity for a hearing, submit the data and information upon which the appli- cant intends to rely
p.000172: at the hearing.
p.000172: (d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not
p.000172: apply at any point in withdrawal proceedings under this section.
p.000172: (e) Procedures for hearings. Hearings held under this section will be con- ducted in accordance
p.000172: with the provi- sions of part 15 of this chapter, with the following modifications:
p.000172: (1) An advisory committee duly con- stituted under part 14 of this chapter will be present at the
p.000172: hearing. The committee will be asked to review the issues involved and to provide advice and
p.000172: recommendations to the Commis- sioner of Food and Drugs.
p.000172: (2) The presiding officer, the advisory committee members, up to three rep- resentatives of the applicant, and up
p.000172: to three representatives of the Center may question any person during or at
p.000173: 173
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173:
p.000173: § 314.540
p.000173: the conclusion of the person’s presen- tation. No other person attending the hearing may question a person
p.000173: making a presentation. The presiding officer may, as a matter of discretion, permit questions to be
p.000173: submitted to the pre- siding officer for response by a person making a presentation.
p.000173: (f) Judicial revie . The Commis- sioner’s decision constitutes final agency action from
p.000173: which the appli- cant may petition for judicial review. Before requesting an order from a court
p.000173: for a stay of action pending re- view, an applicant must first submit a petition for a stay of
p.000173: action under
p.000173: § 10.35 of this chapter.
p.000173: [57 FR 58958, Dec. 11, 1992, as amended at 64
p.000173: FR 402, Jan. 5, 1999]
p.000173:
p.000173: § 314.540 Postmarketing safety report- ing.
p.000173: Drug products approved under this program are subject to the post- marketing recordkeeping
p.000173: and safety reporting applicable to all approved drug products, as provided in §§ 314.80 and 314.81.
p.000173: § 314.550 Promotional materials.
p.000173: For drug products being considered for approval under this subpart, unless otherwise informed by the
p.000173: agency, ap- plicants must submit to the agency for consideration during the preapproval review period copies of
p.000173: all promotional materials, including promotional label- ing as well as advertisements, intended for dissemination or
p.000173: publication within 120 days following marketing approval. After 120 days following marketing ap- proval, unless
p.000173: otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior
p.000173: to the intended time of initial dissemination of the labeling or initial publication of the advertisement.
p.000173: § 314.560 Termination of requirements.
...
p.000175: the approval of an application approved under this sub- part. The notice, which will ordinarily be a
p.000175: letter, will state generally the rea- sons for the action and the proposed grounds for the order.
p.000175: (c) Submission of data and information.
p.000175: (1) If the applicant fails to file a writ- ten request for a hearing within 15 days of receipt of the
p.000175: notice, the applicant waives the opportunity for a hearing.
p.000175: (2) If the applicant files a timely re- quest for a hearing, the agency will publish a notice of
p.000175: hearing in the FED- ERAL REGISTER in accordance with
p.000175: §§ 12.32(e) and 15.20 of this chapter.
p.000175: (3) An applicant who requests a hear- ing under this section must, within 30 days of receipt of the notice
p.000175: of oppor- tunity for a hearing, submit the data and information upon which the appli- cant intends to rely
p.000175: at the hearing.
p.000175: (d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not
p.000175: apply at any point in withdrawal proceedings under this section.
p.000175: (e) Procedures for hearings. Hearings held under this section will be con- ducted in accordance
p.000175: with the provi- sions of part 15 of this chapter, with the following modifications:
p.000175: (1) An advisory committee duly con- stituted under part 14 of this chapter will be present at the
p.000175: hearing. The committee will be asked to review the issues involved and to provide advice and
p.000175: recommendations to the Commis- sioner of Food and Drugs.
p.000175: (2) The presiding officer, the advisory committee members, up to three rep- resentatives of the applicant, and up
p.000175: to three representatives of CDER may question any person during or at the conclusion of the
p.000175: person’s presen- tation. No other person attending the hearing may question a person making a presentation.
p.000175: The presiding officer may, as a matter of discretion, permit questions to be submitted to the pre-
p.000175: 21 CFR Ch. I (4–1–12 Edition)
p.000175: siding officer for response by a person making a presentation.
p.000175: (f) Judicial revie . The Commissioner of Food and Drugs’ decision constitutes final agency action from which the
p.000175: ap- plicant may petition for judicial re- view. Before requesting an order from a court for a stay of
p.000175: action pending re- view, an applicant must first submit a petition for a stay of action under
p.000175: § 10.35 of this chapter.
p.000175:
p.000175: § 314.630 Postmarketing safety report- ing.
p.000175: Drug products approved under this subpart are subject to the post- marketing recordkeeping
p.000175: and safety reporting requirements applicable to all approved drug products, as provided in §§ 314.80 and
p.000175: 314.81.
p.000175: § 314.640 Promotional materials.
p.000175: For drug products being considered for approval under this subpart, unless otherwise informed by the
p.000175: agency, ap- plicants must submit to the agency for consideration during the preapproval review period copies of
p.000175: all promotional materials, including promotional label- ing as well as advertisements, intended for dissemination or
p.000175: publication within 120 days following marketing approval. After 120 days following marketing ap- proval, unless
p.000175: otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior
p.000175: to the intended time of initial dissemination of the labeling or initial publication of the advertisement.
p.000175: § 314.650 Termination of requirements.
...
Social / Property Ownership
Searching for indicator home:
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p.000097: performed by each contract facility; and the results of any test performed on the components used in
p.000097: the manu- facture of the drug product as required by § 211.84(d) of this chapter and on the drug product as
p.000097: required by § 211.165 of this chapter.
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097:
p.000097: § 314.50
p.000097: (c) The proposed or actual master production record, including a descrip- tion of the equipment, to
p.000097: be used for the manufacture of a commercial lot of the drug product or a comparably de- tailed description
p.000097: of the production process for a representative batch of the drug product.
p.000097: (iii) Environmental impact. The appli- cation is required to contain either a claim for categorical
p.000097: exclusion under
p.000097: § 25.30 or 25.31 of this chapter or an en- vironmental assessment under § 25.40 of this chapter.
p.000097: (iv) The applicant may, at its option, submit a complete chemistry, manu- facturing, and controls section 90 to
p.000097: 120 days before the anticipated submission of the remainder of the application. FDA will review
p.000097: such early submis- sions as resources permit.
p.000097: (v) The applicant shall include a statement certifying that the field copy of the application
p.000097: has been pro- vided to the applicant’s home FDA dis- trict office.
p.000097: (2) Nonclinical pharmacology and toxi- cology section. A section describing, with the aid of graphs
p.000097: and tables, ani- mal and in vitro studies with drug, in- cluding the following:
p.000097: (i) Studies of the pharmacological ac- tions of the drug in relation to its pro- posed therapeutic indication and
p.000097: stud- ies that otherwise define the pharma- cologic properties of the drug or are pertinent to possible
p.000097: adverse effects.
p.000097: (ii) Studies of the toxicological ef- fects of the drug as they relate to the drug’s intended clinical
p.000097: uses, includ- ing, as appropriate, studies assessing the drug’s acute, subacute, and chronic toxicity;
p.000097: carcinogenicity; and studies of toxicities related to the drug’s par- ticular mode of administration or
p.000097: con- ditions of use.
p.000097: (iii) Studies, as appropriate, of the ef- fects of the drug on reproduction and on the developing fetus.
p.000097: (iv) Any studies of the absorption, distribution, metabolism, and excre- tion of the drug in animals.
p.000097: (v) For each nonclinical laboratory study subject to the good laboratory practice regulations under part
...
p.000114: period of exclusivity in accordance with sec- tion 505(c)(3)(D)(ii) of the act that has not expired;
p.000114: (ii) The applicant seeks to amend the unapproved application to include a published report of an
p.000114: investigation that was conducted or sponsored by the applicant entitled to exclusivity for the drug;
p.000114: (iii) The applicant has not obtained a right of reference to the investigation described in paragraph
p.000114: (c)(1)(ii) of this section; and
p.000114: (iv) The report of the investigation described in paragraph (c)(1)(ii) of this section would be essential
p.000114: to the ap- proval of the unapproved application.
p.000114: (2) The submission of an amendment described in paragraph (c)(1) of this section will cause the
p.000114: unapproved ap- plication to be deemed to be withdrawn by the applicant under § 314.65 on the date of receipt
p.000114: by FDA of the amend- ment. The amendment will be consid- ered a resubmission of the application, which
p.000114: may not be accepted except as
p.000115: 115
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115:
p.000115: § 314.65
p.000115: provided in accordance with section 505(c)(3)(D)(ii) of the act.
p.000115: (d) The applicant shall submit a field copy of each amendment to
p.000115: § 314.50(d)(1). The applicant shall in- clude in its submission of each such amendment to FDA a
p.000115: statement certi- fying that a field copy of the amend- ment has been sent to the applicant’s home FDA
p.000115: district office.
p.000115: [50 FR 7493, Feb. 22, 1985, as amended at 57
p.000115: FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8,
p.000115: 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr.
p.000115: 8, 2004; 73 FR 39608, July 10, 2008]
p.000115:
p.000115: § 314.65 Withdrawal by the applicant of an unapproved application.
p.000115: An applicant may at any time with- draw an application that is not yet ap- proved by notifying the Food and Drug
p.000115: Administration in writing. If, by the time it receives such notice, the agen- cy has identified any
p.000115: deficiencies in the application, we will list such defi- ciencies in the letter we send the appli- cant
p.000115: acknowledging the withdrawal. A decision to withdraw the application is without prejudice to refiling. The agen- cy
p.000115: will retain the application and will provide a copy to the applicant on re- quest under the fee schedule in
p.000115: § 20.45 of FDA’s public information regulations.
p.000115: [50 FR 7493, Feb. 22, 1985, as amended at 68
p.000115: FR 25287, May 12, 2003; 73 FR 39609, July 10,
p.000115: 2008]
p.000115:
p.000115: § 314.70 Supplements and other changes to an approved application.
p.000115: (a) Changes to an approved application. (1)(i) Except as provided in paragraph (a)(1)(ii) of this section, the
p.000115: applicant must notify FDA about each change in each condition established in an ap- proved application
p.000115: beyond the vari- ations already provided for in the ap- plication. The notice is required to de- scribe
p.000115: the change fully. Depending on the type of change, the applicant must notify FDA about the change in a
...
p.000120: i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have
p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
p.000120: includes events that may be symptomatically and pathophysiologically related to an event listed
p.000120: in the labeling, but differ from the event because of greater se-
p.000120:
p.000120: verity or specificity. For example, under this definition, hepatic necrosis would be unexpected
p.000120: (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis.
p.000120: Similarly, cerebral thrombo- embolism and cerebral vasculitis would be unexpected (by virtue of greater
p.000120: specificity) if the labeling only listed cerebral vascular accidents. ‘‘Unex- pected,’’ as used in this
p.000120: definition, re- fers to an adverse drug experience that has not been previously observed (i.e., included in the
p.000120: labeling) rather than from the perspective of such experience not being anticipated from the pharma- cological
p.000120: properties of the pharma- ceutical product.
p.000120: (b) Revie of adverse drug experiences.
...
p.000138: conducted by the applicant on the same drug product formulation, unless the information has previously been
p.000138: submitted to FDA in the abbreviated new drug applica- tion. A complete study report must be submitted for
p.000138: any bioequivalence study upon which the applicant relies for ap- proval. For all other bioequivalence
p.000138: studies conducted on the same drug product formulation as defined in
p.000138: § 320.1(g) of this chapter, the applicant
p.000138: must submit either a complete or sum- mary report. If a summary report of a bioequivalence study is submitted
p.000138: and FDA determines that there may be bio- equivalence issues or concerns with the product, FDA may require that the
p.000138: ap- plicant submit a complete report of the bioequivalence study to FDA.
p.000138: (2) Submission of an amendment con-
p.000138: taining significant data or information before the end of the initial review cycle constitutes an
p.000138: agreement be- tween FDA and the applicant to extend the initial review cycle only for the time necessary to
p.000138: review the signifi- cant data or information and for no more than 180 days.
p.000138: (b) The applicant shall submit a field
p.000138: copy of each amendment to
p.000138: § 314.94(a)(9). The applicant, other than a foreign applicant, shall include in its submission of each such
p.000138: amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant’s
p.000138: home FDA district office.
p.000138: [57 FR 17983, Apr. 28, 1992, as amended at 58
p.000138: FR 47352, Sept. 8, 1993; 64 FR 401, Jan. 5, 1999;
p.000138: 73 FR 39609, July 10, 2008; 74 FR 2861, Jan. 16,
p.000138: 2009]
p.000138:
p.000138: § 314.97 Supplements and other changes to an approved abbre- viated application.
p.000138: The applicant shall comply with the requirements of §§ 314.70 and 314.71 re- garding the submission
p.000138: of supple- mental applications and other changes to an approved abbreviated applica- tion.
p.000138: § 314.98 Postmarketing reports.
p.000138: (a) Except as provided in paragraph
p.000138: (b) of this section, each applicant hav- ing an approved abbreviated new drug
p.000139: 139
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139:
p.000139: § 314.99
p.000139: application under § 314.94 that is effec- tive shall comply with the require- ments of § 314.80
p.000139: regarding the report- ing and recordkeeping of adverse drug experiences.
p.000139: (b) Each applicant shall submit one copy of each report required under
p.000139: § 314.80 to the Central Document Room, Center for Drug Evaluation and Re- search, Food and Drug
p.000139: Administration, 5901–B Ammendale Rd., Beltsville, MD 20705–1266.
p.000139: (c) Each applicant shall make the re- ports required under § 314.81 and section 505(k) of the act for each
p.000139: of its ap- proved abbreviated applications.
p.000139: [57 FR 17983, Apr. 28, 1992, as amended at 64
...
p.000170: Standish Pl., Rockville, MD 20855. This includes items sent by parcel post or overnight courier serv- ice.
