21 CFR Part 514 — New Animal Drug Applications

PART 514—NEW ANIMAL DRUG APPLICATIONS Authority: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 360ddd, 360ddd-1, 371, 379e, 381. Source: 40 FR 13825, Mar. 27, 1975, unless otherwise noted. Subpart A—General Provisions § 514.1 Applications. (a) Applications to be filed under section 512(b) of the act shall be submitted in the form and contain the information described in paragraph (b) of this section, as appropriate to support the particular submission. If any part of the application is in a foreign language, an accurate and complete English translation shall be appended to such part. Translations of literature printed in a foreign language shall be accompanied by copies of the original publication. The application must be signed by the applicant or by an authorized attorney, agent, or official. If the applicant or such authorized representative does not reside or have a place of business within the United States, the application must also furnish the name and post office address of, and must be countersigned by, an authorized attorney, agent, or official residing or maintaining a place of business within the United States. Pertinent information may be incorporated in, and will be considered as part of, an application on the basis of specific reference to such information, including information submitted under the provisions of § 511.1 of this chapter, in the files of the Food and Drug Administration; however, the reference must be specific in identifying the information. Any reference to information furnished by a person other than the applicant may not be considered unless its use is authorized in a written statement signed by the person who submitted it. The following provisions do not apply to designated medical gases, which are subject to the certification requirements under part 230 of this chapter: §§ 514.1(b) and (c), 514.3 through 514.8, 514.12, and 514.15, and subpart B of this part. (b) Applications for new animal drugs shall be submitted in triplicate and assembled in the manner prescribed by paragraph (b)(15) of this section, and shall include the following information, as appropriate to support the particular submission: (1) Identification. (2) Table of contents and summary. (i) Chemistry: ( a ( b ( c (ii) Scientific rationale and purpose the new animal drug is to serve: ( a ( b ( c ( d (3) Labeling. (i) All labeling should be identified to show its position on, or the manner in which it is to accompany the market package. (ii) Labeling for nonprescription new animal drugs should include adequate directions for use by the layman under all conditions of use for which the new animal drug is intended, recommended, or suggested in any of the labeling or advertising sponsored by the applicant. (iii) Labeling for prescription veterinary drugs should bear adequate information for use under which veterinarians can use the new animal drug safely and for the purposes for which it is intended, including those purposes for which it is to be advertised or represented, in accord with § 201.105 of this chapter. (iv) All labeling for prescription or nonprescription new animal drugs shall be submitted with any necessary use restrictions prominently and conspicuously displayed. (v) Labeling for new animal drugs intended for use in the manufacture of medicated feeds shall include: ( a ( b (vi) Draft labeling may be submitted for preliminary consideration of an application. Final printed labeling will ordinarily be required prior to approval of an application. Proposed advertising for veterinary prescription drugs may be submitted for comment or approval. (4) Components and composition. (i) A full list of the articles used as components of the new animal drug. This list should include all substances used in the synthesis, extraction, or other method of preparation of any new animal drug and in the preparation of the finished dosage form, regardless of whether they undergo chemical change or are removed in the process. Each component should be identified by its established name, if any, or complete chemical name, using structural formulas when necessary for specific identification. If any proprietary name is used, it should be followed by a complete quantitative statement of composition. Reasonable alternatives for any listed component may be specified. (ii) A full statement of the composition of the new animal drug. The statement shall set forth the name and amount of each ingredient, whether active or not, contained in a stated quantity of the new animal drug in the form in which it is to be distributed (for example, amount per tablet or milliliter) and a batch formula representative of that to be employed for the manufacture of the finished dosage form. All components should be included in the batch formula regardless of whether they appear in the finished product. Any calculated excess of an ingredient over the label declaration should be designated as such and percent excess shown. Reasonable variation may be specified. (iii) If it is a new animal drug produced by fermentation: ( a ( b ( c ( d ( e ( f (5) Manufacturing methods, facilities, and controls. (i) If the applicant does not himself perform all the manufacturing, processing, packaging, labeling, and control operations for any new animal drug, he shall: Identify each person who will perform any part of such operations and designate the part; and provide a signed statement from each such person fully describing, directly or by reference, the methods, facilities, and controls he will use in his part of the operation. The statement shall include a commitment that no changes will be made without prior approval by the Food and Drug Administration, unless permitted under § 514.8. (ii) A description of the qualifications, including educational background and experience, of the technical and professional personnel who are responsible for assuring that the new animal drug has the identity, strength, quality, and purity it purports or is represented to possess, and a statement of their responsibilities. (iii) A description of the physical facilities including building and equipment used in manufacturing, processing, packaging, labeling, storage, and control operations. (iv) The methods used in the synthesis, extraction, isolation, or purification of any new animal drug. When the specifications and controls applied to such new animal drugs are inadequate in themselves to determine its identity, strength, quality, and purity, the methods should be described in sufficient detail, including quantities used, times, temperature, pH, solvents, etc., to determine these characteristics. Alternative methods or variations in methods within reasonable limits that do not affect such characteristics of the new animal drug may be specified. A flow sheet and indicated equations should be submitted when needed to explain the process. (v) Precautions to insure proper identity, strength, quality, and purity of the raw materials, whether active or not, including: ( a ( b (vi) The instructions used in the manufacturing, processing, packaging, and labeling of each dosage form of the new animal drug, including: ( a ( b ( c ( d ( e ( f (vii) The analytical controls used during the various stages of the manufacturing, processing, packaging, and labeling of the new animal drug, including a detailed description of the collection of samples and the analytical procedures to which they are subjected. The analytical procedures should be capable of determining the active components within a reasonable degree of accuracy and of assuring the identity of such components. ( a ( b (viii) An explanation of the exact significance of any batch control numbers used in the manufacturing, processing, packaging, and labeling of the new animal drug, including such control numbers that may appear on the label of the finished article. State whether these numbers enable determination of the complete manufacturing history of the product. Describe any methods used to permit determination of the distribution of any batch if its recall is required. (ix) Adequate information with respect to the characteristics of and the test methods employed for the container, closure, or other component parts of the drug package to assure their suitability for the intended use. (x) A complete description of, and data derived from, studies of the stability of the new animal drug in the final dosage form, including information showing the suitability of the analytical methods used. A description of any additional stability studies underway or planned. Stability data for the finished dosage form of the new animal drug in the container in which it is to be marketed, including any proposed multiple dose container, and, if it is to be put into solution at the time of dispensing, for the solution prepared as directed. If the new animal drug is intended for use in the manufacture of Type C medicated feed as defined in § 558.3 of this chapter, stability data derived from studies in which representative formulations of the medicated feed articles are used. Similar data may be required for Type B medicated feeds as determined by the Food and Drug Administration on a case-by-case basis. Expiration dates shall be proposed for finished pharmaceutical dosage forms and Type A medicated articles. If the data indicate that an expiration date is needed for Type B or Type C medicated feeds, the applicant shall propose such expiration date. If no expiration date is proposed for Type B or Type C medicated feeds, the applicant shall justify its absence with data. (xi) Additional procedures employed which are designed to prevent contamination and otherwise assure proper control of the product. An application may be refused unless it includes adequate information showing that the methods used in, and the facilities and controls used for, the manufacturing, processing, and packaging of the new animal drug are adequate to preserve its identity, strength, quality, and purity in conformity with good manufacturing practice and identifies each establishment, showing the location of the plant conducting these operations. (6) Samples. (i) Each sample shall consist of four identical, separately packaged subdivisions, each containing at least three times the amount required to perform the laboratory test procedures described in the application to determine compliance with its control specifications for identity and assays. Each of the samples submitted shall be appropriately packaged and labeled to preserve its characteristics, to identify the material and the quantity in each subdivision of the sample, and to identify each subdivision with the name of the applicant and the new animal drug application to which it relates. Included are: ( a ( b ( c (ii) The following information shall be included for the samples when requested: ( a ( b (7) Analytical methods for residues. (i) The kind of information required by this subdivision may include: Complete experimental protocols for determining drug residue levels in the edible products, and the length of time required for residues to be eliminated from such products following the drug's use; residue studies conducted under appropriate (consistent with the proposed usage) conditions of dosage, time, and route of administration to show levels, if any, of the drug and/or its metabolites in test animals during and upon cessation of treatment and at intervals thereafter in order to establish a disappearance curve; if the drug is to be used in combination with other drugs, possible effects of interaction demonstrated by the appropriate disappearance curve or depletion patterns after drug withdrawal under appropriate (consistent with the proposed usage) conditions of dosage, time, and route of administration; if the drug is given in the feed or water, appropriate consumption records of the medicated feed or water and appropriate performance data in the treated animal; if the drug is to be used in more than one species, drug residue studies or appropriate metabolic studies conducted for each species that is food-producing. To provide these data, a sufficient number of birds or animals should be used at each sample interval. Appropriate use of labeled compounds (e.g. radioactive tracers), may be utilized to establish metabolism and depletion curves. Drug residue levels ordinarily should be determined in muscle, liver, kidney, and fat and where applicable, in skin, milk, and eggs (yolk and egg white). As a part of the metabolic studies, levels of the drug or metabolite should be determined in blood where feasible. Samples may be combined where necessary. Where residues are suspected or known to be present in litter from treated animals, it may be necessary to include data with respect to such residues becoming components of other agricultural commodities because of use of litter from treated animals. (ii) A new animal drug that has the potential to contaminate human food with residues whose consumption could present a risk of cancer to people must satisfy the requirements of subpart E of part 500 of this chapter. (8) Evidence to establish safety and effectiveness. (ii) An application may be refused unless it includes substantial evidence of the effectiveness of the new animal drug as defined in § 514.4. (iii) An application may be refused unless it contains detailed reports of the investigations, including studies made on laboratory animals, in which the purpose, methods, and results obtained are clearly set forth of acute, subacute, and chronic toxicity, and unless it contains appropriate clinical laboratory results related to safety and efficacy. Such information should include identification of the person who conducted each investigation, a statement of where the investigations were conducted, and where the raw data are available in the application. (iv) All information pertinent to an evaluation of the safety and effectiveness of the new animal drug received or otherwise obtained by the applicant from any source, including information derived from other investigations or commercial marketing (for example, outside the United States), or reports in the scientific literature, both favorable and unfavorable, involving the new animal drug that is the subject of the application and related new animal drugs shall be submitted. An adequate summary may be acceptable in lieu of a reprint of a published report that only supports other data submitted. Include any evaluation of the safety or effectiveness of the new animal drug that has been made by the applicant's veterinary or medical department, expert committee, or consultants. (v) If the new animal drug is a combination of active ingredients or animal drugs, an application may be refused unless it includes substantial evidence of the effectiveness of the combination new animal drug as required in § 514.4. (vi) An application shall include a complete list of the names and post office addresses of all investigators who received the new animal drug. This may be incorporated in whole or in part by reference to information submitted under the provisions of § 511.1 of this chapter. (vii) Explain any omission of reports from any investigator to whom the investigational new animal drug has been made available. The unexplained omission of any reports of investigations made with the new animal drug by the applicant or submitted to him by an investigator or the unexplained omission of any pertinent reports of investigations or clinical experience received or otherwise obtained by the applicant from published literature or other sources that would bias an evaluation of the safety of the new animal drug or its effectiveness in use, constitutes grounds for the refusal or withdrawal of the approval of an application. (viii) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, the application is required to include a statement containing the name and address of the contract research organization, identifying the clinical study, and listing the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer—in lieu of a listing of the specific obligations transferred—may be submitted. (ix) If original subject records were audited or reviewed by the sponsor in the course of monitoring any clinical study to verify the accuracy of the case reports submitted to the sponsor, a list identifying each clinical study so audited or reviewed. (9) Veterinary feed directive. (10) Supplemental applications. (11) Applicant's commitment. (12) Additional commitments. (ii) The methods, facilities, and controls described under item 5 of this application conform to the current good manufacturing practice regulations in subchapter C of this chapter. (iii) With respect to each nonclinical laboratory study contained in the application, either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance. (13) [Reserved] (14) Environmental assessment. (15) Assembling and binding the application. (i) Bind the original or ribbon copy of the application as copy No. 1. (ii) Bind two identical copies as copy No. 2 and copy No. 3. (iii) Identify each front cover with the name of the applicant, new animal drug, and the copy number. (iv) Number each page of the application sequentially in the upper right hand corner or in another location so that the page numbers remain legible after the application has been bound, and organize the application consistent with paragraphs (b) (1) through (14) of this section. Each copy should bear the same page numbering, whether sequential in each volume or continuous and sequential throughout the application. (v) Include complete labeling in each of the copies. It is suggested that labeling be identified by date of printing or date of preparation. (vi) Submit separate applications for each different dosage form of the drug proposed. Repeating basic information pertinent to all dosage forms in each application is unnecessary if reference is made to the application containing such information. Include in each application information applicable to the specific dosage form, such as labeling, composition, stability data, and method of manufacture. (vii) Submit in folders amendments, supplements, and other correspondence sent after submission of an original application. The front cover of these submissions should be identified with the name of the applicant, new animal drug, copy number, and the new animal drug application number, if known. (c) When a new animal drug application is submitted for a new animal drug which has a stimulant, depressant, or hallucinogenic effect on the central nervous system, if it appears that the drug has a potential for abuse, the Commissioner shall forward that information to the Attorney General of the United States. [40 FR 13825, Mar. 27, 1975] Editorial Note: For Federal Register www.govinfo.gov. § 514.3 Definitions. The definition and interpretation of terms contained in this section apply to those terms as used throughout subchapter E. Adverse drug experience (1) An adverse event occurring in animals in the course of the use of an animal drug product by a veterinarian or by a livestock producer or other animal owner or caretaker. (2) Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of expected effectiveness). (3) An adverse event occurring in humans from exposure during manufacture, testing, handling, or use of a new animal drug. ANADA Applicant Increased frequency of adverse drug experience NADA Nonapplicant Potential applicant (1) Intending to investigate a new animal drug under section 512(j) of the Federal Food, Drug, and Cosmetic Act (the act), (2) Investigating a new animal drug under section 512(j) of the act, (3) Intending to file a new animal drug application (NADA) or supplemental NADA under section 512(b)(1) of the act, or (4) Intending to file an abbreviated new animal drug application (ANADA) under section 512(b)(2) of the act. Presubmission conference Presubmission conference agreement Product defect/manufacturing defect Serious adverse drug experience Unexpected adverse drug experience [68 FR 15365, Mar. 31, 2003, as amended at 69 FR 51170, Aug. 18, 2004] § 514.4 Substantial evidence. (a) Definition of substantial evidence. (b) Characteristics of substantial evidence Qualifications of experts. (2) Intended uses and conditions of use. (i) Dose range labeling. (ii) [Reserved] (3) Studies Number. (A) To determine that the parameters selected for measurement and the measured responses reliably reflect the effectiveness of the new animal drug; (B) To determine that the results obtained are likely to be repeatable, and that valid inferences can be drawn to the target animal population; and (C) To conclude that the new animal drug is effective for the intended use at the dose or dose range and associated conditions of use prescribed, recommended, or suggested in the proposed labeling. (ii) Types. (c) Substantial evidence for combination new animal drugs Definitions. (i) Combination new animal drug (ii) Dosage form combination new animal drug (iii) Antibacterial (iv) Appropriate concurrent use (2) Combination new animal drugs that contain only active ingredients or animal drugs that have previously been separately approved. (A) By substantial evidence, as defined in this section, that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the effectiveness of the combination new animal drug; (B) That each active ingredient or animal drug intended for at least one use that is different from all the other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target animal population; and (C) That the active ingredients or animal drugs are physically compatible and do not have disparate dosing regimens if FDA, based on scientific information, has reason to believe the active ingredients or animal drugs are physically incompatible or have disparate dosing regimens. (ii) For combination new animal drugs intended for use in animal feed or drinking water that contain only active ingredients or animal drugs that have previously been separately approved for the particular uses and conditions of use for which they are intended in combination, the sponsor shall demonstrate: (A) By substantial evidence, as defined in this section, that any active ingredient or animal drug intended only for the same use as another active ingredient or animal drug in the combination makes a contribution to the effectiveness of the combination new animal drug; (B) For such