p.000170: Correspondence not associated with an abbreviated application should be addressed specifically to the
p.000170: in- tended office or division and to the per- son as follows: Office of Generic Drugs,
p.000171: 171
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171:
p.000171: § 314.445
p.000171: Center for Drug Evaluation and Re- search, Food and Drug Administration, Attn: [insert name of person],
p.000171: Metro Park North II, HFD–[insert mail code of office or division], 7500 Standish Place, rm. 150,
p.000171: Rockville, MD 20855. The mail code for the Office of Generic Drugs is HFD–600, the mail codes for the
p.000171: Divisions of Chemistry I, II, and III are HFD–620, HFD–640, and HFD–630,
p.000171: respectively, and the mail code for the Division of Bioequivalence is HFD–650.
p.000171: (3) A request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds
p.000171: for deny- ing approval of an application, except an application under paragraph (b) of this section,
p.000171: should be directed to the Associate Director for Policy (HFD–5).
p.000171: (4) The field copy of an application, an abbreviated application, amend- ments, supplements,
p.000171: resubmissions, re- quests for waivers, and other cor- respondence about an application and an
p.000171: abbreviated application shall be sent to the applicant’s home FDA dis- trict office, except that a foreign
p.000171: appli- cant shall send the field copy to the ap- propriate address identified in para- graphs (a)(1) and (a)(2)
p.000171: of this section.
p.000171: (b) Applicants shall send applications and other correspondence relating to matters covered by this part
p.000171: for the drug products listed below to the Docu- ment Control Center (HFM–99), Center for Biologics Evaluation
p.000171: and Research, 1401 Rockville Pike, suite 200N, Rock- ville, MD 20852–1448, except applicants shall send a
p.000171: request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds
p.000171: for denying approval of an application to the Director, Center for Biologics Evaluation and Research
p.000171: (HFM–1), at the same address.
p.000171: (1) Ingredients packaged together with containers intended for the collec- tion, processing, or storage
p.000171: of blood and blood components;
p.000171: (2) Plasma volume expanders and hy- droxyethyl starch for leukapheresis;
p.000171: (3) Blood component processing solu- tions and shelf life extenders; and
p.000171: 21 CFR Ch. I (4–1–12 Edition)
p.000171: (4) Oxygen carriers.
p.000171: [50 FR 7493, Feb. 22, 1985, as amended at 50
p.000171: FR 21238, May 23, 1985; 55 FR 11581, Mar. 29,
p.000171: 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352,
p.000171: Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR
p.000171: 13473, Mar. 23, 2004; 70 FR 14981, Mar. 24, 2005;
p.000171: 73 FR 39610, July 10, 2008; 74 FR 13113, Mar.
p.000171: 26, 2009; 75 FR 37295, June 29, 2010]
p.000171: § 314.445 Guidance documents.
p.000171: (a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain
...
Social / Racial Minority
Searching for indicator racial:
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p.000098: clinical studies that have not been analyzed in detail for any reason (e.g., because they have been
p.000098: discon- tinued or are incomplete) are to be in- cluded in this section, including a copy of the protocol and
p.000098: a brief description of the results and status of the study.
p.000098: (iii) A description of each uncon-
p.000098: trolled clinical study, a summary of the results, and a brief statement ex- plaining why the study
p.000098: is classified as uncontrolled.
p.000098: (iv) A description and analysis of any other data or information relevant to an evaluation of the safety and
p.000098: effec- tiveness of the drug product obtained or otherwise received by the applicant from any source,
p.000098: foreign or domestic, including information derived from clinical investigations, including con- trolled
p.000098: and uncontrolled studies of uses of the drug other than those proposed in the application, commercial
p.000098: mar- keting experience, reports in the sci- entific literature, and unpublished sci- entific papers.
p.000098: (v) An integrated summary of the
p.000098: data demonstrating substantial evi- dence of effectiveness for the claimed indications. Evidence is
p.000098: also required to support the dosage and administra- tion section of the labeling, including support for
p.000098: the dosage and dose inter- val recommended. The effectiveness data shall be presented by gender,
p.000098: age, and racial subgroups and shall identify any modifications of dose or dose inter- val needed for specific
p.000098: subgroups. Ef-
p.000099: 99
p.000099:
p.000099: fectiveness data from other subgroups of the population of patients treated, when appropriate, such
p.000099: as patients with renal failure or patients with dif- ferent levels of severity of the disease, also
p.000099: shall be presented.
p.000099: (vi) A summary and updates of safety information, as follows:
p.000099: (a) The applicant shall submit an in- tegrated summary of all available in- formation about the safety
p.000099: of the drug product, including pertinent animal data, demonstrated or potential ad- verse effects of
p.000099: the drug, clinically sig- nificant drug/drug interactions, and other safety considerations, such as
p.000099: data from epidemiological studies of related drugs. The safety data shall be presented by gender,
p.000099: age, and racial subgroups. When appropriate, safety data from other subgroups of the popu- lation of
p.000099: patients treated also shall be presented, such as for patients with renal failure or patients with
p.000099: different levels of severity of the disease. A de- scription of any statistical analyses performed in
p.000099: analyzing safety data should also be included, unless already included under paragraph (d)(5)(ii) of
p.000099: this section.
p.000099: (b) The applicant shall, under section
p.000099: 505(i) of the act, update periodically its pending application with new safety in- formation learned about the drug
p.000099: that may reasonably affect the statement of contraindications, warnings, pre- cautions, and adverse
p.000099: reactions in the draft labeling and, if applicable, any Medication Guide required under part
p.000099: 208 of this chapter. These ‘‘safety up- date reports’’ are required to include the same kinds of
p.000099: information (from clinical studies, animal studies, and other sources) and are required to be submitted
p.000099: in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition,
p.000099: the reports are required to include the case report forms for each patient who died during a clinical
p.000099: study or who did not complete the study because of an adverse event (unless this requirement is waived).
p.000099: The applicant shall submit these reports (1) 4 months after the ini- tial submission; (2) in a resubmission
p.000099: following receipt of a complete re- sponse letter; and (3) at other times as requested by FDA. Prior
p.000099: to the submis- sion of the first such report, applicants
p.000099:
...
Social / Religion
Searching for indicator belief:
(return to top)
p.000103: submitted, the application will no longer be consid- ered to be one containing a certifi- cation
p.000103: under paragraph (i)(1)(i)(A)(4) of this section.
p.000103: (iii) Other amendments. (A) Except as
p.000103: provided in paragraphs (i)(4) and (i)(6)(iii)(B) of this section, an appli- cant shall amend a
p.000103: submitted certifi- cation if, at any time before the effec- tive date of the approval of the applica- tion, the
p.000103: applicant learns that the sub- mitted certification is no longer accu- rate.
p.000103: (B) An applicant is not required to amend a submitted certification when information on an otherwise
p.000103: applicable patent is submitted after the effective date of approval for the 505(b)(2) appli- cation.
p.000103: (j) Claimed exclusivity. A new drug product, upon approval, may be enti- tled to a period of
p.000103: marketing exclu- sivity under the provisions of § 314.108. If an applicant believes its drug prod- uct is
p.000103: entitled to a period of exclu- sivity, it shall submit with the new drug application prior
p.000103: to approval the following information:
p.000103: (1) A statement that the applicant is claiming exclusivity.
p.000103: (2) A reference to the appropriate paragraph under § 314.108 that supports its claim.
p.000103: (3) If the applicant claims exclusivity under § 314.108(b)(2), information to
p.000103: 21 CFR Ch. I (4–1–12 Edition)
p.000103: show that, to the best of its knowledge or belief, a drug has not previously been approved under section
p.000103: 505(b) of the act containing any active moiety in the drug for which the applicant is seeking approval.
p.000103: (4) If the applicant claims exclusivity under § 314.108(b)(4) or (b)(5), the fol- lowing information to
p.000103: show that the application contains ‘‘new clinical in- vestigations’’ that are ‘‘essential to ap- proval of
p.000103: the application or supple- ment’’ and were ‘‘conducted or spon- sored by the applicant:’’
p.000103: (i) ‘‘Ne clinical investigations.’’ A cer- tification that to the best of the appli- cant’s knowledge each of the
p.000103: clinical investigations included in the applica- tion meets the definition of ‘‘new clin- ical
p.000103: investigation’’ set forth in
p.000103: § 314.108(a).
p.000103: (ii) ‘‘Essential to approval.’’ A list of all published studies or publicly avail- able reports of
p.000103: clinical investigations known to the applicant through a lit- erature search that are relevant to the conditions
p.000103: for which the applicant is seeking approval, a certification that the applicant has thoroughly searched
p.000103: the scientific literature and, to the best of the applicant’s knowledge, the list is complete and
p.000103: accurate and, in the applicant’s opinion, such published studies or publicly available reports do not provide a
p.000103: sufficient basis for the approval of the conditions for which the applicant is seeking approval with- out
p.000103: reference to the new clinical inves- tigation(s) in the application, and an explanation as to why the studies
...
p.000164: B. A statement whether such labeling has at any subsequent time been discontinued or changed in any manner.
p.000164: If such discontinu- ance or change has been made, the exact
p.000165: 165
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165:
p.000165: § 314.200
p.000165: date, nature, and rationale for each dis- continuance or change and a copy of each pertinent
p.000165: document or record to establish each such discontinuance or change should be submitted, including, but
p.000165: not limited to, the labeling which resulted from each such discontinuance or change. If no such
p.000165: dis- continuance or change has been made, a copy of representative documents or records show- ing labeling at
p.000165: representative points in time should be submitted to support the state- ment.
p.000165: III. Marketing.
p.000165: A. A copy of each pertinent document or record to establish the exact date the drug was initially
p.000165: marketed.
p.000165: B. A statement whether such marketing has at any subsequent time been discon- tinued. If such
p.000165: marketing has been discon- tinued, the exact date of each such dis- continuance should be
p.000165: submitted, together with a copy of each pertinent document or record to establish each such date.
p.000165: IV. Verification.
p.000165: A statement signed by the person respon- sible for such submission, that all appro- priate records
p.000165: have been searched and to the best of that person’s knowledge and belief it includes a true and accurate
p.000165: presentation of the facts.
p.000165: (WARNING: A willfully false statement is a criminal offense, 18 U.S.C. 1001.)
p.000165: (3) The Food and Drug Administra- tion will not find a drug product, in- cluding any active ingredient,
p.000165: which is identical, related, or similar, as de- scribed in § 310.6, to a drug product, in- cluding any active
p.000165: ingredient for which an application is or at any time has been effective or deemed approved, or approved
p.000165: under section 505 of the act, to be exempt from part or all of the new drug provisions of the act.
p.000165: (4) A contention that a drug product
p.000165: is not a new drug for any other reason is required to be supported by submis- sion of the factual
p.000165: records, data, and information that are necessary and ap- propriate to support the contention.
p.000165: (5) It is the responsibility of every person who manufactures or distrib- utes a drug product in
p.000165: reliance upon a ‘‘grandfather’’ provision of the act to maintain files that contain the data and
p.000165: information necessary fully to doc- ument and support that status.
p.000165: (f) Separation of functions. Separation of functions commences upon receipt of a request for hearing. The
...
Social / Threat of Stigma
Searching for indicator threat:
(return to top)
p.000120: of a drug product in professional practice; an adverse event occurring from drug overdose whether
p.000120: accidental or intentional; an adverse event occurring from drug abuse; an adverse event
p.000120: occurring from drug withdrawal; and any failure of expected pharmacological action.
p.000120: Disability. A substantial disruption of
p.000120: a person’s ability to conduct normal life functions.
p.000120: Life-threatening adverse drug experi- ence. Any adverse drug experience that places the patient, in the
p.000120: view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred,
p.000120: i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have
p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
...
p.000128: (2) The certification must be signed by the applicant or the applicant’s at- torney, agent (representative),
p.000128: or other
p.000128:
p.000128: authorized official. If the person sign- ing the certification does not reside or have a place of
p.000128: business within the United States, the certification must contain the name and address of, and must also
p.000128: be signed by, an attorney, agent, or other authorized official who resides or maintains a place of business
p.000128: within the United States.
p.000128: (3) For drugs regulated by the Center for Drug Evaluation and Research (CDER) or the Center for
p.000128: Biologics Evaluation and Research (CBER), one copy of the certification must be sub- mitted to the Drug
p.000128: Shortage Coordi- nator at the address of the Director of CDER, one copy to the CDER Drug
p.000128: Registration and Listing Team, Divi- sion of Compliance Risk Management and Surveillance in CDER, and
p.000128: one copy to either the director of the re- view division in CDER responsible for reviewing the application,
p.000128: or the direc- tor of the office in CBER responsible for reviewing the application.
p.000128: (d) What circumstances and information can establish good cause for a reduction in the discontinuance
p.000128: notification period?
p.000128: (1) A public health problem may result from continuation of manufacturing for the 6-month period. This
p.000128: certifi- cation must include a detailed descrip- tion of the potential threat to the pub- lic health.
p.000128: (2) A biomaterials shortage prevents the continuation of the manufacturing for the 6-month period. This
p.000128: certifi- cation must include a detailed descrip- tion of the steps taken by the applicant in an attempt to secure
p.000128: an adequate supply of biomaterials to enable manu- facturing to continue for the 6-month period and an
p.000128: explanation of why the biomaterials could not be secured.
p.000128: (3) A liability problem may exist for the manufacturer if the manufacturing is continued for the 6-month
p.000128: period. This certification must include a de- tailed description of the potential li- ability problem.
p.000128: (4) Continuation of the manufac- turing for the 6-month period may cause substantial economic
p.000128: hardship for the manufacturer. This certifi- cation must include a detailed descrip- tion of the
p.000128: financial impact of con- tinuing to manufacture the drug prod- uct over the 6-month period.
p.000129: 129
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129:
p.000129: § 314.92
p.000129: (5) The manufacturer has filed for bankruptcy under chapter 7 or 11 of title 11, United States
p.000129: Code (11 U.S.C. 701 et seq. and 1101 et seq.). This certifi- cation must be accompanied by docu-
p.000129: mentation of the filing or proof that the filing occurred.
p.000129: (6) The manufacturer can continue distribution of the drug product to sat- isfy existing market need for 6
p.000129: months. This certification must include a de- tailed description of the manufactur- er’s processes to
...