combination new animal drugs that contain more than one antibacterial ingredient or animal drug, by substantial evidence, as defined in this section, that each antibacterial makes a contribution to labeled effectiveness; (C) That each active ingredient or animal drug intended for at least one use that is different from all other active ingredients or animal drugs used in the combination provides appropriate concurrent use for the intended target animal population; and (D) That the active ingredients or animal drugs intended for use in drinking water are physically compatible if FDA, based on scientific information, has reason to believe the active ingredients or animal drugs are physically incompatible. (3) Other combination new animal drugs. [64 FR 40756, July 28, 1999] § 514.5 Presubmission conferences. (a) General principle underlying the conduct of a presubmission conference. (b) Requesting a presubmission conference. (c) Timing. (d) Advance information. (e) Conduct of a presubmission conference. (f) Documentation of a presubmission conference Memorandum of conference Preparation. (ii) Sending a copy to the potential applicant. (iii) Requests for changes or clarification. (iv) Administrative record. (2) Field studies. (g) Modification of presubmission conference agreements. (1) FDA and the potential applicant mutually agree to modify, in part or in whole, the agreement and such modification is documented and provided to the potential applicant as described in paragraph (f)(1) of this section; or (2) FDA by written order determines that a substantiated scientific requirement essential to the determination of safety or effectiveness of the new animal drug appeared after the conference. (h) When the terms of a presubmission conference agreement are not valid. (i) The potential applicant makes to FDA, before, during, or after the presubmission conference, any untrue statement of material fact; or (ii) The potential applicant fails to follow any material term of the agreement; and (2) A presubmission conference may no longer be valid if the potential applicant submits false or misleading data relating to a new animal drug to FDA. (i) Dispute resolution. [69 FR 51170, Aug. 18, 2004] § 514.6 Amended applications. The applicant may submit an amendment to an application that is pending, including changes that may alter the conditions of use, the labeling, safety, effectiveness, identity, strength, quality, or purity of the drug or the adequacy of the manufacturing methods, facilities, and controls to preserve them, in which case the unamended application may be considered as withdrawn and the amended application may be considered resubmitted on the date on which the amendment is received by the Food and Drug Administration. The applicant will be notified of such date. § 514.7 Withdrawal of applications without prejudice. The sponsor may withdraw his pending application from consideration as a new animal drug application upon written notification to the Food and Drug Administration. Such withdrawal may be made without prejudice to a future filing. Upon resubmission, the time limitation will begin to run from the date the resubmission is received by the Food and Drug Administration. The original application will be retained by the Food and Drug Administration although it is considered withdrawn. The applicant shall be furnished a copy at cost on request. § 514.8 Supplements and other changes to an approved application. (a) Definitions. (2) The following definitions of terms apply to this part: (i) Assess the effects of the change (ii) Drug substance (iii) Minor changes and stability report (MCSR) (iv) Specification (b) Manufacturing changes to an approved application General provisions. (ii) The holder of an approved application under section 512 of the act must assess the effects of the change before distributing a drug made with a manufacturing change. (iii) Notwithstanding the requirements of paragraphs (b)(2) and (b)(3) of this section, an applicant must make a change provided for in those paragraphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a supplement that does not require approval prior to distribution of the drug, or by notification in the next annual report described in paragraph (b)(4) of this section). (iv) In each supplement and amendment to a supplement providing for a change under paragraph (b)(2) or (b)(3) of this section, the applicant must include a statement certifying that a field copy has been provided to the appropriate FDA district office. No field copy is required for a supplement providing for a change made to a drug manufactured outside of the United States. (v) A supplement or annual report described in paragraph (b)(4) of this section must include a list of all changes contained in the supplement or annual report. For supplements, this list must be provided in the cover letter. (2) Changes requiring submission and approval of a supplement prior to distribution of the drug made using the change (major changes). (ii) These changes include, but are not limited to: (A) Except those described in paragraphs (b)(3) and (b)(4) of this section, changes in the qualitative or quantitative formulation of the drug, including inactive ingredients, or in the specifications provided in the approved application; (B) Changes requiring completion of appropriate clinical studies to demonstrate the equivalence of the drug to the drug as manufactured without the change; (C) Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation; (D) Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance; (E) Changes in a drug product container closure system that controls the drug delivered to the animal or changes in the type or composition of a packaging component that may affect the impurity profile of the drug product; (F) Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody for the following: ( 1 ( 2 ( 3 (G) Changes to a drug under an application that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that application. (iii) The applicant must obtain approval of a supplement from FDA prior to distribution of a drug made using a change under paragraph (b)(2) of this section. The supplement must be labeled “Prior Approval Supplement.” Except for submissions under paragraph (b)(2)(v) of this section, the following information must be contained in the supplement: (A) A completed Form FDA 356V; (B) A detailed description of the proposed change; (C) The drug(s) involved; (D) The manufacturing site(s) or area(s) affected; (E) A description of the methods used and studies performed to assess the effects of the change; (F) The data derived from such studies; (G) Appropriate documentation (for example, updated master batch records, specification sheets) including previously approved documentation (with the changes highlighted) or references to previously approved documentation; (H) For a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section; (I) For sterilization process and test methodologies related to sterilization process validation, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section; and (J) Any other information as directed by FDA. (iv) An applicant may ask FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover must be plainly marked: “Prior Approval Supplement-Expedited Review Requested.” (v) Comparability Protocols. (3) Changes requiring submission of a supplement at least 30 days prior to distribution of the drug made using the change (moderate changes). (ii) These changes include, but are not limited to: (A) A change in the container closure system that does not affect the quality of the drug except as otherwise described in paragraphs (b)(2) and (b)(4) of this section; (B) Changes solely affecting a natural protein, a recombinant DNA-derived protein/polypeptide or a complex or conjugate of a drug substance with a monoclonal antibody, including: ( 1 ( 2 (C) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements. (iii) A supplement submitted under paragraph (b)(3)(i) or (b)(3)(vi) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is made. The supplement submitted under paragraph (b)(3)(i) must be labeled “Supplement-Changes Being Effected in 30 Days.” (iv) Pending approval of the supplement by FDA and except as provided in paragraph (b)(3)(vi) of this section, distribution of the drug made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement. (v) The applicant must not distribute the drug made using the change if within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either: (A) The change requires approval prior to distribution of the drug in accordance with paragraph (b)(2) of this section; or (B) Any of the information required under paragraph (b)(3)(iv) of this section is missing. In this case, the applicant must not distribute the drug made using the change until the supplement has been amended to provide the missing information. (vi) The agency may designate a category of changes for the purpose of providing that, in the case of a change in such category, the holder of an approved application may commence distribution of the drug involved upon receipt by the agency of a supplement for the change. The information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained in the supplement. The supplement must be labeled “Supplement-Changes Being Effected.” These changes include, but are not limited to: (A) Addition to a specification or changes in the methods or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess; and (B) A change in the size and/or shape of a container for a nonsterile drug product, except for solid dosage forms, without a change in the labeled amount of drug product or from one container closure system to another. (vii) If the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the drug(s) made with the manufacturing change. (4) Changes and updated stability data to be described and submitted in an annual report (minor changes). (ii) These changes include but are not limited to: (A) Any change made to comply with a change to an official compendium, except a change in paragraph (b)(3)(ii)(C) of this section, that is consistent with FDA statutory and regulatory requirements; (B) The deletion or reduction of an ingredient intended to affect only the color of the drug product; (C) Replacement of equipment with that of the same design and operating principles except for those equipment changes described in paragraph (b)(3)(ii)(B)(2) of this section; (D) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another; (E) A change within the container closure system for a nonsterile drug product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium; (F) An extension of an expiration dating period based upon full shelf-life data on production batches obtained from a protocol approved in the application; (G) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the drug being tested as the analytical procedure described in the approved application, or deletion of an alternative analytical procedure; and (H) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint. (iii) For changes under this category, the applicant is required to submit in the annual report: (A) A completed Form FDA 356V; (B) A statement by the holder