Social / Victim of Abuse
Searching for indicator abuse:
(return to top)
p.000092: 314.71 Procedures for submission of a sup- plement to an approved application.
p.000092: 314.72 Change in ownership of an applica- tion.
p.000092: 314.80 Postmarketing reporting of adverse drug experiences.
p.000092: 314.81 Other postmarketing reports.
p.000092: 314.90 Waivers.
p.000092: Subpart C—Abbreviated Applications
p.000092: 314.91 Obtaining a reduction in the dis- continuance notification period.
p.000092: 314.92 Drug products for which abbreviated applications may be submitted.
p.000092: 314.93 Petition to request a change from a listed drug.
p.000092: 314.94 Content and format of an abbreviated application.
p.000092: 314.95 Notice of certification of invalidity or noninfringement of a patent.
p.000092: 314.96 Amendments to an unapproved abbre- viated application.
p.000092: 314.97 Supplements and other changes to an approved abbreviated application.
p.000092: 314.98 Postmarketing reports.
p.000092: 314.99 Other responsibilities of an applicant of an abbreviated application.
p.000092: Subpart D—FDA Action on Applications and Abbreviated Applications
p.000092: 314.100 Timeframes for reviewing applica- tions and abbreviated applications.
p.000092: 314.101 Filing an application and receiving an abbreviated new drug application.
p.000092: 314.102 Communications between FDA and applicants.
p.000092: 314.103 Dispute resolution.
p.000092:
p.000092: 92
p.000092:
p.000092: 21 CFR Ch. I (4–1–12 Edition)
p.000092: 314.104 Drugs with potential for abuse.
p.000092: 314.105 Approval of an application and an abbreviated application.
p.000092: 314.106 Foreign data.
p.000092: 314.107 Effective date of approval of a 505(b)(2) application or abbreviated new drug
p.000092: application under section 505(j) of the act.
p.000092: 314.108 New drug product exclusivity.
p.000092: 314.110 Complete response letter to the ap- plicant.
p.000092: 314.120 [Reserved]
p.000092: 314.122 Submitting an abbreviated applica- tion for, or a 505(j)(2)(C) petition that re- lies on, a listed
p.000092: drug that is no longer marketed.
p.000092: 314.125 Refusal to approve an application.
p.000092: 314.126 Adequate and well-controlled stud- ies.
p.000092: 314.127 Refusal to approve an abbreviated new drug application.
p.000092: 314.150 Withdrawal of approval of an appli- cation or abbreviated application.
p.000092: 314.151 Withdrawal of approval of an abbre- viated new drug application under sec- tion 505(j)(5) of the
p.000092: act.
p.000092: 314.152 Notice of withdrawal of approval of an application or abbreviated application for a new drug.
p.000092: 314.153 Suspension of approval of an abbre- viated new drug application.
p.000092: 314.160 Approval of an application or abbre- viated application for which approval was previously
p.000092: refused, suspended, or withdrawn.
...
p.000099: this section.
p.000099: (b) The applicant shall, under section
p.000099: 505(i) of the act, update periodically its pending application with new safety in- formation learned about the drug
p.000099: that may reasonably affect the statement of contraindications, warnings, pre- cautions, and adverse
p.000099: reactions in the draft labeling and, if applicable, any Medication Guide required under part
p.000099: 208 of this chapter. These ‘‘safety up- date reports’’ are required to include the same kinds of
p.000099: information (from clinical studies, animal studies, and other sources) and are required to be submitted
p.000099: in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition,
p.000099: the reports are required to include the case report forms for each patient who died during a clinical
p.000099: study or who did not complete the study because of an adverse event (unless this requirement is waived).
p.000099: The applicant shall submit these reports (1) 4 months after the ini- tial submission; (2) in a resubmission
p.000099: following receipt of a complete re- sponse letter; and (3) at other times as requested by FDA. Prior
p.000099: to the submis- sion of the first such report, applicants
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099:
p.000099: § 314.50
p.000099: are encouraged to consult with FDA re- garding further details on its form and content.
p.000099: (vii) If the drug has a potential for abuse, a description and analysis of studies or information
p.000099: related to abuse of the drug, including a proposal for scheduling under the Controlled Sub- stances Act. A
p.000099: description of any stud- ies related to overdosage is also re- quired, including information on dialy- sis,
p.000099: antidotes, or other treatments, if known.
p.000099: (viii) An integrated summary of the benefits and risks of the drug, includ- ing a discussion of why the
p.000099: benefits ex- ceed the risks under the conditions stated in the labeling.
p.000099: (ix) A statement with respect to each clinical study involving human sub- jects that it either was
p.000099: conducted in compliance with the institutional re- view board regulations in part 56, or was not subject
p.000099: to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the in- formed
p.000099: consent regulations in part 50.
p.000099: (x) If a sponsor has transferred any obligations for the conduct of any clin- ical study to a contract
p.000099: research orga- nization, a statement containing the name and address of the contract re- search
p.000099: organization, identification of the clinical study, and a listing of the obligations transferred. If
p.000099: all obliga- tions governing the conduct of the study have been transferred, a general statement of
p.000099: this transfer—in lieu of a listing of the specific obligations trans- ferred—may be submitted.
p.000099: (xi) If original subject records were audited or reviewed by the sponsor in the course of monitoring any
...
p.000117: assurance that the drug substance or drug product will have the characteristics of identity,
p.000117: strength, quality, purity, or potency that it purports or is represented to possess;
p.000117: (ii) A change in the size and/or shape of a container for a nonsterile drug product, except for solid
p.000117: dosage forms, without a change in the labeled amount of drug product or from one container
p.000117: closure system to another;
p.000117: (iii) Changes in the labeling to reflect newly acquired information, except for changes to the information
p.000117: required in
p.000117: § 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish
p.000117: any of the following:
p.000117: (A) To add or strengthen a contra- indication, warning, precaution, or ad- verse reaction for which the
p.000117: evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c)
p.000117: of this chapter;
p.000118: 118
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118: Food and Drug Administration, HHS § 314.70
p.000118:
p.000118:
p.000118: (B) To add or strengthen a statement about drug abuse, dependence, psycho- logical effect, or overdosage;
p.000118: (C) To add or strengthen an instruc- tion about dosage and administration that is intended to increase
p.000118: the safe use of the drug product;
p.000118: (D) To delete false, misleading, or un- supported indications for use or claims for effectiveness; or
p.000118: (E) Any labeling change normally re- quiring a supplement submission and approval prior to distribution of
p.000118: the drug product that FDA specifically re- quests be submitted under this provi- sion.
p.000118: (7) If the agency disapproves the sup- plemental application, it may order the manufacturer to cease
p.000118: distribution of the drug product(s) made with the manufacturing change.
p.000118: (d) Changes to be described in an an- nual report (minor changes). (1) Changes in the drug substance,
p.000118: drug product, production process, quality controls, equipment, or facilities that have a minimal
p.000118: potential to have an adverse effect on the identity, strength, qual- ity, purity, or potency of the
p.000118: drug product as these factors may relate to the safety or effectiveness of the drug product must be
...
p.000119: § 314.70, except the new owner may advise FDA in the next annual report about a change in the drug
p.000119: product’s label or labeling to change the product’s brand or the name of its manufacturer, pack- er, or
p.000119: distributor.
p.000119: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000119: 1985, as amended at 50 FR 21238, May 23, 1985;
p.000119: 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12,
p.000119: 2003]
p.000119:
p.000119: § 314.80 Postmarketing reporting of adverse drug experiences.
p.000119: (a) Definitions. The following defini- tions of terms apply to this section:
p.000120: 120
p.000120:
p.000120:
p.000120:
p.000120:
p.000120:
p.000120:
p.000120:
p.000120: Food and Drug Administration, HHS § 314.80
p.000120:
p.000120:
p.000120: Adverse drug experience. Any adverse event associated with the use of a drug in humans, whether or not
p.000120: considered drug related, including the following: An adverse event occurring in the course of the use
p.000120: of a drug product in professional practice; an adverse event occurring from drug overdose whether
p.000120: accidental or intentional; an adverse event occurring from drug abuse; an adverse event
p.000120: occurring from drug withdrawal; and any failure of expected pharmacological action.
p.000120: Disability. A substantial disruption of
p.000120: a person’s ability to conduct normal life functions.
p.000120: Life-threatening adverse drug experi- ence. Any adverse drug experience that places the patient, in the
p.000120: view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred,
p.000120: i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have
p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
p.000120: includes events that may be symptomatically and pathophysiologically related to an event listed
p.000120: in the labeling, but differ from the event because of greater se-
p.000120:
p.000120: verity or specificity. For example, under this definition, hepatic necrosis would be unexpected
p.000120: (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis.
p.000120: Similarly, cerebral thrombo- embolism and cerebral vasculitis would be unexpected (by virtue of greater
p.000120: specificity) if the labeling only listed cerebral vascular accidents. ‘‘Unex- pected,’’ as used in this
p.000120: definition, re- fers to an adverse drug experience that has not been previously observed (i.e., included in the
p.000120: labeling) rather than from the perspective of such experience not being anticipated from the pharma- cological
p.000120: properties of the pharma- ceutical product.
p.000120: (b) Revie of adverse drug experiences.
p.000120: Each applicant having an approved ap- plication under § 314.50 or, in the case of a 505(b)(2)
p.000120: application, an effective approved application, shall promptly review all adverse drug experience in-
...
p.000142: with the re- sponsible reviewing officials. If nec- essary, applicants may request a meet- ing with the
p.000142: appropriate reviewing offi- cials and management representatives in order to seek a resolution. Ordi-
p.000142: narily, such meetings would be held first with the Division Director, then with the Office
p.000142: Director, and finally with the Center Director if the matter is still unresolved. Requests for such
p.000142: meetings shall be directed to the direc- tor of the division responsible for re- viewing the application or
p.000142: abrreviated application. FDA will make every at- tempt to grant requests for meetings that involve
p.000142: important issues and that can be scheduled at mutually conven- ient times.
p.000142: (3) In requesting a meeting designed
p.000142: to resolve a scientific or medical dis- pute, applicants may suggest that FDA seek the advice of outside
p.000142: experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee
p.000142: members or other consultants, as designated by the agen- cy. Applicants may also bring their own
p.000142: consultants. For major scientific
p.000143: 143
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143:
p.000143: § 314.104
p.000143: and medical policy issues not resolved by informal meetings, FDA may refer the matter to one of its
p.000143: standing advi- sory committees for its consideration and recommendations.
p.000143: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11,
p.000143: 1985, as amended at 57 FR 17989, Apr. 28, 1992;
p.000143: 73 FR 39609, July 10, 2008]
p.000143:
p.000143: § 314.104 Drugs with potential for abuse.
p.000143: The Food and Drug Administration will inform the Drug Enforcement Ad- ministration under section 201(f) of the
p.000143: Controlled Substances Act (21 U.S.C. 801) when an application or abbreviated application is submitted for
p.000143: a drug that appears to have an abuse poten- tial.
p.000143: [57 FR 17989, Apr. 28, 1992]
p.000143:
p.000143: § 314.105 Approval of an application and an abbreviated application.
p.000143: (a) The Food and Drug Administra- tion will approve an application and send the applicant an approval
p.000143: letter if none of the reasons in § 314.125 for re- fusing to approve the application ap- plies. An approval
p.000143: becomes effective on the date of the issuance of the approval letter, except with regard to an ap- proval
p.000143: under section 505(b)(2) of the act with a delayed effective date. An ap- proval with a delayed effective
p.000143: date is tentative and does not become final until the effective date. A new drug product or
p.000143: antibiotic approved under this paragraph may not be marketed until an approval is effective.
p.000143: (b) FDA will approve an application
p.000143: and issue the applicant an approval let- ter on the basis of draft labeling if the only deficiencies in
p.000143: the application concern editorial or similar minor defi- ciencies in the draft labeling. Such ap- proval will
p.000143: be conditioned upon the ap- plicant incorporating the specified la- beling changes exactly as directed, and upon
p.000143: the applicant submitting to FDA a copy of the final printed labeling prior to marketing.
p.000143: (c) FDA will approve an application
p.000143: after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.000093: abbre- viated application.
p.000093: Assess the effects of the change means to evaluate the effects of a manufac- turing change on
p.000093: the identity, strength, quality, purity, and potency of a drug product as these factors may relate to
p.000093: the safety or effectiveness of the drug product.
p.000093: Authorized generic drug means a listed drug, as defined in this section, that has been approved under section
p.000093: 505(c) of the act and is marketed, sold, or dis- tributed directly or indirectly to retail class of trade with
p.000093: labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or
p.000093: similar packaging for use in institu- tions), product code, labeler code, trade name, or trademark that
p.000093: differs from that of the listed drug.
p.000093: Class 1 resubmission means the resub- mission of an application or efficacy supplement, following receipt of
p.000093: a com- plete response letter, that contains one or more of the following: Final printed labeling, draft labeling,
p.000093: certain safety updates, stability updates to support provisional or final dating periods,
p.000093: commitments to perform post- marketing studies (including proposals for such studies),
p.000093: assay validation data, final release testing on the last lots used to support approval, minor reanalyses
p.000093: of previously submitted data, and other comparatively minor information.
p.000093: Class 2 resubmission means the resub- mission of an application or efficacy supplement, following receipt of
p.000093: a com- plete response letter, that includes any item not specified in the definition of ‘‘Class 1
p.000093: resubmission,’’ including any item that would require presentation to an advisory committee.
p.000093: Complete response letter means a writ- ten communication to an applicant from FDA usually describing
p.000093: all of the deficiencies that the agency has identi- fied in an application or abbreviated application that
p.000093: must be satisfactorily addressed before it can be approved.