of the approved application that the effects of the change have been assessed; (C) A detailed description of the change(s); (D) The manufacturing site(s) or area(s) involved; (E) The date each change was implemented; (F) Data from studies and tests performed to assess the effects of the change; (G) For a natural product, recombinant DNA-derived protein/polypeptide, complex or conjugate of a drug substance with a monoclonal antibody, sterilization process or test methodology related to sterilization process validation, relevant validation protocols and/or standard operating procedures; (H) Appropriate documentation (for example, updated master batch records, specification sheets, etc.) including previously approved documentation (with the changes highlighted) or references to previously approved documentation; (I) Updated stability data generated on commercial or production batches according to an approved stability protocol or commitment; and (J) Any other information as directed by FDA. (c) Labeling and other changes to an approved application General provisions. (2) Labeling changes requiring the submission and approval of a supplement prior to distribution of the drug made using the change (major changes). (A) Revision in labeling, such as updating information pertaining to effects, dosages, adverse reactions, contraindications, which includes information headed “adverse reactions,” “warnings,” “precautions,” and “contraindications,” except ones described in (c)(3) of this section; (B) Addition of an intended use; (C) If it is a prescription drug, any mailing or promotional piece used after the drug is placed on the market is labeling requiring a supplemental application, unless: ( 1 ( 2 ( 3 (D) Any other changes in labeling, except ones described in paragraph (c)(3) of this section. (ii) The applicant must obtain approval of the supplement from FDA prior to distribution of the drug. The supplement must contain the following: (A) A completed Form FDA 356V; (B) A detailed description of the proposed change; (C) The drug(s) involved; (D) The data derived from studies in support of the change; and (E) Any other information as directed by FDA. (3) Labeling changes to be placed into effect prior to receipt of a written notice of approval of a supplemental application. (A) The addition to package labeling, promotional labeling, or prescription drug advertising of additional warning, contraindication, adverse reaction, and precaution information; (B) The deletion from package labeling, promotional labeling, or drug advertising of false, misleading, or unsupported intended uses or claims for effectiveness; and (C) Any other changes as directed by FDA. (ii) Labeling changes (for example, design and style) that do not decrease safety of drug use proposed in supplemental applications may be placed into effect prior to written notice of approval from FDA of a supplemental application. (iii) A supplement submitted under paragraph (c)(3) of this section must include the following information: (A) A full explanation of the basis for the changes, the date on which such changes are being effected, and plainly marked on the mailing cover and on the supplement, “Supplement—Labeling Changes Being Effected”; (B) Two sets of printed copies of any revised labeling to be placed in use, identified with the new animal drug application number; and (C) A statement by the applicant that all promotional labeling and all drug advertising will promptly be revised consistent with the changes made in the labeling on or within the new animal drug package no later than upon approval of the supplemental application. (iv) If the supplemental application is not approved and the drug is being distributed with the proposed labeling, FDA may initiate an enforcement action because the drug is misbranded under section 502 of the act and/or adulterated under section 501 of the act. In addition, under section 512(e) of the act, FDA may, after due notice and opportunity for a hearing, issue an order withdrawing approval of the application. (4) Changes providing for additional distributors to be reported under Records and reports concerning experience with approved new animal drugs (§ 514.80). (d) Patent information. (e) Claimed exclusivity. (f) Good laboratory practice for nonclinical laboratory studies. [71 FR 74782, Dec. 13, 2006] § 514.11 Confidentiality of data and information in a new animal drug application file. (a) For purposes of this section the NADA file (b) The existence of an NADA file will not be disclosed by the Food and Drug Administration before the application has been approved, unless it has been previously disclosed or acknowledged. (c) If the existence of an NADA file has not been publicly disclosed or acknowledged, no data or information in the NADA file is available for public disclosure. (d) If the existence of an NADA file has been publicly disclosed or acknowledged before the application has been approved, no data or information contained in the file is available for public disclosure, but the Commissioner may, in his discretion, disclose a summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, i.e., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government. (e) After an application has been approved, the following data and information in the NADA file are immediately available for public disclosure unless extraordinary circumstances are shown: (1) All safety and effectiveness data and information previously disclosed to the public, as defined in § 20.81 of this chapter. (2) A summary or summaries of the safety and effectiveness data and information submitted with or incorporated by reference in the NADA file. Such summaries do not constitute the full reports of investigations under section 512(b)(1) of the act (21 U.S.C. 360b(b)(1)) on which the safety or effectiveness of the drug may be approved. Such summaries shall consist of the following: (i) For an NADA approved prior to July 1, 1975, internal agency records that describe such data and information, e.g., a summary of basis for approval or internal reviews of the data and information, after deletion of: ( a ( b (ii) For an NADA approved after July 1, 1975, a summary of such data and information prepared in one of the following two alternative ways shall be publicly released when the application is approved. ( a ( b (3) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61 of this chapter. (4) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of: (i) Names and any information that would identify the person using the product. (ii) Names and any information that would identify any third party involved with the report, such as a physician, hospital, or other institution. (5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as defined in § 20.81 of this chapter. (6) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and is shown to fall within the exemption established in § 20.61 of this chapter. (7) All correspondence and written summaries of oral discussions relating to the NADA, in accordance with the provisions of part 20 of this chapter. (f) All safety and effectiveness data and information not previously disclosed to the public are available for public disclosure at the time any one of the following events occurs unless extraordinary circumstances are known: (1) The NADA has been abandoned and no further work is being undertaken with respect to it. (2) A final determination is made that the NADA is not approvable, and all legal appeals have been exhausted. (3) Approval of the NADA is withdrawn, and all legal appeals have been exhausted. (4) A final determination has been made that the animal drug is not a new animal drug. (5) A final determination has been made that the animal drug may be marketed without submission of such safety and/or effectiveness data and information. (g) The following data and information in an NADA file are not available for public disclosure unless they have been previously disclosed to the public as defined in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 20.61 of this chapter: (1) Manufacturing methods or processes, including quality control procedures. (2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure. (3) Quantitative or semiquantitative formulas. (h) For purposes of this regulation, safety and effectiveness data include all studies and tests of an animal drug on animals and all studies and tests on the animal drug for identity, stability, purity, potency, and bioavailability. [40 FR 13825, Mar. 27, 1975, as amended at 42 FR 3109, Jan. 14, 1977; 42 FR 15675, Mar. 22, 1977; 54 FR 18280, Apr. 28, 1989; 68 FR 15365, Mar. 31, 2003; 79 FR 14611, Mar. 17, 2014] § 514.12 Confidentiality of data and information in an investigational new animal drug notice. (a) The existence of an INAD notice will not be disclosed by the Food and Drug Administration unless it has previously been publicly disclosed or acknowledged. (b) The availability for public disclosure of all data and information in an INAD file shall be handled in accordance with provisions established in § 514.11. § 514.15 Untrue statements in applications. Among the reasons why an application for a new animal drug or animal feed bearing or containing a new animal drug may contain an untrue statement of a material fact are: (a) Differences in: (1) Conditions of use prescribed, recommended, or suggested by the applicant for the product from the conditions of such use stated in the application; (2) Articles used as components of the product from those listed in the application; (3) Composition of the product from that stated in the application; (4) Methods used in or the facilities and controls used for the manufacture, processing, or packing of the product from such methods, facilities, and controls described in the application; (5) Labeling from the specimens contained in the application; or (b) The unexplained omission in whole or in part from an application or from an amendment or supplement to an application or from any record or report required under the provisions of section 512 of the act and § 514.80 or § 510.301 of this chapter of any information obtained from: (1) Investigations as to the safety, effectiveness, identity, strength, quality, or purity of the drug, made by the applicant on the drug, or (2) Investigations or experience with the product that is the subject of the application, or any related product, available to the applicant from any source if such information is pertinent to an evaluation of the safety, effectiveness, identity, strength, quality, or purity of the drug, when such omission would bias an evaluation of the safety or effectiveness of the product. (c) Any nonclinical laboratory study contained in the application was not conducted in compliance with the good laboratory practice regulations as set forth in part 58 of this chapter, and the application fails to include a brief statement of the reason for the noncompliance. [40 FR 13825, Mar. 27, 1975, as amended at 49 FR 7226, Feb. 28, 1984; 50 FR 7517, Feb. 22, 1985; 68 FR 15365, Mar. 31, 2003] Subpart B—Administrative Actions on Applications § 514.80 Records and reports concerning experience with approved new animal drugs. The following table outlines the purpose for each paragraph of this section: Purpose 21 CFR Paragraph and Title What information must be reported concerning approved NADAs or ANADAs? 