p.000093: Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a
p.000093: drug sub- stance, generally, but not necessarily,
p.000093:
p.000094: 94
p.000094: 21 CFR Ch. I (4–1–12 Edition)
p.000094: in association with one or more other ingredients.
p.000094: Drug substance means an active ingre- dient that is intended to furnish phar- macological activity or other
p.000094: direct ef- fect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the
p.000094: structure or any function of the human body, but does not in- clude intermediates use in the syn-
p.000094: thesis of such ingredient.
p.000094: Efficacy supplement means a supple- ment to an approved application pro- posing to make one or more
p.000094: related changes from among the following changes to product labeling:
p.000094: (1) Add or modify an indication or claim;
...
p.000114: may, at its discretion, review such an amendment during the initial review cycle or defer review until the
p.000114: subsequent review cycle.
p.000114: (4) Submission of a major amend- ment to a manufacturing supplement within 2 months of the end of
p.000114: the ini- tial review cycle constitutes an agree- ment by the applicant under section 505(c) of the act
p.000114: to extend the initial review cycle by 2 months. FDA may in- stead defer review of the amendment until the
p.000114: subsequent review cycle. If the agency extends the initial review cycle for a manufacturing supplement
p.000114: under this paragraph, the division re- sponsible for reviewing the supplement will notify the applicant of
p.000114: the exten- sion. The initial review cycle for a manufacturing supplement may be ex- tended only once
p.000114: due to submission of a major amendment. FDA may, at its discretion, review any subsequent
p.000114:
p.000114: major amendment during the initial review cycle (as extended) or defer re- view until the subsequent
p.000114: review cycle.
p.000114: (5) Submission of an amendment to a supplement other than an efficacy or manufacturing supplement will not ex-
p.000114: tend the initial review cycle. FDA may, at its discretion, review such an amendment during the
p.000114: initial review cycle or defer review until the subse- quent review cycle.
p.000114: (6) A major amendment may not in- clude data to support an indication or claim that was not
p.000114: included in the original application, supplement, or re- submission, but it may include data to support a
p.000114: minor modification of an in- dication or claim that was included in the original application,
p.000114: supplement, or resubmission.
p.000114: (7) When FDA defers review of an amendment until the subsequent re- view cycle, the agency will
p.000114: notify the applicant of the deferral in the com- plete response letter sent to the appli- cant under §
p.000114: 314.110 of this part.
p.000114: (c)(1) An unapproved application may not be amended if all of the following conditions apply:
p.000114: (i) The unapproved application is for a drug for which a previous application has been approved and granted a
p.000114: period of exclusivity in accordance with sec- tion 505(c)(3)(D)(ii) of the act that has not expired;
p.000114: (ii) The applicant seeks to amend the unapproved application to include a published report of an
p.000114: investigation that was conducted or sponsored by the applicant entitled to exclusivity for the drug;
p.000114: (iii) The applicant has not obtained a right of reference to the investigation described in paragraph
p.000114: (c)(1)(ii) of this section; and
p.000114: (iv) The report of the investigation described in paragraph (c)(1)(ii) of this section would be essential
p.000114: to the ap- proval of the unapproved application.
p.000114: (2) The submission of an amendment described in paragraph (c)(1) of this section will cause the
p.000114: unapproved ap- plication to be deemed to be withdrawn by the applicant under § 314.65 on the date of receipt
p.000114: by FDA of the amend- ment. The amendment will be consid- ered a resubmission of the application, which
p.000114: may not be accepted except as
p.000115: 115
p.000115:
...
p.000117: any of the following:
p.000117: (A) To add or strengthen a contra- indication, warning, precaution, or ad- verse reaction for which the
p.000117: evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c)
p.000117: of this chapter;
p.000118: 118
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118:
p.000118: Food and Drug Administration, HHS § 314.70
p.000118:
p.000118:
p.000118: (B) To add or strengthen a statement about drug abuse, dependence, psycho- logical effect, or overdosage;
p.000118: (C) To add or strengthen an instruc- tion about dosage and administration that is intended to increase
p.000118: the safe use of the drug product;
p.000118: (D) To delete false, misleading, or un- supported indications for use or claims for effectiveness; or
p.000118: (E) Any labeling change normally re- quiring a supplement submission and approval prior to distribution of
p.000118: the drug product that FDA specifically re- quests be submitted under this provi- sion.
p.000118: (7) If the agency disapproves the sup- plemental application, it may order the manufacturer to cease
p.000118: distribution of the drug product(s) made with the manufacturing change.
p.000118: (d) Changes to be described in an an- nual report (minor changes). (1) Changes in the drug substance,
p.000118: drug product, production process, quality controls, equipment, or facilities that have a minimal
p.000118: potential to have an adverse effect on the identity, strength, qual- ity, purity, or potency of the
p.000118: drug product as these factors may relate to the safety or effectiveness of the drug product must be
p.000118: documented by the ap- plicant in the next annual report in ac- cordance with § 314.81(b)(2).
p.000118: (2) These changes include, but are not
p.000118: limited to:
p.000118: (i) Any change made to comply with a change to an official compendium, except a change described in
p.000118: paragraph (c)(2)(iii) of this section, that is con- sistent with FDA statutory and regu- latory
p.000118: requirements.
p.000118: (ii) The deletion or reduction of an ingredient intended to affect only the color of the drug product;
p.000118: (iii) Replacement of equipment with that of the same design and operating principles except those
p.000118: equipment changes described in paragraph (c) of this section;
p.000118: (iv) A change in the size and/or shape of a container containing the same number of dosage units for a
p.000118: nonsterile solid dosage form drug product, with- out a change from one container clo- sure system to
p.000118: another;
p.000118: (v) A change within the container closure system for a nonsterile drug product, based upon
p.000118: a showing of
p.000118:
p.000118: equivalency to the approved system under a protocol approved in the appli- cation or published in an
p.000118: official com- pendium;
p.000118: (vi) An extension of an expiration dating period based upon full shelf life data on production
p.000118: batches obtained from a protocol approved in the appli- cation;
p.000118: (vii) The addition or revision of an al- ternative analytical procedure that provides the same or
p.000118: increased assur- ance of the identity, strength, quality, purity, or potency of the material being
p.000118: tested as the analytical proce- dure described in the approved applica- tion, or deletion of an alternative
p.000118: ana- lytical procedure;
p.000118: (viii) The addition by embossing, de- bossing, or engraving of a code imprint to a solid oral dosage form
p.000118: drug prod- uct other than a modified release dos- age form, or a minor change in an ex- isting code
p.000118: imprint;
p.000118: (ix) A change in the labeling con- cerning the description of the drug product or in the
p.000118: information about how the drug product is supplied, that does not involve a change in the dosage strength or
p.000118: dosage form; and
p.000118: (x) An editorial or similar minor change in labeling, including a change to the information
p.000118: allowed by para- graphs (b)(2)(v)(C)(1) and (2) of this sec- tion.
p.000118: (3) For changes under this category, the applicant is required to submit in the annual report:
p.000118: (i) A statement by the holder of the approved application that the effects of the change have been assessed;
p.000118: (ii) A full description of the manufac- turing and controls changes, including the manufacturing site(s) or area(s)
p.000118: in- volved;
p.000118: (iii) The date each change was imple- mented;
p.000118: (iv) Data from studies and tests per- formed to assess the effects of the change; and,
p.000118: (v) For a natural product, recom- binant DNA-derived protein/ polypeptide, complex or
p.000118: conjugate of a drug substance with a monoclonal anti- body, sterilization process or test methodology
p.000118: related to sterilization process validation, a cross-reference to relevant validation protocols and/or
p.000118: standard operating procedures.
p.000119: 119
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119:
p.000119: § 314.71
p.000119: (e) Protocols. An applicant may sub- mit one or more protocols describing the specific tests and studies
p.000119: and ac- ceptance criteria to be achieved to demonstrate the lack of adverse effect for specified
p.000119: types of manufacturing changes on the identity, strength, quality, purity, and potency of the
...
p.000143: The Food and Drug Administration will inform the Drug Enforcement Ad- ministration under section 201(f) of the
p.000143: Controlled Substances Act (21 U.S.C. 801) when an application or abbreviated application is submitted for
p.000143: a drug that appears to have an abuse poten- tial.
p.000143: [57 FR 17989, Apr. 28, 1992]
p.000143:
p.000143: § 314.105 Approval of an application and an abbreviated application.
p.000143: (a) The Food and Drug Administra- tion will approve an application and send the applicant an approval
p.000143: letter if none of the reasons in § 314.125 for re- fusing to approve the application ap- plies. An approval
p.000143: becomes effective on the date of the issuance of the approval letter, except with regard to an ap- proval
p.000143: under section 505(b)(2) of the act with a delayed effective date. An ap- proval with a delayed effective
p.000143: date is tentative and does not become final until the effective date. A new drug product or
p.000143: antibiotic approved under this paragraph may not be marketed until an approval is effective.
p.000143: (b) FDA will approve an application
p.000143: and issue the applicant an approval let- ter on the basis of draft labeling if the only deficiencies in
p.000143: the application concern editorial or similar minor defi- ciencies in the draft labeling. Such ap- proval will
p.000143: be conditioned upon the ap- plicant incorporating the specified la- beling changes exactly as directed, and upon
p.000143: the applicant submitting to FDA a copy of the final printed labeling prior to marketing.
p.000143: (c) FDA will approve an application
p.000143: after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and
p.000143: con- trols, and labeling, and an abbreviated application after it determines that the drug meets the statutory
p.000143: standards for manufacturing and controls, labeling,
p.000143: 21 CFR Ch. I (4–1–12 Edition)
p.000143: and, where applicable, bioequivalence. While the statutory standards apply to all drugs, the many kinds of drugs
p.000143: that are subject to the statutory standards and the wide range of uses for those drugs demand
p.000143: flexibility in applying the standards. Thus FDA is required to exercise its scientific judgment to de- termine
p.000143: the kind and quantity of data and information an applicant is re- quired to provide for a
p.000143: particular drug to meet the statutory standards. FDA makes its views on drug products and classes of drugs
p.000143: available through guid- ance documents, recommendations, and other statements of policy.
p.000143: (d) FDA will approve an abbreviated
p.000143: new drug application and send the ap- plicant an approval letter if none of the reasons in § 314.127 for
...
p.000148: approval.
p.000148: (b) Applicant actions. After receiving a complete response letter, the appli- cant must take one of
p.000148: following ac- tions:
p.000148: (1) Resubmission. Resubmit the appli- cation or abbreviated application, ad- dressing all deficiencies
p.000148: identified in the complete response letter.
p.000148: (i) A resubmission of an application or efficacy supplement that FDA clas- sifies as a Class 1
p.000148: resubmission con- stitutes an agreement by the applicant to start a new 2-month review cycle be- ginning on the
p.000148: date FDA receives the resubmission.
p.000148: (ii) A resubmission of an application or efficacy supplement that FDA clas- sifies as a Class 2
p.000148: resubmission con- stitutes an agreement by the applicant
p.000149: 149
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149:
p.000149: § 314.120
p.000149: to start a new 6-month review cycle be- ginning on the date FDA receives the resubmission.
p.000149: (iii) A resubmission of an NDA sup- plement other than an efficacy supple- ment constitutes an agreement
p.000149: by the applicant to start a new review cycle the same length as the initial review cycle for the
p.000149: supplement (excluding any extension due to a major amend- ment of the initial supplement), begin- ning on the
p.000149: date FDA receives the re- submission.
p.000149: (iv) A major resubmission of an ab- breviated application constitutes an agreement by the applicant to
p.000149: start a new 6-month review cycle beginning on the date FDA receives the resubmis- sion.
p.000149: (v) A minor resubmission of an abbre- viated application constitutes an agreement by the applicant to
p.000149: start a new review cycle beginning on the date FDA receives the resubmission.
p.000149: (2) Withdra al. Withdraw the applica- tion or abbreviated application. A deci- sion to withdraw an application
p.000149: or ab- breviated application is without preju- dice to a subsequent submission.
p.000149: (3) Request opportunity for hearing. Ask the agency to provide the appli- cant an opportunity for a
p.000149: hearing on the question of whether there are grounds for denying approval of the ap- plication or
p.000149: abbreviated application under section 505(d) or (j)(4) of the act, respectively. The applicant must sub-
p.000149: mit the request to the Associate Direc- tor for Policy, Center for Drug Evalua- tion and Research, Food and Drug
p.000149: Ad- ministration, 10903 New Hampshire Ave., Silver Spring, MD 20993. Within 60 days of the date of the
p.000149: request for an opportunity for a hearing, or within a different time period to which FDA and the applicant agree,
p.000149: the agency will ei- ther approve the application or abbre- viated application under § 314.105, or refuse
p.000149: to approve the application under
p.000149: § 314.125 or abbreviated application
p.000149: under § 314.127 and give the applicant written notice of an opportunity for a hearing under § 314.200
p.000149: and section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether there are grounds for denying
p.000149: approval of the application or abbreviated application under sec- tion 505(d) or (j)(4) of the act, respec-
p.000149: tively.
...