514.80(a) Applicability. What authority does FDA have for requesting records and reports? 514.80(a)(1). What records must be established and maintained and what reports filed with FDA? 514.80(a)(2). What is FDA's purpose for requiring reports? 514.80(a)(3). Do applicants of Type A medicated articles have to establish, maintain, and report information required under § 514.80? 514.80(a)(4). How do the requirements under § 514.80 relate to current good manufacturing practices? 514.80(a)(5). Does this section apply to designated medical gases subject to the certification requirements under part 230? 514.80(a)(6) 514.80(b) Reporting requirements. What are the requirements for reporting product/manufacturing defects? 514.80(b)(1) Three-day NADA/ANADA field alert report. 514.80(b)(2) Fifteen-day NADA/ANADA alert report. What are the requirements for reporting serious and unexpected adverse drug experiences? 514.80(b)(2)(i) Initial report. What are the requirements for followup reporting of serious and unexpected adverse drug experiences? 514.80(b)(2)(ii) Followup report. What are the requirements for nonapplicants for reporting adverse drug experiences? 514.80(b)(3) Nonapplicant report. What are the general requirements for submission of periodic drug experience reports, e.g., 514.80(b)(4) Periodic drug experience report. What must be submitted in the periodic drug experience reports? 514.80(b)(4)(i) through (b)(4)(iv). What distribution data must be submitted? 514.80(b)(4)(i) Distribution data. What labeling materials should be submitted? 514.80(b)(4)(ii) Labeling. 514.80(b)(4)(iii) Nonclinical laboratory studies and clinical data not previously reported. What are the requirements for submission of nonclinical laboratory studies? 514.80(b)(4)(iii)(A). What are the requirements for submission of clinical laboratory data? 514.80(b)(4)(iii)(B). When must results of clinical trials conducted by or for the applicant be reported? 514.80(b)(4)(iii)(C). 514.80(b)(4)(iv) Adverse drug experiences. How do I report product/manufacturing defects and adverse drug experiences not previously reported to FDA? 514.80(b)(4)(iv)(A). What are the requirements for submitting adverse drug experiences cited in literature? 514.80(b)(4)(iv)(B). What are the requirements for submitting adverse drug experiences in postapproval studies and clinical trials? 514.80(b)(4)(iv)(C). What are the requirements for reporting increases in the frequency of serious, expected, and unexpected adverse drug experiences? 514.80(b)(4)(v) Summary report of increased frequency of adverse drug experience. 514.80(b)(5) Other reporting. Can FDA request that an applicant submit information at different times than stated specifically in this regulation? 514.80(b)(5)(i) Special drug experience report. What are the requirements for submission of advertisement and promotional labeling to FDA? 514.80(b)(5)(ii) Advertisements and promotional labeling. What are the requirements for adding a new distributor to the approved application? 514.80(b)(5)(iii) Distributor's statement. What labels and how many labels need to be submitted for review? 514.80(b)(5)(iii)(A). What changes are required and allowed to distributor labeling? 514.80(b)(5)(iii)(A)( 1 What are the requirements for making other changes to the distributor labeling? 514.80(b)(5)(iii)(A)( 2 What information should be included in each new distributor's signed statement? 514.80(b)(5)(iii)(B)( 1 5 What are the conditions for submitting information that is common to more than one application? (i.e., can I submit common information to one application?) 514.80(c) Multiple applications. What information has to be submitted to the common application and related application? 514.80(c)(1) through (c)(4). What reports must be submitted to FDA electronically? 514.80(d) Format for Submissions. How long must I maintain records and reports required by this section? 514.80(e) Records to be maintained. What are the requirements for allowing access to these records and reports, and copying by authorized FDA officer or employee? 514.80(f) Access to records and reports. Where do I mail reports that are not required to be submitted electronically? 514.80(g) Mailing addresses. What happens if the applicant fails to establish, maintain, or make the required reports? 514.80(h) Withdrawal of approval. Does an adverse drug experience reflect a conclusion that the report or information constitutes an admission that the drug caused an adverse effect? 514.80(i) Disclaimer. (a) Applicability. (2) Each applicant must submit reports of data, studies, and other information concerning experience with new animal drugs to the Food and Drug Administration (FDA) for each approved NADA and ANADA, as required in this section. A nonapplicant must submit data, studies, and other information concerning experience with new animal drugs to the appropriate applicant, as required in this section. The applicant, in turn, must report the nonapplicant's data, studies, and other information to FDA. Applicants and nonapplicants must submit data, studies, and other information described in this section from domestic, as well as foreign sources. (3) FDA reviews the records and reports required in this section to facilitate a determination under section 512(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b(e)) as to whether there may be grounds for suspending or withdrawing approval of the NADA or ANADA. (4) The requirements of this section also apply to any approved Type A medicated article. In addition, the requirements contained in § 514.80(b)(1), (b)(2), (b)(4)(iv), and (b)(4)(v) apply to any approved Type A medicated article incorporated in animal feeds. (5) The records and reports referred to in this section are in addition to those required by the current good manufacturing practice regulations in parts 211, 225, and 226 of this chapter. (6) This section does not apply to designated medical gases, which are subject to the certification requirements under part 230 of this chapter. Part 230 of this chapter contains requirements related to records and reports concerning experience with the use of a designated medical gas in animals. (b) Reporting requirements Three-day NADA/ANADA field alert report. (2) Fifteen-day NADA/ANADA alert report Initial report. (ii) Followup report. (3) Nonapplicant report. (4) Periodic drug experience report. (i) Distribution data. e.g., (B) Applicants submitting annual sales and distribution reports for antimicrobial new animal drug products under § 514.87 have the option not to report distribution data under paragraph (b)(4)(i)(A) of this section for the approved applications that include these same products, but only provided each of the following conditions are met: ( 1 ( 2 ( 3 ( 4 (ii) Labeling. (iii) Nonclinical laboratory studies and clinical data not previously reported. (A) Copies of in vitro studies (e.g., mutagenicity) and other nonclinical laboratory studies conducted by or otherwise obtained by the applicant. (B) Copies of published clinical trials of the new animal drug (or abstracts of them) including clinical trials on safety and effectiveness, clinical trials on new uses, and reports of clinical experience pertinent to safety conducted by or otherwise obtained by the applicant. Review articles, papers, and abstracts in which the drug is used as a research tool, promotional articles, press clippings, and papers that do not contain tabulations or summaries of original data are not required to be reported. (C) Descriptions of completed clinical trials conducted by or for the applicant must be submitted no later than 1 year after completion of research. Supporting information is not to be reported. (iv) Adverse drug experiences. (B) Reports of adverse drug experiences in the literature must be noted in the periodic drug experience report. A bibliography of pertinent references must be included with the report. Upon FDA's request, the applicant must provide a full text copy of these publications. (C) Reports of previously not reported adverse drug experiences that occur in postapproval studies must be reported individually to FDA in electronic format as described in paragraph (d)(1) of this section, unless the applicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format. (v) Summary report of increased frequency of adverse drug experience. (5) Other reporting Special drug experience report. (ii) Advertisements and promotional labeling. (iii) Distributor's statement. (A) The distributor's current product labeling. ( 1 ( 2 (B) A signed statement by the distributor stating: ( 1 ( 2 ( 3 ( 4 ( 5 (c) Multiple applications. (1) State when a report applies to multiple applications and identify all related applications for which the report is submitted by NADA or ANADA number. (2) Ensure that the primary application contains a list of the NADA or ANADA numbers of all related applications. (3) Submit a completed Form FDA 2301 to the primary application and each related application with reference to the primary application by NADA/ANADA number and submission date for the complete report of the common information. (4) All other information specific to a particular NADA/ANADA must be included in the report for that particular NADA/ANADA. (d) Format for submissions Electronic submissions. e.g., (2) Waivers. (3) Paper forms. (e) Records to be maintained. (f) Access to records and reports. (g) Mailing addresses. (h) Withdrawal of approval. (i) Disclaimer. [68 FR 15365, Mar. 31, 2003, as amended at 81 FR 29141, May 11, 2016; 85 FR 45512, July 29, 2020; 90 FR 51782, June 18, 2024] § 514.87 Annual reports for antimicrobial animal drug sales and distribution. (a) The applicant for each new animal drug product approved under section 512 of the Federal Food, Drug, and Cosmetic Act, or conditionally approved under section 571 of the Federal Food, Drug, and Cosmetic Act, and containing an antimicrobial active ingredient, must submit an annual report to FDA on the amount of each such antimicrobial active ingredient in the drug that is sold or distributed in the reporting year for use in food-producing animal species, including information on any distributor-labeled product. (b) This report must identify the approved or conditionally approved application and must include the following information for each new animal drug product described in paragraph (a) of this section: (1) A listing of each antimicrobial active ingredient contained in the product; (2) A description of each product sold or distributed by unit, including the container size, strength, and dosage form of such product units; (3) For each such product, a listing of the target animal species, indications, and production classes that are specified on the approved label; (4) For each such product, the number of units sold or distributed in the United States ( i.e., (5) For each such product, the number of units sold or distributed outside the United States ( i.e., (c) Each report must also provide a species-specific estimate of the percentage of each product described in paragraph (b)(2) of this section that was sold or distributed domestically in the reporting year for use in any of the following animal species categories, but only for such species that appear on the approved label: Cattle, swine, chickens, turkeys. The total of the species-specific percentages reported for each product must account for 100 percent of its sales and distribution; therefore, a fifth category of “other species/unknown” must also be reported. (d) Each report must: (1) Be submitted not later than March 31 each year; (2) Cover the period of the preceding calendar year; and (3) Be submitted using Form FDA 3744, “Antimicrobial Animal Drug Distribution Report.” (e) Sales and distribution data and information reported under this section will be considered to fall within the exemption for confidential commercial information established in § 20.61 of this chapter and will not be publicly disclosed, except that summary reports of such information aggregated in such a way that does not reveal information that is not available for public disclosure under this provision will be prepared by FDA and made available to the public as provided in paragraph (f) of this section. (f) FDA will publish an annual summary report of the data and information it receives under this section for each calendar year by December 31 of the following year. Such annual reports must include a summary of sales and distribution data and information by antimicrobial drug class and may include additional summary data and information as determined by FDA. In order to protect confidential commercial information, each individual datum appearing in the summary report must: (1) Reflect combined product sales and distribution data and information obtained from three or more distinct sponsors of approved products that were actively sold or distributed that reporting year, and (2) Be reported in a manner consistent with protecting both national security and confidential commercial information. [81 FR 29141, May 11, 2016] § 514.100 Evaluation and comment on applications. (a) After the filed application has been evaluated, the applicant will be furnished written comment on any apparent deficiencies in the application. (b) When the description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such new animal drug appears adequate on its face, but it is not feasible to reach a conclusion as to the safety and effectiveness of the new animal drug solely from consideration of this description, the applicant may be notified that an establishment inspection is required to verify their adequacy. (c) A request for samples of a new animal drug or any edible tissues and byproducts of animals treated with such a drug, shall specify the quantity deemed adequate to permit tests of analytical methods to determine their adequacy for regulatory purposes. The request should be made as early in the 180-day period as possible to assure timely completion. The date used for computing the 180-day limit for the purposes of section 512(c) of the act shall be moved forward 1 day for each day after the mailing date of the request until all of the requested samples are received. If the samples are not received within 90 days after the request, the application will be considered withdrawn without prejudice. (d) The information contained in an application may be insufficient to determine whether a new animal drug is safe or effective in use if it fails to include (among other things) a statement showing whether such drug is to be limited to prescription sale and exempt under section 502(f) of the act from the requirement that its labeling bear adequate directions for lay use. If such drug is to be exempt, the information may also be insufficient if: (1) The specimen labeling proposed fails to bear adequate information for professional use including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer such drug can use the drug for the purposes for which it is intended, including all purposes for which it is to be advertised, or represented, in accordance with § 201.105 of this chapter, and information concerning hazards, contraindications, side effects, and precautions relevant with respect to any uses for which such drug is to be prescribed. (2) The application fails to show that the labeling and advertising of such drug will offer the drug for use only under those conditions for which it is offered in the labeling that is part of the application. (3) The application fails to show that all labeling that furnishes or purports to furnish information for professional use of such drug will contain, in the same language and emphasis, the information for use including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant warnings, hazards, contraindications, side effects, and precautions, which is contained in the labeling that is part of the application in accordance with § 201.105 of this chapter. (e) The information contained in an application will be considered insufficient to determine whether a new animal drug is safe and effective for use when there is a refusal or failure upon written notice to furnish inspectors authorized by the Food and Drug Administration an adequate opportunity to inspect the facilities, controls, and records pertinent to the application. (f) On the basis of preliminary consideration of an application or supplemental application containing typewritten or other draft labeling in lieu of final printed labeling, an applicant may be informed that such application is approvable when satisfactory final printed labeling identical in content to such draft copy is submitted. (g) When an application has been found incomplete on the basis of a need for the kind of information described in § 514.6, such application shall be considered withdrawn without prejudice to future filing on the date of issuance of the letter citing the inadequacies contained in the application, unless within 30 days the sponsor chooses to avail himself of the opportunity for hearing as prescribed by § 514.111. § 514.105 Approval of applications. (a) The Commissioner shall forward for publication in the Federal Register (b) He shall notify the applicant by sending him a copy of the proposed publication as described in paragraph (a)(1) of this section. [40 FR 13825, Mar. 27, 1975, as amended at 51 FR 7392, Mar. 3, 1986; 64 FR 63203, Nov. 19, 1999] § 514.106 Approval of supplemental applications. (a) Within 180 days after a supplement to an approved application is filed pursuant to § 514.8, the Commissioner shall approve the supplemental application in accordance with procedures set forth in § 514.105(a)(1) and (2) if he/she determines that the application satisfies the requirements of applicable statutory provisions and regulations. (b) The Commissioner will assign a supplemental application to its proper category to ensure processing of the application. (1) Category I. (i) A corporate change that alters the identity or address of the sponsor of the new animal drug application (NADA). (ii) The sale, purchase, or construction of manufacturing facilities. (iii) The sale or purchase of an NADA. (iv) A change in container, container style, shape, size, or components. (v) A change in approved labeling (color, style, format, addition, deletion, or revision of certain statements, e.g., trade name, storage, expiration dates, etc). (vi) A change in promotional material for a prescription new animal drug not exempted by § 514.8(c)(2)(i)(C)( 1 3 (vii) Changes in manufacturing processes that do not alter the method of manufacture or change the final dosage form. (viii) A change in bulk drug shipments. (ix) A change in an analytical method or control procedures that do not alter the approved standards. (x) A change in an expiration date. (xi) Addition of an alternate manufacturer, repackager, or relabeler of the drug product. (xii) Addition of an alternate supplier of the new drug substance. (xiii) A change permitted in advance of approval as described under § 514.8(b)(3). (2) Category II. (i) A change in the active ingredient concentration or composition of the final product. (ii) A change in quality, purity, strength, and identity specifications of the active or inactive ingredients. (iii) A change in dose (amount of drug administered per dose). (iv) A change in the treatment regimen (schedule of dosing). (v) Addition of a new therapeutic claim to the approved uses of the product. (vi) Addition of a new or revised animal production claim. (vii) Addition of a new species. (viii) A change in the prescription or over-the-counter status of a drug product. (ix) A change in statements regarding side effects, warnings, precautions, and contraindications, except the addition of approved statements to container, package, and promotional labeling, and prescription drug advertising. (x) A change in the drug withdrawal period prior to slaughter or in the milk discard time. (xi) A change in the tolerance for drug residues. (xii) A change in analytical methods for drug residues. (xiii) A revised method of synthesis or fermentation of the new drug substance. (xiv) Updating or changes in the manufacturing process of the new drug substance and/or final dosage form (other than a change in equipment that does not alter the method of manufacture of a new animal drug, or a change from one commercial batch size to another without any change in manufacturing procedure), or changes in the methods, facilities, or controls used for the manufacture, processing, packaging, or holding of the new animal drug (other than use of an establishment not covered by the approval that is in effect) that give increased assurance that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess. [55 FR 46052, Nov. 1, 1990; 55 FR 49973, Dec. 3, 1990; 56 FR 12422, Mar. 25, 1991, as amended at 71 FR 74785, Dec. 13, 2006] § 514.110 Reasons for refusing to file applications. (a) The date of receipt of an application for a new animal drug shall be the date on which the application shall be deemed to be filed. (b) An application for a new animal drug shall not be considered acceptable for filing for any of the following reasons: (1) It does not contain complete and accurate English translations of any pertinent part in a foreign language. (2) Fewer than three copies are submitted. (3) It is incomplete on its face in that it is not properly organized and indexed. (4) On its face the information concerning required matter is so inadequate that the application is clearly not approvable. (5) The new animal drug is to be manufactured, prepared, propagated, compounded, or processed in whole or in part in any State in an establishment that has not been registered or exempted from registration under the provisions of section 510 of the act. (6) The sponsor does not reside or maintain a place of business within the United States and the application has not been countersigned by an attorney, agent, or other representative of the applicant, which representative resides in the United States and has been duly authorized to act on behalf of the applicant and to receive communications on all matters pertaining to the application. (7) The new animal drug is a drug subject to licensing under the animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832; 21 U.S.C. 151 et seq. (8) It fails to include, with respect to each nonclinical laboratory study contained in the application, either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reasons for the noncompliance. (9) [Reserved] (10) The applicant fails to submit a complete environmental assessment under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.33 of this chapter. (c) If an application is determined not to be acceptable for filing, the applicant shall be notified within 30 days of receipt of the application and shall be given the reasons therefore. (d) If the applicant disputes the findings that his application is not acceptable for filing, he may make written request that the application be filed over protest, in which case it will be filed as of the day originally received. [40 FR 13825, Mar. 27, 1975, as amended at 50 FR 7517, Feb. 22, 1985; 50 FR 16668, Apr. 26, 1985; 62 FR 40600, July 29, 1997] § 514.111 Refusal to approve an application. (a) The Commissioner shall, within 180 days after the filing of the application, inform the applicant in writing of his intention to issue a notice of opportunity for a hearing on a proposal to refuse to approve the application, if the Commissioner determines upon the basis of the application, or upon the basis of other information before him with respect to a new animal drug, that: (1) The reports of investigations required to be submitted pursuant to section 512(b) of the act do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; or (2) The results of such tests show that such drug is unsafe for use under such conditions or do not show that such drug is safe for use under such conditions; or (3) The methods used in and the facilities and controls used for the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; or (4) Upon the basis of the information submitted to the Food and Drug Administration as part of the application, or upon the basis of any other information before it with respect to such drug, it has insufficient information to determine whether such drug is safe for use under such conditions. In making this determination the Commissioner shall consider, among other relevant factors: (i) The probable consumption of such drug and of any substance formed in or on food because of the use of such drug; (ii) The cumulative effect on man or animal of such drug, taking into account any chemically or pharmacologically related substances; (iii) Safety factors which, in the opinion of experts qualified by scientific training and experience to evaluate the safety of such drugs, are appropriate for the use of animal experimentation data; and (iv) Whether the conditions of use prescribed, recommended, or suggested in the proposed labeling are reasonably certain to be followed in practice; or (5) Evaluated on the basis of information submitted as part of the application and any other information before the Food and Drug Administration with respect to such drug, there is lack of substantial evidence as defined in § 514.4. (6) Failure to include an appropriate proposed tolerance for residues in edible products derived from animals or a withdrawal period or other restrictions for use of such drug if any tolerance or withdrawal period or other restrictions for use are required in order to assure that the edible products derived from animals treated with such drug will be safe. (7) Based on a fair evaluation of all material facts, the labeling is false or misleading in any particular; or (8) Such drug induces cancer when ingested by man or animal or, after appropriate tests for evaluation of the safety of such drug, induces cancer in man or animal, except that this subparagraph shall not apply with respect to such drug if the Commissioner finds that, under the conditions of use specified in proposed labeling and reasonably certain to be followed in practice: (i) Such drug will not adversely affect the animal for which it is intended; and (ii) No residue of such drug will be found (by methods of examination prescribed or approved by the Commissioner by regulations) in any edible portion of such animal after slaughter or in any food yielded by, or derived from the living animals. (9) The applicant fails to submit an adequate environmental assessment under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.33 of this chapter. (10) The drug fails to satisfy the requirements of subpart E of part 500 of this chapter. (11) Any nonclinical laboratory study that is described in the application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations as set forth in part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study. (12) The drug will be produced in whole or in part in an establishment that is not registered and not exempt from registration under section 510 of the Federal Food, Drug, and Cosmetic Act and part 207 of this chapter. (b) The Commissioner, as provided in § 514.200 of this chapter, shall expeditiously notify the applicant of an opportunity for a hearing on the question of whether such application is approvable, unless by the 30th day following the date of issuance of the letter informing the applicant of the intention to issue a notice of opportunity for a hearing the applicant: (1) Withdraws the application; or (2) Waives the opportunity for a hearing; or (3) Agrees with the Commissioner on an additional period to precede issuance of such notice of hearing. [40 FR 13825, Mar. 27, 1975, as amended at 43 FR 22675, May 26, 1978; 44 FR 16007, Mar. 16, 1979; 50 FR 7517, Feb. 22, 1985; 50 FR 16668, Apr. 26, 1985; 52 FR 49588, Dec. 31, 1987; 54 FR 18280, Apr. 28, 1989; 62 FR 40600, July 29, 1997; 63 FR 10770, Mar. 5, 1998; 64 FR 40757, July 28, 1999; 64 FR 63204, Nov. 19, 1999; 81 FR 60221, Aug. 31, 2016] § 514.115 Withdrawal of approval of applications. (a) The Secretary may suspend approval of an application approved pursuant to section 512(c) of the act and give the applicant prompt notice of his action and afford the applicant the opportunity for an expedited hearing on a finding that there is an imminent hazard to the health of man or of the animals for which such new animal drug or animal feed is intended. (b) The Commissioner shall notify in writing the person holding an application approved pursuant to section 512(c) of the act and afford an opportunity for a hearing on a proposal to withdraw approval of such application if he finds: (1) That the application contains any untrue statement of a material fact; or (2) That the applicant has made any changes from the standpoint of safety or effectiveness beyond the variations provided for in the application unless he has supplemented the application by filing with the Secretary adequate information respecting all such changes and unless there is in effect an approval of the supplemental application, or such changes are those for which written authorization or approval is not required as provided for in § 514.8. The supplemental application shall be treated in the same manner as the original application. (3) That in the case of an application for use of a new animal drug approved or deemed approved pursuant to section 512(c) of the act: (i) Experience or scientific data show that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved; or (ii) New evidence not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved or that section 512 (d)(1)(H) of the act applies to such drug; or (iii) On the basis of new information before him with respect to such drug, evaluated together with the evidence available to him when the application was approved, there is a lack of substantial evidence that such drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling thereof. (4) That any nonclinical laboratory study that is described in the application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling, was not conducted in compliance with the good laboratory practice regulations as set forth in part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study. (c) The Commissioner may notify in writing the person holding an application approved pursuant to section 512(c) of the act and afford an opportunity for a hearing on a proposal to withdraw approval of such application if he finds: (1) That the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain such records or to make required reports in accordance with a regulation or order under section 512(l)(1) of the act, or the applicant has refused to permit access to, or copying, or verification of, such records as required by section 512(l)(2) of the act; or (2) That on the basis of new information before him evaluated together with the evidence before him when the application was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of such drug or animal feed are inadequate to assure and preserve its identity, strength, quality, and purity and were not made adequate within a reasonable time after receipt of written notice from the Secretary specifying the matter complained of; or (3) That on the basis of new information before him, evaluated together with the evidence before him when the application was approved, the labeling of such drug, based on a fair evaluation of all material facts, is false or misleading in any particular and was not corrected within a reasonable time after receipt of written notice from the Secretary specifying the matter complained of. (d) Approval of an application pursuant to section 512(c) of the act will be withdrawn on the basis of a request for its withdrawal submitted in writing by a person holding an approved new animal drug application on the grounds that the drug subject to such application is no longer being marketed and information is included in support of this finding, provided none of the conditions cited in paragraphs (a), (b), and (c) of this section pertain to the subject drug. A written request for such withdrawal shall be construed as a waiver of the opportunity for a hearing as otherwise provided for in this section. Withdrawal of approval of an application under the provisions of this paragraph shall be without prejudice. (e) On the basis of the withdrawal of approval of an application for a new animal drug approved pursuant to section 512(c) of the act, the regulation published pursuant to section 512(i) of the act covering the conditions of use of such drug as provided for in the application shall be revoked. [40 FR 13825, Mar. 27, 1975, as amended at 50 FR 7517, Feb. 22, 1985; 64 FR 63204, Nov. 19, 1999] § 514.116 Notice of withdrawal of approval of application. When an approval of an application submitted pursuant to section 512 of the act is withdrawn by the Commissioner, he will give appropriate public notice of such action by publication in the Federal Register. § 514.117 Adequate and well-controlled studies. (a) Purpose. (b) Characteristics. (1) The protocol for the study (protocol) and the report of the study results (study report) must include a clear statement of the study objective(s). (2) The study is conducted in accordance with an appropriate standard of conduct that addresses, among other issues, study conduct, study personnel, study facilities, and study documentation. The protocol contains a statement acknowledging