Social / gender
Searching for indicator gender:
(return to top)
p.000098: is an interim analysis, this is to be noted and a pro- jected completion date provided. Con- trolled
p.000098: clinical studies that have not been analyzed in detail for any reason (e.g., because they have been
p.000098: discon- tinued or are incomplete) are to be in- cluded in this section, including a copy of the protocol and
p.000098: a brief description of the results and status of the study.
p.000098: (iii) A description of each uncon-
p.000098: trolled clinical study, a summary of the results, and a brief statement ex- plaining why the study
p.000098: is classified as uncontrolled.
p.000098: (iv) A description and analysis of any other data or information relevant to an evaluation of the safety and
p.000098: effec- tiveness of the drug product obtained or otherwise received by the applicant from any source,
p.000098: foreign or domestic, including information derived from clinical investigations, including con- trolled
p.000098: and uncontrolled studies of uses of the drug other than those proposed in the application, commercial
p.000098: mar- keting experience, reports in the sci- entific literature, and unpublished sci- entific papers.
p.000098: (v) An integrated summary of the
p.000098: data demonstrating substantial evi- dence of effectiveness for the claimed indications. Evidence is
p.000098: also required to support the dosage and administra- tion section of the labeling, including support for
p.000098: the dosage and dose inter- val recommended. The effectiveness data shall be presented by gender,
p.000098: age, and racial subgroups and shall identify any modifications of dose or dose inter- val needed for specific
p.000098: subgroups. Ef-
p.000099: 99
p.000099:
p.000099: fectiveness data from other subgroups of the population of patients treated, when appropriate, such
p.000099: as patients with renal failure or patients with dif- ferent levels of severity of the disease, also
p.000099: shall be presented.
p.000099: (vi) A summary and updates of safety information, as follows:
p.000099: (a) The applicant shall submit an in- tegrated summary of all available in- formation about the safety
p.000099: of the drug product, including pertinent animal data, demonstrated or potential ad- verse effects of
p.000099: the drug, clinically sig- nificant drug/drug interactions, and other safety considerations, such as
p.000099: data from epidemiological studies of related drugs. The safety data shall be presented by gender,
p.000099: age, and racial subgroups. When appropriate, safety data from other subgroups of the popu- lation of
p.000099: patients treated also shall be presented, such as for patients with renal failure or patients with
p.000099: different levels of severity of the disease. A de- scription of any statistical analyses performed in
p.000099: analyzing safety data should also be included, unless already included under paragraph (d)(5)(ii) of
p.000099: this section.
p.000099: (b) The applicant shall, under section
p.000099: 505(i) of the act, update periodically its pending application with new safety in- formation learned about the drug
p.000099: that may reasonably affect the statement of contraindications, warnings, pre- cautions, and adverse
p.000099: reactions in the draft labeling and, if applicable, any Medication Guide required under part
p.000099: 208 of this chapter. These ‘‘safety up- date reports’’ are required to include the same kinds of
p.000099: information (from clinical studies, animal studies, and other sources) and are required to be submitted
p.000099: in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition,
p.000099: the reports are required to include the case report forms for each patient who died during a clinical
p.000099: study or who did not complete the study because of an adverse event (unless this requirement is waived).
p.000099: The applicant shall submit these reports (1) 4 months after the ini- tial submission; (2) in a resubmission
...
Social / orphan
Searching for indicator orphan:
(return to top)
p.000113: pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that
p.000113: the product would be ineffective or unsafe in pediatric populations, this information will be included in
p.000113: the product’s labeling.
p.000113: (5) Definition of ‘‘meaningful thera- peutic benefit’’. For purposes of this sec- tion and § 201.23 of this
p.000113: chapter, a drug will be considered to offer a meaningful
p.000113: 21 CFR Ch. I (4–1–12 Edition)
p.000113: therapeutic benefit over existing thera- pies if FDA estimates that:
p.000113: (i) If approved, the drug would rep- resent a significant improvement in the treatment, diagnosis, or
p.000113: prevention of a disease, compared to marketed products adequately labeled for that use in the
p.000113: relevant pediatric popu- lation. Examples of how improvement might be demonstrated include, for ex- ample,
p.000113: evidence of increased effective- ness in treatment, prevention, or diag- nosis of disease, elimination
p.000113: or sub- stantial reduction of a treatment-lim- iting drug reaction, documented en- hancement of
p.000113: compliance, or evidence of safety and effectiveness in a new subpopulation; or
p.000113: (ii) The drug is in a class of drugs or
p.000113: for an indication for which there is a need for additional therapeutic op- tions.
p.000113: (d) Exemption for orphan drugs. This section does not apply to any drug for an indication or indications
p.000113: for which orphan designation has been granted under part 316, subpart C, of this chap- ter.
p.000113: [63 FR 66670, Dec. 2, 1998]
p.000113:
p.000113: § 314.60 Amendments to an unap- proved application, supplement, or resubmission.
p.000113: (a) FDA generally assumes that when an original application, supplement to an approved application, or
p.000113: resubmis- sion of an application or supplement is submitted to the agency for review, the applicant believes that
p.000113: the agency can approve the application, supplement, or resubmission as submitted. How- ever, the
p.000113: applicant may submit an amendment to an application that has been filed under § 314.101 but is not
p.000113: yet approved.
p.000113: (b)(1) Submission of a major amend-
p.000113: ment to an original application, effi- cacy supplement, or resubmission of an application or efficacy
p.000113: supplement within 3 months of the end of the ini- tial review cycle constitutes an agree- ment by the
p.000113: applicant under section 505(c) of the act to extend the initial review cycle by 3 months. (For
p.000113: ref- erences to a resubmission of an appli- cation or efficacy supplement in para- graph (b) of this
p.000113: section, the timeframe for reviewing the resubmission is the ‘‘review cycle’’ rather than the ‘‘initial
p.000114: 114
p.000114:
p.000114:
p.000114:
p.000114:
p.000114:
p.000114:
p.000114:
p.000114: Food and Drug Administration, HHS § 314.60
p.000114:
p.000114:
p.000114: review cycle.’’) FDA may instead defer review of the amendment until the sub- sequent review cycle. If the
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.000101: by the manufacture, use, or sale of) (name of proposed drug product) for which this application
p.000101: is submitted.
p.000101: The certification shall be accompanied by a statement that the applicant will comply with the
p.000101: requirements under
p.000101: § 314.52(a) with respect to providing a notice to each owner of the patent or their representatives and
p.000101: to the holder of the approved application for the drug product which is claimed by the patent or a
p.000101: use of which is claimed by the patent and with the requirements under § 314.52(c) with respect to
p.000101: the content of the notice.
p.000101: (B) If the drug on which investiga- tions that are relied upon by the appli- cant were conducted is itself a
p.000101: licensed generic drug of a patented drug first approved under section 505(b) of the act, the
p.000101: appropriate patent certifi- cation under this section with respect to each patent that claims the first-ap-
p.000101: proved patented drug or that claims an approved use for such a drug.
p.000101: (ii) No relevant patents. If, in the opin- ion of the applicant and to the best of its knowledge, there are no
p.000101: patents de- scribed in paragraph (i)(1)(i) of this sec- tion, a certification in the following form:
p.000101: In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the drug
p.000101: or drugs on which investiga- tions that are relied upon in this application were conducted or that claim a
p.000101: use of such drug or drugs.
p.000101: (iii) Method of use patent. (A) If infor- mation that is submitted under section 505(b) or (c) of the act and §
p.000101: 314.53 is for
p.000102: 102
p.000102:
p.000102:
p.000102:
p.000102:
p.000102:
p.000102:
p.000102:
p.000102: Food and Drug Administration, HHS § 314.50
p.000102:
p.000102:
p.000102: a method of use patent, and the label- ing for the drug product for which the applicant is seeking
p.000102: approval does not include any indications that are cov- ered by the use patent, a statement ex- plaining that
p.000102: the method of use patent does not claim any of the proposed in- dications.
p.000102: (B) If the labeling of the drug product for which the applicant is seeking ap- proval includes an indication
p.000102: that, ac- cording to the patent information sub- mitted under section 505(b) or (c) of the act and § 314.53 or
p.000102: in the opinion of the applicant, is claimed by a use patent, the applicant shall submit an applica- ble
p.000102: certification under paragraph (i)(1)(i) of this section.
p.000102: (2) Method of manufacturing patent. An applicant is not required to make a certification with respect to
p.000102: any pat- ent that claims only a method of man- ufacturing the drug product for which the applicant is seeking
p.000102: approval.
p.000102: (3) Licensing agreements. If a 505(b)(2) application is for a drug or method of using a drug claimed by
p.000102: a patent and the applicant has a licensing agree- ment with the patent owner, the appli- cant shall
p.000102: submit a certification under paragraph (i)(1)(i)(A)(4) of this section (‘‘Paragraph IV Certification’’) as
p.000102: to that patent and a statement that it has been granted a patent license. If the patent owner consents to an
p.000102: immediate effective date upon approval of the 505(b)(2) application, the application shall contain a
p.000102: written statement from the patent owner that it has a licens- ing agreement with the applicant and that it
p.000102: consents to an immediate effec- tive date.
p.000102: (4) Late submission of patent informa-
p.000102: tion. If a patent described in paragraph (i)(1)(i)(A) of this section is issued and the holder of the
p.000102: approved application for the patented drug does not submit the required information on the patent within 30
p.000102: days of issuance of the pat- ent, an applicant who submitted a 505(b)(2) application that, before
...
p.000103: (3) If the applicant claims exclusivity under § 314.108(b)(2), information to
p.000103: 21 CFR Ch. I (4–1–12 Edition)
p.000103: show that, to the best of its knowledge or belief, a drug has not previously been approved under section
p.000103: 505(b) of the act containing any active moiety in the drug for which the applicant is seeking approval.
p.000103: (4) If the applicant claims exclusivity under § 314.108(b)(4) or (b)(5), the fol- lowing information to
p.000103: show that the application contains ‘‘new clinical in- vestigations’’ that are ‘‘essential to ap- proval of
p.000103: the application or supple- ment’’ and were ‘‘conducted or spon- sored by the applicant:’’
p.000103: (i) ‘‘Ne clinical investigations.’’ A cer- tification that to the best of the appli- cant’s knowledge each of the
p.000103: clinical investigations included in the applica- tion meets the definition of ‘‘new clin- ical
p.000103: investigation’’ set forth in
p.000103: § 314.108(a).
p.000103: (ii) ‘‘Essential to approval.’’ A list of all published studies or publicly avail- able reports of
p.000103: clinical investigations known to the applicant through a lit- erature search that are relevant to the conditions
p.000103: for which the applicant is seeking approval, a certification that the applicant has thoroughly searched
p.000103: the scientific literature and, to the best of the applicant’s knowledge, the list is complete and
p.000103: accurate and, in the applicant’s opinion, such published studies or publicly available reports do not provide a
p.000103: sufficient basis for the approval of the conditions for which the applicant is seeking approval with- out
p.000103: reference to the new clinical inves- tigation(s) in the application, and an explanation as to why the studies
p.000103: or reports are insufficient.
p.000103: (iii) ‘‘Conducted or sponsored by.’’ If
p.000103: the applicant was the sponsor named in the Form FDA–1571 for an investiga- tional new drug application
p.000103: (IND) under which the new clinical investiga- tion(s) that is essential to the approval of its application was
p.000103: conducted, iden- tification of the IND by number. If the applicant was not the sponsor of the IND under which
p.000103: the clinical investiga- tion(s) was conducted, a certification that the applicant or its predecessor in interest
p.000103: provided substantial support for the clinical investigation(s) that is essential to the approval of its
p.000103: applica- tion, and information supporting the certification. To demonstrate ‘‘sub- stantial support,’’
p.000103: an applicant must
p.000104: 104
p.000104:
p.000104:
p.000104:
p.000104:
p.000104:
p.000104:
p.000104:
p.000104: Food and Drug Administration, HHS § 314.52
p.000104:
p.000104:
p.000104: either provide a certified statement from a certified public accountant that the applicant provided 50
p.000104: percent or more of the cost of conducting the study or provide an explanation of why FDA should
p.000104: consider the applicant to have conducted or sponsored the study if the applicant’s financial contribu-
...
p.000105: (3) This paragraph does not apply to a use patent that claims no uses for which the applicant is
p.000105: seeking ap- proval.
p.000105: (b) Sending the notice. The applicant shall send the notice required by para- graph (a) of this section
p.000105: when it re- ceives from FDA an acknowledgment letter stating that its application has been filed. At the
p.000105: same time, the appli- cant shall amend its application to in- clude a statement certifying that the notice
p.000105: has been provided to each person identified under paragraph (a) of this section and that the notice met
p.000105: the content requirement under paragraph
p.000105: (c) of this section.
p.000105: (c) Content of a notice. In the notice, the applicant shall cite section 505(b)(3)(B) of the act
p.000105: and shall include, but not be limited to, the following in- formation:
p.000105: (1) A statement that a 505(b)(2) appli- cation submitted by the applicant has been filed by FDA.
p.000105: (2) The application number.
p.000105: (3) The established name, if any, as defined in section 502(e)(3) of the act, of the proposed drug product.
p.000105: 21 CFR Ch. I (4–1–12 Edition)
p.000105: (4) The active ingredient, strength, and dosage form of the proposed drug product.
p.000105: (5) The patent number and expiration date, as submitted to the agency or as known to the applicant, of each
p.000105: patent alleged to be invalid, unenforceable, or not infringed.
p.000105: (6) A detailed statement of the fac- tual and legal basis of the applicant’s opinion that the patent is
p.000105: not valid, unenforceable, or will not be infringed. The applicant shall include in the de- tailed statement:
p.000105: (i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is
p.000105: not in- fringed.
p.000105: (ii) For each claim of a patent al- leged to be invalid or unenforceable, a full and detailed
p.000105: explanation of the grounds supporting the allegation.
p.000105: (7) If the applicant does not reside or have a place of business in the United States, the name and
p.000105: address of an agent in the United States authorized to accept service of process for the ap- plicant.
p.000105: (d) Amendment to an application. If an application is amended to include the certification described in §
p.000105: 314.50(i), the applicant shall send the notice required by paragraph (a) of this section at the same time that
p.000105: the amendment to the application is submitted to FDA.
p.000105: (e) Documentation of receipt of notice. The applicant shall amend its applica- tion to document receipt
p.000105: of the notice required under paragraph (a) of this section by each person provided the no- tice. The
p.000105: applicant shall include a copy of the return receipt or other similar evidence of the date the notification
p.000105: was received. FDA will accept as ade- quate documentation of the date of re- ceipt a return receipt or
p.000105: a letter ac- knowledging receipt by the person pro- vided the notice. An applicant may rely on another form
p.000105: of documentation only if FDA has agreed to such docu- mentation in advance. A copy of the notice itself
p.000105: need not be submitted to the agency.
...
p.000128: (a) What is the discontinuance notifica- tion period? The discontinuance notifi- cation period is the
p.000128: 6-month period re- quired under § 314.81(b)(3)(iii)(a). The discontinuance notification period be- gins
p.000128: when an applicant who is the sole manufacturer of certain products noti- fies FDA that it will discontinue
p.000128: manu- facturing the product. The discontinu- ance notification period ends when manufacturing ceases.
p.000128: (b) When can FDA reduce the dis-
p.000128: continuance notification period? FDA can reduce the 6-month discontinuance no- tification period when it
p.000128: finds good cause exists for the reduction. FDA may find good cause exists based on in- formation certified
p.000128: by an applicant in a request for a reduction of the dis- continuance notification period. In
p.000128: limited circumstances, FDA may find good cause exists based on information already known to the agency.
p.000128: These circumstances can include the with- drawal of the drug from the market based upon formal FDA
p.000128: regulatory ac- tion (e.g., under the procedures de- scribed in § 314.150 for the publication of a
p.000128: notice of opportunity for a hearing describing the basis for the proposed withdrawal of a drug from the market) or
p.000128: resulting from the applicant’s con- sultations with the agency.
p.000128: (c) Ho can an applicant request a re- duction in the discontinuance notification period? (1) The applicant
p.000128: must certify in a written request that, in its opinion and to the best of its knowledge, good cause exists
p.000128: for the reduction. The ap- plicant must submit the following cer- tification:
p.000128: The undersigned certifies that good cause exists for a reduction in the 6-month notifi- cation period
p.000128: required in § 314.81(b)(3)(iii)(a) for discontinuing the manufacture of (name of the drug product).
p.000128: The following cir- cumstances establish good cause (one or more of the circumstances in paragraph (d) of
p.000128: this section).
p.000128: (2) The certification must be signed by the applicant or the applicant’s at- torney, agent (representative),
p.000128: or other
p.000128:
p.000128: authorized official. If the person sign- ing the certification does not reside or have a place of
p.000128: business within the United States, the certification must contain the name and address of, and must also
p.000128: be signed by, an attorney, agent, or other authorized official who resides or maintains a place of business
p.000128: within the United States.
p.000128: (3) For drugs regulated by the Center for Drug Evaluation and Research (CDER) or the Center for
p.000128: Biologics Evaluation and Research (CBER), one copy of the certification must be sub- mitted to the Drug
p.000128: Shortage Coordi- nator at the address of the Director of CDER, one copy to the CDER Drug
p.000128: Registration and Listing Team, Divi- sion of Compliance Risk Management and Surveillance in CDER, and
...
p.000133: use, solutions for
p.000134: 134
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134:
p.000134: Food and Drug Administration, HHS § 314.94
p.000134:
p.000134:
p.000134: aerosolization or nebulization, and nasal solutions shall contain the same inactive ingredients as
p.000134: the reference listed drug identified by the applicant under paragraph (a)(3) of this section. However, an
p.000134: abbreviated application may include different inactive ingredi- ents provided that the applicant identi- fies
p.000134: and characterizes the differences and provides information dem- onstrating that the differences
p.000134: do not affect the safety or efficacy of the pro- posed drug product.
p.000134: (10) Samples. The information re- quired under § 314.50(e)(1) and (e)(2)(i). Samples need not be
p.000134: submitted until requested by FDA.
p.000134: (11) Other. The information required under § 314.50(g).
p.000134: (12) Patent certification—(i) Patents claiming drug, drug product, or method of use. (A) Except as
p.000134: provided in para- graph (a)(12)(iv) of this section, a cer- tification with respect to each patent
p.000134: issued by the United States Patent and Trademark Office that, in the opinion of the applicant and to the
p.000134: best of its knowledge, claims the reference listed drug or that claims a use of such listed drug for which the
p.000134: applicant is seeking approval under section 505(j) of the act and for which information is required to be filed
p.000134: under section 505(b) and (c) of the act and § 314.53. For each such patent, the applicant shall provide
p.000134: the patent number and certify, in its opin- ion and to the best of its knowledge, one of the following
p.000134: circumstances:
p.000134: (1) That the patent information has not been submitted to FDA. The appli- cant shall entitle such a
p.000134: certification ‘‘Paragraph I Certification’’;
p.000134: (2) That the patent has expired. The applicant shall entitle such a certifi- cation ‘‘Paragraph II
p.000134: Certification’’;
p.000134: (3) The date on which the patent will expire. The applicant shall entitle such a certification ‘‘Paragraph III
p.000134: Certifi- cation’’; or
p.000134: (4) That the patent is invalid, unen- forceable, or will not be infringed by the manufacture, use, or
p.000134: sale of the drug product for which the abbreviated application is submitted. The applicant shall entitle
p.000134: such a certification ‘‘Paragraph IV Certification’’. This cer- tification shall be submitted in the fol- lowing
p.000134: form:
p.000134:
p.000134: I, (name of applicant), certify that Patent No. llllll (is invalid, unenforceable, or ill not be infringed
p.000134: by the manufacture, use, or sale of) (name of proposed drug product) for
p.000134: which this application is submitted.
p.000134: The certification shall be accompanied by a statement that the applicant will comply with the
p.000134: requirements under
p.000134: § 314.95(a) with respect to providing a notice to each owner of the patent or their representatives and
p.000134: to the holder of the approved application for the list- ed drug, and with the requirements under §
p.000134: 314.95(c) with respect to the content of the notice.
p.000134: (B) If the abbreviated new drug appli- cation refers to a listed drug that is itself a licensed generic
p.000134: product of a patented drug first approved under sec- tion 505(b) of the act, the appropriate patent
p.000134: certification under paragraph (a)(12)(i) of this section with respect to each patent that claims the first-ap-
p.000134: proved patented drug or that claims a use for such drug.
p.000134: (ii) No relevant patents. If, in the opin-
p.000134: ion of the applicant and to the best of its knowledge, there are no patents de- scribed in paragraph
p.000134: (a)(12)(i) of this section, a certification in the following form:
p.000134: In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the listed drug
p.000134: referred to in this ap- plication or that claim a use of the listed drug.
p.000134: (iii) Method of use patent. (A) If pat- ent information is submitted under section 505(b) or (c)
p.000134: of the act and
p.000134: § 314.53 for a patent claiming a method of using the listed drug, and the label- ing for the drug
p.000134: product for which the applicant is seeking approval does not include any indications that are cov- ered by
p.000134: the use patent, a statement ex- plaining that the method of use patent does not claim any of the proposed in-
p.000134: dications.
p.000134: (B) If the labeling of the drug product for which the applicant is seeking ap- proval includes an indication
p.000134: that, ac- cording to the patent information sub- mitted under section 505(b) or (c) of the act and § 314.53 or
p.000134: in the opinion of the applicant, is claimed by a use patent, an applicable certification under para-
p.000134: graph (a)(12)(i) of this section.
p.000134: (iv) Method of manufacturing patent.
p.000134: An applicant is not required to make a
p.000135: 135
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135:
p.000135: § 314.94
p.000135: certification with respect to any pat- ent that claims only a method of man- ufacturing the listed drug.
p.000135: (v) Licensing agreements. If the abbre- viated new drug application is for a drug or method of using a
p.000135: drug claimed by a patent and the applicant has a li- censing agreement with the patent owner, a
p.000135: certification under paragraph (a)(12)(i)(A)(4) of this section (‘‘Para- graph IV Certification’’) as to that pat-
p.000135: ent and a statement that it has been granted a patent license.
p.000135: (vi) Late submission of patent informa- tion. If a patent on the listed drug is issued and the holder
p.000135: of the approved application for the listed drug does not submit the required information on the patent within 30 days
p.000135: of issuance of the patent, an applicant who submitted an abbreviated new drug application for that drug
p.000135: that contained an appro- priate patent certification before the submission of the patent information is not
...
p.000137: is sufficiently com- plete to permit a substantive review. At the same time, the applicant shall amend
p.000137: its abbreviated new drug appli- cation to include a statement certi- fying that the notice has been
p.000137: provided to each person identified under para- graph (a) of this section and that the notice met the
p.000137: content requirements under paragraph (c) of this section.
p.000137: (c) Contents of a notice. In the notice,
p.000137: the applicant shall cite section 505(j)(2)(B)(ii) of the act and shall in- clude, but not be
p.000137: limited to, the fol- lowing information:
p.000137: (1) A statement that FDA has re- ceived an abbreviated new drug appli- cation submitted by the
p.000137: applicant con- taining any required bioavailability or bioequivalence data or information.
p.000137: (2) The abbreviated application num- ber.
p.000137: (3) The established name, if any, as defined in section 502(e)(3) of the act, of the proposed drug product.
p.000137: (4) The active ingredient, strength, and dosage form of the proposed drug product.
p.000137: (5) The patent number and expiration date, as submitted to the agency or as known to the applicant, of each
p.000137: patent alleged to be invalid, unenforceable, or not infringed.
p.000137: (6) A detailed statement of the fac- tual and legal basis of the applicant’s opinion that the patent is
p.000137: not valid, unenforceable, or will not be infringed. The applicant shall include in the de- tailed statement:
p.000137: (i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is
p.000137: not in- fringed.
p.000137: (ii) For each claim of a patent al- leged to be invalid or unenforceable, a full and detailed
p.000137: explanation of the grounds supporting the allegation.
p.000138: 138
p.000138:
p.000138:
p.000138:
p.000138:
p.000138:
p.000138:
p.000138:
p.000138: Food and Drug Administration, HHS § 314.98
p.000138:
p.000138:
p.000138: (7) If the applicant does not reside or have a place of business in the United States, the name and
p.000138: address of an agent in the United States authorized to accept service of process for the ap- plicant.
p.000138: (d) Amendment to an abbreviated appli- cation. If an abbreviated application is amended to include the
p.000138: certification described in § 314.94(a)(12)(i)(A)(4), the applicant shall send the notice required by paragraph
p.000138: (a) of this section at the same time that the amendment to the abbreviated application is submitted to FDA.
p.000138: (e) Documentation of receipt of notice.
p.000138: The applicant shall amend its abbre- viated application to document receipt of the notice required under
p.000138: paragraph
p.000138: (a) of this section by each person pro- vided the notice. The applicant shall include a copy of the
p.000138: return receipt or other similar evidence of the date the notification was received. FDA will ac- cept as
...
p.000162: with which there is a lack of compliance, or pro- viding a detailed description and anal- ysis of the
p.000162: specific facts resulting in the notice).
p.000162: (2) FDA will publish the notice in the FEDERAL REGISTER and will state that the applicant, and other persons
p.000162: sub- ject to the notice under § 310.6, who wishes to participate in a hearing, has 30 days after
p.000162: the date of publication of the notice to file a written notice of participation and request for hearing.
p.000162: The applicant, or other persons subject to the notice under § 310.6, who fails to file a written notice of
p.000162: participation and request for hearing within 30 days, waives the opportunity for a hearing.
p.000162: (3) It is the responsibility of every manufacturer and distributor of a drug product to review every notice
p.000162: of op- portunity for a hearing published in the FEDERAL REGISTER to determine whether it covers
p.000162: any drug product that person manufactures or distrib- utes. Any person may request an opin- ion of
p.000162: the applicability of a notice to a specific product that may be identical, related, or similar to a product
p.000162: listed in a notice by writing to the Division of New Drugs and Labeling Compli- ance, Office of
p.000162: Compliance, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New
p.000162: Hampshire Ave., Silver Spring, MD 20993–0002. A person shall request an opinion within 30 days of
p.000162: the date of publication of the notice to be eligible for an opportunity for a hearing under the notice.
p.000162: If a person requests an opin- ion, that person’s time for filing an ap- pearance and request for a hearing and
p.000162: supporting studies and analyses begins on the date the person receives the opinion from FDA.
p.000162: (b) FDA will provide the notice of op- portunity for a hearing to applicants and to other persons subject to the
p.000162: no- tice under § 310.6, as follows:
p.000162: (1) To any person who has submitted an application or abbreviated applica- tion, by delivering the notice in
p.000162: person or by sending it by registered or cer- tified mail to the last address shown in the application or
p.000162: abbreviated applica- tion.
p.000162:
p.000162: (2) To any person who has not sub- mitted an application or abbreviated application but who is
p.000162: subject to the notice under § 310.6 of this chapter, by publication of the notice in the FED- ERAL
p.000162: REGISTER.
p.000162: (c)(1) Notice of participation and re-
p.000162: quest for a hearing, and submission of studies and comments. The applicant, or any other person
p.000162: subject to the notice under § 310.6, who wishes to participate in a hearing, shall file with the Divi-
p.000162: sion of Dockets Management (HFA– 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
p.000162: Rockville, MD 20852, (i) within 30 days after the date of the publication of the notice (or of the date of
p.000162: receipt of an opinion re- quested under paragraph (a)(3) of this section) a written notice of participa-
p.000162: tion and request for a hearing and (ii) within 60 days after the date of publi- cation of the notice,
p.000162: unless a different period of time is specified in the notice of opportunity for a hearing, the stud- ies on
p.000162: which the person relies to justify a hearing as specified in paragraph (d) of this section. The applicant,
p.000162: or other person, may incorporate by reference the raw data underlying a study if the data were previously
p.000162: submitted to FDA as part of an application, abbreviated application, or other report.
p.000162: (2) FDA will not consider data or
p.000162: analyses submitted after 60 days in de- termining whether a hearing is war- ranted unless they
p.000162: are derived from well-controlled studies begun before the date of the notice of opportunity for hearing
p.000162: and the results of the stud- ies were not available within 60 days after the date of publication of the
p.000162: no- tice. Nevertheless, FDA may consider other studies on the basis of a showing by the person requesting a
p.000162: hearing of inadvertent omission and hardship. The person requesting a hearing shall list in the request
p.000162: for hearing all stud- ies in progress, the results of which the person intends later to submit in sup- port of
p.000162: the request for a hearing. The person shall submit under paragraph (c)(1)(ii) of this section a copy
p.000162: of the complete protocol, a list of the partici- pating investigators, and a brief status report of the studies.
p.000162: (3) Any other interested person who
p.000162: is not subject to the notice of oppor- tunity for a hearing may also submit
p.000163: 163
...