the applicability of, and intention to follow, a standard of conduct acceptable to FDA. The study report contains a statement describing adherence to the standard. (3) The study is conducted with a new animal drug that is produced in accordance with appropriate manufacturing practices, which include, but are not necessarily limited to, the manufacture, processing, packaging, holding, and labeling of the new animal drug such that the critical characteristics of identity, strength, quality, purity, and physical form of the new animal drug are known, recorded, and reproducible, to permit meaningful evaluations of and comparisons with other studies conducted with the new animal drug. The physical form of a new animal drug includes the formulation and physical characterization (including delivery systems thereof, if any) of the new animal drug as presented to the animal. The protocol and study report must include an identification number which can be correlated with the specific formulation and production process used to manufacture the new animal drug used in the study. (4) The study uses a design that permits a valid comparison with one or more controls to provide a quantitative evaluation of drug effects. The protocol and the study report must describe the precise nature of the study design, e.g., duration of treatment periods, whether treatments are parallel, sequential, or crossover, and the determination of sample size. Within the broad range of studies conducted to support a determination of the effectiveness of a new animal drug, certain of the controls listed below would be appropriate and preferred depending on the study conducted: (i) Placebo concurrent control. (ii) Untreated concurrent control. (iii) Active treatment concurrent control. (iv) Historical control. (5) The study uses a method of selecting animals that provides adequate assurances that the animals are suitable for the purposes of the study. For example, the animals can reasonably be expected to have animal production characteristics typical of the class(es) of animals for which the new animal drug is intended, there is adequate assurance that the animals have the disease or condition being studied, or, in the case of prophylactic agents, evidence of susceptibility and exposure to the condition against which prophylaxis is desired has been provided. The protocol and the study report describe the method of selecting animals for the study. (6) The study uses a method to assign a treatment or a control to each experimental unit of animals that is random and minimizes bias. Experimental units of animals are groups of animals that are comparable with respect to pertinent variables such as age, sex, class of animal, severity of disease, duration of disease, dietary regimen, level of animal production, and use of drugs or therapy other than the new animal drug. The protocol and the study report describe the method of assignment of animals to an experimental unit to account for pertinent variables and method of assignment of a treatment or a control to the experimental units. When the effect of such variables is accounted for by an appropriate design, and when, within the same animal, effects due to the test drug can be obtained free of the effects of such variables, the same animal may be used for both the test drug and the control using the controls set forth in paragraph (b)(4) of this section. (7) The study uses methods to minimize bias on the part of observers and analysts of the data that are adequate to prevent undue influences on the results and interpretation of the study data. The protocol and study report explain the methods of observation and recording of the animal response variables and document the methods, such as “blinding” or “masking,” used in the study for excluding or minimizing bias in the observations. (8) The study uses methods to assess animal response that are well defined and reliable. The protocol and study report describe the methods for conducting the study, including any appropriate analytical and statistical methods, used to collect and analyze the data resulting from the conduct of the study, describe the criteria used to assess response, and, when appropriate, justify the selection of the methods to assess animal response. (9) There is an analysis and evaluation of the results of the study in accord with the protocol adequate to assess the effects of the new animal drug. The study report evaluates the methods used to conduct, and presents and evaluates the results of, the study as to their adequacy to assess the effects of the new animal drug. This evaluation of the results of the study assesses, among other items, the comparability of treatment and control groups with respect to pertinent variables and the effects of any interim analyses performed. (c) Field studies. (2) Studies of a new animal drug conducted under field conditions shall, consistent with generally recognized scientific principles and procedures, use an appropriate control that permits comparison, employ procedures to minimize bias, and have the characteristics generally described in paragraph (b) of this section. However, because field studies are conducted under field conditions, it is recognized that the level of control over some study conditions need not or should not be the same as the level of control in laboratory studies. While not all conditions relating to a field study need to be or should be controlled, observations of the conditions under which the new animal drug is tested shall be recorded in sufficient detail to permit evaluation of the study. Adequate and well-controlled field studies shall balance the need to control study conditions with the need to observe the true effect of the new animal drug under closely approximated actual use conditions. (d) Waiver. (e) Uncontrolled studies. [63 FR 10770, Mar. 5, 1998] § 514.120 Revocation of order refusing to approve an application or suspending or withdrawing approval of an application. The Commissioner, upon his own initiative or upon request of an applicant stating reasonable grounds therefor and if he finds that the facts so require, may issue an order approving an application that previously has had its approval refused, suspended, or withdrawn. § 514.121 Service of notices and orders. All notices and orders under this subchapter E and section 512 of the act pertaining to new animal drug applications shall be served: (a) In person by any officer or employee of the Department designated by the Commissioner; or (b) By mailing the order by certified mail addressed to the applicant or respondent at his last known address in the records of the Food and Drug Administration. Subpart C—Hearing Procedures § 514.200 Notice of opportunity for hearing; notice of participation and requests for hearing; grant or denial of hearing. (a) The notice to the applicant of opportunity for a hearing on a proposal by the Commissioner to refuse to approve an application or to withdraw the approval of an application will be published in the Federal Register (b) If the applicant fails to request a hearing within the 30-day timeframe, the Commissioner, without further notice, will publish a final order denying or withdrawing approval of the application. (c) If the applicant desires to request a hearing: (1) Within 30 days after publication of the notice of opportunity for hearing, the applicant must submit to the Dockets Management Staff written objections and a request for a hearing in accordance with §§ 12.20 and 12.22. This request for a hearing must include each specific objection to the proposal on which a hearing is requested, together with a detailed description and analysis of the factual information (including all relevant clinical and other investigational data) the applicant will present in support of that objection. A request for a hearing may not rest upon mere allegations or denials or general descriptions of positions or contentions, but must set forth specific reliable evidence showing there is a genuine and substantial issue of fact that requires a hearing. (2) If the Commissioner determines upon review of the data and information submitted in the objections and request for a hearing that a hearing is not justified because no genuine and substantial issue of fact precludes the refusal to approve the application or the withdrawal of approval of the application (for example, the applicant has not identified any adequate and well-controlled clinical investigations to support the claims of effectiveness), the Commissioner will enter an order denying the hearing and stating the final findings and conclusions. (3) If the Commissioner determines upon review of the data and information submitted in the objections and request for a hearing that a hearing is justified, the Commissioner will publish a notice setting forth the following: (i) The regulation or order that is the subject of the hearing; (ii) A statement specifying any part of the regulation or order that has been stayed by operation of law or in the Commissioner's discretion; (iii) The parties to the hearing; (iv) The specific issues of fact for resolution at the hearing; (v) The presiding officer, or a statement that the presiding officer will be designated in a later notice; and (vi) The date, time, and place of the prehearing conference, or a statement that the date, time, and place will be announced in a later notice. However, in the case of a denial of approval, the hearing must not occur more than 90 days after expiration of the 30-day time period in which to request a hearing, unless the presiding officer and the applicant otherwise agree; and in the case of withdrawal of approval, the hearing will occur as soon as practicable. (d) The hearing will be open to the public; however, if the Commissioner finds that portions of the application which serve as a basis for the hearing contain information concerning a method or process entitled to protection as a trade secret, the part of the hearing involving such portions will not be public, unless the respondent so specifies in the request for a hearing. [81 FR 52997, Aug. 11, 2016, as amended 88 FR 45066, July 14, 2023] § 514.201 Procedures for hearings. Hearings relating to new animal drugs under section 512(d) and (e) of the act shall be governed by part 12 of this chapter. [64 FR 63204, Nov. 19, 1999] Subparts D-E [Reserved] Subpart F—Judicial Review § 514.235 Judicial review. (a) The transcript and record shall be certified by the Commissioner. In any case in which the Commissioner enters an order without a hearing pursuant to § 314.200(g) of this chapter, the request(s) for hearing together with the data and information submitted and the Commissioner's findings and conclusions shall be included in the record certified by the Commissioner. (b) Judicial review of an order withdrawing approval of a new drug application, whether or not a hearing has been held, may be sought by a manufacturer or distributor of an identical, related, or similar drug product, as defined in § 310.6 of this chapter, in a United States court of appeals pursuant to section 505(h) of the act. [42 FR 4717, Jan. 25, 1977]

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