General/Other / Incapacitated
Searching for indicator incapacity:
(return to top)
p.000120: accidental or intentional; an adverse event occurring from drug abuse; an adverse event
p.000120: occurring from drug withdrawal; and any failure of expected pharmacological action.
p.000120: Disability. A substantial disruption of
p.000120: a person’s ability to conduct normal life functions.
p.000120: Life-threatening adverse drug experi- ence. Any adverse drug experience that places the patient, in the
p.000120: view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred,
p.000120: i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have
p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
p.000120: includes events that may be symptomatically and pathophysiologically related to an event listed
p.000120: in the labeling, but differ from the event because of greater se-
p.000120:
p.000120: verity or specificity. For example, under this definition, hepatic necrosis would be unexpected
...
General/Other / Natural Hazards
Searching for indicator hazard:
(return to top)
p.000159: abbreviated new drug application for such drug is not withdrawn.
p.000159: [57 FR 17994, Apr. 28, 1992]
p.000159:
p.000159: § 314.152 Notice of withdrawal of ap- proval of an application or abbre- viated application for a new drug.
p.000159: If the Food and Drug Administration withdraws approval of an application or abbreviated application for a
p.000159: new drug, FDA will publish a notice in the FEDERAL REGISTER announcing the withdrawal of approval.
p.000159: If the applica- tion or abbreviated application was withdrawn for grounds described in
p.000159: § 314.150(a) or § 314.151, the notice will announce the removal of the drug from the list of approved
p.000159: drugs published under section 505(j)(6) of the act and shall satisfy the requirement of
p.000159: § 314.162(b).
p.000159: [57 FR 17994, Apr. 28, 1992]
p.000159: 21 CFR Ch. I (4–1–12 Edition)
p.000159:
p.000159: § 314.153 Suspension of approval of an abbreviated new drug application.
p.000159: (a) Suspension of approval. The ap- proval of an abbreviated new drug ap- plication approved
p.000159: under § 314.105(d) shall be suspended for the period stated when:
p.000159: (1) The Secretary of the Department of Health and Human Services, under the imminent hazard authority of
p.000159: sec- tion 505(e) of the act or the authority of this paragraph, suspends approval of a listed drug referred
p.000159: to in the abbre- viated new drug application, for the pe- riod of the suspension;
p.000159: (2) The agency, in the notice de- scribed in paragraph (b) of this section, or in any subsequent
p.000159: written notice given an abbreviated new drug applica- tion holder by the agency, concludes that the risk of
p.000159: continued marketing and use of the drug is inappropriate, pending completion of proceedings to withdraw or
p.000159: suspend approval under
p.000159: § 314.151 or paragraph (b) of this sec- tion; or
p.000159: (3) The agency, under the procedures set forth in paragraph (b) of this sec- tion, issues a final decision
p.000159: stating the determination that the abbreviated ap- plication is suspended because the list- ed drug on which the
p.000159: approval of the abbreviated new drug application de- pends has been withdrawn from sale for reasons of safety or
p.000159: effectiveness or has been suspended under paragraph (b) of this section. The suspension will take effect on
p.000159: the date stated in the decision and will remain in effect until the agency determines that the
...
p.000161: de- termination that the drug is not with- drawn for safety or effectiveness rea- sons may be made at any
p.000161: time after its removal from the list, upon the agen- cy’s initiative, or upon the submission of a petition
p.000161: under §§ 10.25(a) and 10.30 of this chapter. If the agency deter- mines that the drug is not
p.000161: withdrawn for safety or effectiveness reasons, the agency shall publish a notice of this de- termination in the
p.000161: FEDERAL REGISTER. The notice will also announce that the drug is relisted, under § 314.162(c). The notice
p.000161: will also serve to reinstate ap- proval of all suspended abbreviated new drug applications that referred to
p.000161: the listed drug.
p.000161: [57 FR 17995, Apr. 28, 1992]
p.000161:
p.000161: § 314.162 Removal of a drug product from the list.
p.000161: (a) FDA will remove a previously ap- proved new drug product from the list for the period stated when:
p.000161: (1) The agency withdraws or suspends approval of a new drug application or an abbreviated new drug
p.000161: application under § 314.150(a) or § 314.151 or under the imminent hazard authority of sec- tion 505(e) of
p.000161: the act, for the same pe- riod as the withdrawal or suspension of the application; or
p.000161: (2) The agency, in accordance with the procedures in § 314.153(b) or § 314.161, issues a final decision
p.000161: stating that the listed drug was withdrawn from sale for safety or effectiveness reasons, or suspended
p.000161: under § 314.153(b), until the agency determines that the withdrawal from the market has ceased or is not for
p.000161: safety or effectiveness reasons.
p.000161: 21 CFR Ch. I (4–1–12 Edition)
p.000161: (b) FDA will publish in the FEDERAL REGISTER a notice announcing the re- moval of a drug from the list.
p.000161: (c) At the end of the period specified in paragraph (a)(1) or (a)(2) of this sec- tion, FDA will
p.000161: relist a drug that has been removed from the list. The agency will publish in the FEDERAL REGISTER a notice
p.000161: announcing the relisting of the drug.
p.000161: [57 FR 17996, Apr. 28, 1992]
p.000161:
p.000161: § 314.170 Adulteration and mis- branding of an approved drug.
p.000161: All drugs, including those the Food and Drug Administration approves under section 505 of the act
p.000161: and this part, are subject to the adulteration and misbranding provisions in sections 501, 502, and 503
p.000161: of the act. FDA is au- thorized to regulate approved new drugs by regulations issued through in-
...
General/Other / Public Emergency
Searching for indicator emergency:
(return to top)
p.000120: view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred,
p.000120: i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have
p.000120: caused death.
p.000120: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any
p.000120: of the fol- lowing outcomes: Death, a life-threat- ening adverse drug experience, inpa- tient
p.000120: hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or
p.000120: a congenital anomaly/birth defect. Im- portant medical events that may not result in death, be
p.000120: life-threatening, or require hospitalization may be consid- ered a serious adverse drug experience when,
p.000120: based upon appropriate medical judgment, they may jeopardize the pa- tient or subject and may require
p.000120: med- ical or surgical intervention to prevent one of the outcomes listed in this defi- nition. Examples of
p.000120: such medical events include allergic bronchospasm requiring intensive treatment in an emergency
p.000120: room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or
p.000120: the development of drug dependency or drug abuse.
p.000120: Unexpected adverse drug experience.
p.000120: Any adverse drug experience that is not listed in the current labeling for the drug product. This
p.000120: includes events that may be symptomatically and pathophysiologically related to an event listed
p.000120: in the labeling, but differ from the event because of greater se-
p.000120:
p.000120: verity or specificity. For example, under this definition, hepatic necrosis would be unexpected
p.000120: (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis.
p.000120: Similarly, cerebral thrombo- embolism and cerebral vasculitis would be unexpected (by virtue of greater
p.000120: specificity) if the labeling only listed cerebral vascular accidents. ‘‘Unex- pected,’’ as used in this
p.000120: definition, re- fers to an adverse drug experience that has not been previously observed (i.e., included in the
p.000120: labeling) rather than from the perspective of such experience not being anticipated from the pharma- cological
p.000120: properties of the pharma- ceutical product.
...
General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.000092:
p.000092: Subpart F [Reserved]
p.000092: Subpart G—Miscellaneous Provisions
p.000092: 314.410 Imports and exports of new drugs.
p.000092: 314.420 Drug master files.
p.000092: 314.430 Availability for public disclosure of data and information in an application or abbreviated
p.000092: application.
p.000092: 314.440 Addresses for applications and ab- breviated applications.
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092:
p.000092: Food and Drug Administration, HHS § 314.3
p.000092:
p.000092:
p.000092: 314.445 Guidance documents.
p.000092:
p.000092: Subpart H—Accelerated Approval of New Drugs for Serious or Life-Threatening Ill- nesses
p.000092: 314.500 Scope.
p.000092: 314.510 Approval based on a surrogate end- point or on an effect on a clinical end- point other than
p.000092: survival or irreversible morbidity.
p.000092: 314.520 Approval with restrictions to assure safe use.
p.000092: 314.530 Withdrawal procedures.
p.000092: 314.540 Postmarketing safety reporting.
p.000092: 314.550 Promotional materials.
p.000092: 314.560 Termination of requirements.
p.000092:
p.000092: Subpart I—Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible
p.000092: 314.600 Scope.
p.000092: 314.610 Approval based on evidence of effec- tiveness from studies in animals.
p.000092: 314.620 Withdrawal procedures.
p.000092: 314.630 Postmarketing safety reporting. 314.640 Promotional materials.
p.000092: 314.650 Termination of requirements.
p.000092: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000092: 355, 356, 356a, 356b, 356c, 371, 374, 379e.
p.000092: SOURCE: 50 FR 7493, Feb. 22, 1985, unless
p.000092: otherwise noted.
p.000092: EDITORIAL NOTE: Nomenclature changes to part 314 can be found at 69 FR 13717, Mar. 24,
p.000092: 2004.
p.000092:
p.000092: Subpart A—General Provisions
p.000092: § 314.1 Scope of this part.
p.000092: (a) This part sets forth procedures and requirements for the submission to, and the review by,
p.000092: the Food and Drug Administration of applications and abbreviated applications to market a new drug under
p.000092: section 505 of the Federal Food, Drug, and Cosmetic Act, as well as amendments, supplements, and
p.000092: postmarketing reports to them.
p.000092: (b) This part does not apply to drug products subject to licensing by FDA under the Public Health Service
p.000092: Act (58 Stat. 632 as amended (42 U.S.C. 201 et seq.)) and subchapter F of chapter I of title 21 of the
p.000092: Code of Federal Regula- tions.
p.000092: (c) References in this part to regula- tions in the Code of Federal Regula-
p.000092:
p.000093: 93
p.000093:
p.000093: tions are to chapter I of title 21, unless otherwise noted.
p.000093: [50 FR 7493, Feb. 22, 1985, as amended at 57
p.000093: FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999]
p.000093: § 314.2 Purpose.
p.000093: The purpose of this part is to estab- lish an efficient and thorough drug re- view process in order
...
p.000159: [57 FR 17994, Apr. 28, 1992]
p.000159:
p.000159: § 314.152 Notice of withdrawal of ap- proval of an application or abbre- viated application for a new drug.
p.000159: If the Food and Drug Administration withdraws approval of an application or abbreviated application for a
p.000159: new drug, FDA will publish a notice in the FEDERAL REGISTER announcing the withdrawal of approval.
p.000159: If the applica- tion or abbreviated application was withdrawn for grounds described in
p.000159: § 314.150(a) or § 314.151, the notice will announce the removal of the drug from the list of approved
p.000159: drugs published under section 505(j)(6) of the act and shall satisfy the requirement of
p.000159: § 314.162(b).
p.000159: [57 FR 17994, Apr. 28, 1992]
p.000159: 21 CFR Ch. I (4–1–12 Edition)
p.000159:
p.000159: § 314.153 Suspension of approval of an abbreviated new drug application.
p.000159: (a) Suspension of approval. The ap- proval of an abbreviated new drug ap- plication approved
p.000159: under § 314.105(d) shall be suspended for the period stated when:
p.000159: (1) The Secretary of the Department of Health and Human Services, under the imminent hazard authority of
p.000159: sec- tion 505(e) of the act or the authority of this paragraph, suspends approval of a listed drug referred
p.000159: to in the abbre- viated new drug application, for the pe- riod of the suspension;
p.000159: (2) The agency, in the notice de- scribed in paragraph (b) of this section, or in any subsequent
p.000159: written notice given an abbreviated new drug applica- tion holder by the agency, concludes that the risk of
p.000159: continued marketing and use of the drug is inappropriate, pending completion of proceedings to withdraw or
p.000159: suspend approval under
p.000159: § 314.151 or paragraph (b) of this sec- tion; or
p.000159: (3) The agency, under the procedures set forth in paragraph (b) of this sec- tion, issues a final decision
p.000159: stating the determination that the abbreviated ap- plication is suspended because the list- ed drug on which the
p.000159: approval of the abbreviated new drug application de- pends has been withdrawn from sale for reasons of safety or
p.000159: effectiveness or has been suspended under paragraph (b) of this section. The suspension will take effect on
p.000159: the date stated in the decision and will remain in effect until the agency determines that the
p.000159: marketing of the drug has resumed or that the withdrawal is not for safety or effec- tiveness reasons.
p.000159: (b) Procedures for suspension of abbre-
...
p.000161: de- termination that the drug is not with- drawn for safety or effectiveness rea- sons may be made at any
p.000161: time after its removal from the list, upon the agen- cy’s initiative, or upon the submission of a petition
p.000161: under §§ 10.25(a) and 10.30 of this chapter. If the agency deter- mines that the drug is not
p.000161: withdrawn for safety or effectiveness reasons, the agency shall publish a notice of this de- termination in the
p.000161: FEDERAL REGISTER. The notice will also announce that the drug is relisted, under § 314.162(c). The notice
p.000161: will also serve to reinstate ap- proval of all suspended abbreviated new drug applications that referred to
p.000161: the listed drug.
p.000161: [57 FR 17995, Apr. 28, 1992]
p.000161:
p.000161: § 314.162 Removal of a drug product from the list.
p.000161: (a) FDA will remove a previously ap- proved new drug product from the list for the period stated when:
p.000161: (1) The agency withdraws or suspends approval of a new drug application or an abbreviated new drug
p.000161: application under § 314.150(a) or § 314.151 or under the imminent hazard authority of sec- tion 505(e) of
p.000161: the act, for the same pe- riod as the withdrawal or suspension of the application; or
p.000161: (2) The agency, in accordance with the procedures in § 314.153(b) or § 314.161, issues a final decision
p.000161: stating that the listed drug was withdrawn from sale for safety or effectiveness reasons, or suspended
p.000161: under § 314.153(b), until the agency determines that the withdrawal from the market has ceased or is not for
p.000161: safety or effectiveness reasons.
p.000161: 21 CFR Ch. I (4–1–12 Edition)
p.000161: (b) FDA will publish in the FEDERAL REGISTER a notice announcing the re- moval of a drug from the list.
p.000161: (c) At the end of the period specified in paragraph (a)(1) or (a)(2) of this sec- tion, FDA will
p.000161: relist a drug that has been removed from the list. The agency will publish in the FEDERAL REGISTER a notice
p.000161: announcing the relisting of the drug.
p.000161: [57 FR 17996, Apr. 28, 1992]
p.000161:
p.000161: § 314.170 Adulteration and mis- branding of an approved drug.
p.000161: All drugs, including those the Food and Drug Administration approves under section 505 of the act
p.000161: and this part, are subject to the adulteration and misbranding provisions in sections 501, 502, and 503
p.000161: of the act. FDA is au- thorized to regulate approved new drugs by regulations issued through in-
p.000161: formal rulemaking under sections 501, 502, and 503 of the act.
...
p.000175: §§ 314.610(b)(2), 314.620, and 314.630 are no longer nec- essary for the safe and effective use of a drug
p.000175: product, FDA will so notify the applicant. Ordinarily, for drug products approved under § 314.610, these
p.000175: require- ments will no longer apply when FDA determines that the postmarketing study verifies and
p.000175: describes the drug product’s clinical benefit. For drug products approved under § 314.610, the
p.000175: restrictions would no longer apply when FDA determines that safe use of the drug product can
p.000175: be ensured through appropriate labeling. FDA also
p.000176: 176
p.000176:
p.000176:
p.000176:
p.000176:
p.000176:
p.000176:
p.000176:
p.000176: Food and Drug Administration, HHS § 315.5
p.000176:
p.000176:
p.000176: retains the discretion to remove spe- cific postapproval requirements upon review of a petition
p.000176: submitted by the sponsor in accordance with § 10.30 of this chapter.
p.000176:
p.000176: PART 315—DIAGNOSTIC RADIOPHARMACEUTICALS
p.000176: Sec.
p.000176: 315.1 Scope.
p.000176: 315.2 Definition.
p.000176: 315.3 General factors relevant to safety and effectiveness.
p.000176: 315.4 Indications.
p.000176: 315.5 Evaluation of effectiveness.
p.000176: 315.6 Evaluation of safety.
p.000176: AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353,
p.000176: 355, 371, 374, 379e; sec. 122, Pub. L. 105–115, 111
p.000176: Stat. 2322 (21 U.S.C. 355 note).
p.000176: SOURCE: 64 FR 26667, May 17, 1999, unless
p.000176: otherwise noted.
p.000176: § 315.1 Scope.
p.000176: The regulations in this part apply to radiopharmaceuticals intended for in vivo administration for
p.000176: diagnostic and monitoring use. They do not apply to radiopharmaceuticals intended for therapeutic
p.000176: purposes. In situations where a particular radiopharma- ceutical is proposed for both diagnostic
p.000176: and therapeutic uses, the radiopharma- ceutical must be evaluated taking into account each intended use.
p.000176: § 315.2 Definition.
p.000176: For purposes of this part, diagnostic radiopharmaceutical means:
p.000176: (a) An article that is intended for use in the diagnosis or monitoring of a dis- ease or a manifestation of a
p.000176: disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of
p.000176: nuclear particles or photons; or
p.000176: (b) Any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such
p.000176: arti- cle as defined in paragraph (a) of this section.
p.000176: § 315.3 General factors relevant to safety and effectiveness.
p.000176: FDA’s determination of the safety and effectiveness of a diagnostic radio- pharmaceutical includes
p.000176: consideration of the following:
p.000176:
p.000176: (a) The proposed use of the diagnostic radiopharmaceutical in the practice of medicine,
p.000176: (b) The pharmacological and toxi- cological activity of the diagnostic radiopharmaceutical
p.000176: (including any carrier or ligand component of the di- agnostic radiopharmaceutical), and
...
General/Other / participants in a control group
Searching for indicator placebo:
(return to top)
p.000100: the data from the earliest clinical pharmacology studies (Phase 1 studies as described in
p.000100: § 312.21(a) of this chapter), and tabula- tions of the safety data from other clinical studies.
p.000100: Routine submission of other patient data from uncontrolled studies is not required. The tabulations are
p.000100: required to include the data on each patient in each study, except that the applicant may delete those
p.000100: tabula- tions which the agency agrees, in ad- vance, are not pertinent to a review of the drug’s safety or
p.000100: effectiveness. Upon request, FDA will discuss with the ap- plicant in a ‘‘pre-NDA’’ conference those
p.000100: tabulations that may be appro- priate for such deletion. Barring un- foreseen circumstances,
p.000100: tabulations agreed to be deleted at such a con- ference will not be requested during the
p.000100: conduct of FDA’s review of the ap- plication. If such unforeseen cir- cumstances do occur, any
p.000100: request for deleted tabulations will be made by the director of the FDA division respon-
p.000100:
p.000100: sible for reviewing the application, in accordance with paragraph (f)(3) of this section.
p.000100: (2) Case report forms. The application is required to contain copies of indi- vidual case report forms
p.000100: for each pa- tient who died during a clinical study or who did not complete the study be- cause of an
p.000100: adverse event, whether be- lieved to be drug related or not, includ- ing patients receiving reference drugs or
p.000100: placebo. This requirement may be waived by FDA for specific studies if the case report forms are
p.000100: unnecessary for a proper review of the study.
p.000100: (3) Additional data. The applicant shall submit to FDA additional case re- port forms and tabulations
p.000100: needed to conduct a proper review of the applica- tion, as requested by the director of the FDA division
p.000100: responsible for re- viewing the application. The appli- cant’s failure to submit information re- quested by
p.000100: FDA within 30 days after re- ceipt of the request may result in the agency viewing any eventual submis- sion
p.000100: as a major amendment under
p.000100: § 314.60 and extending the review period as necessary. If desired by the appli- cant, the FDA division
p.000100: director will verify in writing any request for addi- tional data that was made orally.
p.000100: (4) Applicants are invited to meet with FDA before submitting an appli- cation to discuss the
p.000100: presentation and format of supporting information. If the applicant and FDA agree, the appli- cant may submit
p.000100: tabulations of patient data and case report forms in a form other than hard copy, for example, on
p.000100: microfiche or computer tapes.
p.000100: (g) Other. The following general re- quirements apply to the submission of information within the summary
p.000100: under paragraph (c) of this section and within the technical sections under paragraph
p.000100: (d) of this section.
p.000100: (1) The applicant ordinarily is not re- quired to resubmit information pre- viously submitted, but may
p.000100: incor- porate the information by reference. A reference to information submitted previously is
...
p.000151: permit an inspection of facilities or records relevant to the
p.000151: 21 CFR Ch. I (4–1–12 Edition)
p.000151: study by a properly authorized officer or employee of the Department of Health and Human Services or
p.000151: refuses to submit reserve samples of the drug products used in the study when re- quested by FDA.
p.000151: (18) For a new drug, the application failed to contain the patent informa- tion required by section
p.000151: 505(b)(1) of the act.
p.000151: (c) For drugs intended to treat life- threatening or severely-debilitating ill- nesses that are developed in
p.000151: accordance with §§ 312.80 through 312.88 of this chapter, the criteria contained in para- graphs (b) (3),
p.000151: (4), and (5) of this section shall be applied according to the con- siderations contained in § 312.84 of
p.000151: this chapter.
p.000151: [50 FR 7493, Feb. 22, 1985, as amended at 53
p.000151: FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28,
p.000151: 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan.
p.000151: 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766,
p.000151: Mar. 6, 2009]
p.000151:
p.000151: § 314.126 Adequate and well-controlled studies.
p.000151: (a) The purpose of conducting clin- ical investigations of a drug is to dis- tinguish the effect of a drug
p.000151: from other influences, such as spontaneous change in the course of the disease, placebo ef- fect, or biased
p.000151: observation. The charac- teristics described in paragraph (b) of this section have been developed over a period
p.000151: of years and are recognized by the scientific community as the essen- tials of an adequate and
p.000151: well-con- trolled clinical investigation. The Food and Drug Administration considers these characteristics
p.000151: in determining whether an investigation is adequate and well-controlled for purposes of sec- tion 505 of the act.
p.000151: Reports of adequate and well-controlled investigations pro- vide the primary basis for determining whether
p.000151: there is ‘‘substantial evi- dence’’ to support the claims of effec- tiveness for new drugs.
p.000151: Therefore, the study report should provide sufficient details of study design, conduct, and analysis to
p.000151: allow critical evaluation and a determination of whether the characteristics of an adequate
p.000151: and well-controlled study are present.
p.000151: (b) An adequate and well-controlled
p.000151: study has the following characteristics:
p.000151: (1) There is a clear statement of the objectives of the investigation and a
p.000152: 152
p.000152:
p.000152:
p.000152:
p.000152:
p.000152:
p.000152:
p.000152:
p.000152: Food and Drug Administration, HHS § 314.126
p.000152:
p.000152:
p.000152: summary of the proposed or actual methods of analysis in the protocol for the study and in the report
p.000152: of its re- sults. In addition, the protocol should contain a description of the proposed methods of
p.000152: analysis, and the study re- port should contain a description of the methods of analysis ultimately used. If the
p.000152: protocol does not contain a descrip- tion of the proposed methods of anal- ysis, the study report should
p.000152: describe how the methods used were selected.
p.000152: (2) The study uses a design that per- mits a valid comparison with a control to provide a quantitative
p.000152: assessment of drug effect. The protocol for the study and report of results should describe the study design
p.000152: precisely; for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover,
p.000152: and whether the sample size is predetermined or based upon some interim analysis. Generally, the fol-
p.000152: lowing types of control are recognized:
p.000152: (i) Placebo concurrent control. The test drug is compared with an inactive preparation designed to
p.000152: resemble the test drug as far as possible. A placebo- controlled study may include addi- tional
p.000152: treatment groups, such as an ac- tive treatment control or a dose-com- parison control, and usually includes
p.000152: randomization and blinding of patients or investigators, or both.
p.000152: (ii) Dose-comparison concurrent con- trol. At least two doses of the drug are compared. A
p.000152: dose-comparison study may include additional treatment groups, such as placebo control or ac- tive
p.000152: control. Dose-comparison trials usually include randomization and blinding of patients or investigators,
p.000152: or both.
p.000152: (iii) No treatment concurrent control. Where objective measurements of effec- tiveness are available and
p.000152: placebo ef- fect is negligible, the test drug is com- pared with no treatment. No treatment concurrent control
p.000152: trials usually in- clude randomization.
p.000152: (iv) Active treatment concurrent con- trol. The test drug is compared with known effective therapy;
p.000152: for example, where the condition treated is such that administration of placebo or no treatment would
p.000152: be contrary to the in- terest of the patient. An active treat- ment study may include additional
p.000152: treatment groups, however, such as a
p.000152:
p.000152: placebo control or a dose-comparison control. Active treatment trials usu- ally include randomization
p.000152: and blind- ing of patients or investigators, or both. If the intent of the trial is to show
p.000152: similarity of the test and control drugs, the report of the study should assess the ability of the study to
p.000152: have detected a difference between treat- ments. Similarity of test drug and ac- tive control can
p.000152: mean either that both drugs were effective or that neither was effective. The analysis of the study should
p.000152: explain why the drugs should be considered effective in the study, for example, by reference to results in pre-
p.000152: vious placebo-controlled studies of the active control drug.
p.000152: (v) Historical control. The results of treatment with the test drug are com- pared with experience
p.000152: historically de- rived from the adequately documented natural history of the disease or condi- tion, or from
p.000152: the results of active treatment, in comparable patients or populations. Because historical control
p.000152: populations usually cannot be as well assessed with respect to pertinent vari- ables as can concurrent control
p.000152: popu- lations, historical control designs are usually reserved for special cir- cumstances.
p.000152: Examples include studies of diseases with high and predictable mortality (for example, certain malig-
p.000152: nancies) and studies in which the effect of the drug is self-evident (general an- esthetics, drug metabolism).
p.000152: (3) The method of selection of sub- jects provides adequate assurance that they have the disease or
p.000152: condition being studied, or evidence of suscepti- bility and exposure to the condition against which
p.000152: prophylaxis is directed.
p.000152: (4) The method of assigning patients to treatment and control groups mini- mizes bias and is intended to
p.000152: assure comparability of the groups with re- spect to pertinent variables such as age, sex, severity
p.000152: of disease, duration of disease, and use of drugs or therapy other than the test drug. The protocol for
...
Orphaned Trigger Words
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| abuse | Victim of Abuse |
| access | Access to Social Goods |
| age | Age |
| authority | Relationship to Authority |
| belief | Religion |
| children | Child |
| criminal | criminal |
| dependence | Drug Dependence |
| dependency | Drug Dependence |
| disability | Mentally Disabled |
| drug | Drug Usage |
| emergency | Public Emergency |
| fetus | Fetus/Neonate |
| freedomXofXinformation | Access to information |
| gender | gender |
| hazard | Natural Hazards |
| home | Property Ownership |
| ill | ill |
| incapacity | Incapacitated |
| influence | Drug Usage |
| minor | Youth/Minors |
| nation | stateless persons |
| native | Indigenous |
| neonates | Fetus/Neonate |
| officer | Police Officer |
| opinion | philosophical differences/differences of opinion |
| orphan | orphan |
| party | political affiliation |
| placebo | participants in a control group |
| racial | Racial Minority |
| restricted | Incarcerated |
| single | Marital Status |
| substance | Drug Usage |
| threat | Threat of Stigma |
| unlawful | Illegal Activity |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| dependence | ['dependency'] |
| dependency | ['dependence'] |
| drug | ['influence', 'substance'] |
| fetus | ['neonates'] |
| influence | ['drug', 'substance'] |
| neonates | ['fetus'] |
| substance | ['drug', 'influence'] |
Trigger Words
consent
developing
risk
sensitive
Applicable Type / Vulnerability / Indicator Overlay for this Input