21 CFR - § 514.1-514.235 - New Animal Drugs Application

90 21 CFR Ch. I (4–1–23 Edition) § 511.3 new animal drugs for investigational use in support of indexing, as described in section 572 of the act, subject to the provisions of § 516.125 of this chapter. [40 FR 13823, Mar. 27, 1975, as amended at 41 FR 48268, Nov. 2, 1976; 42 FR 15675, Mar. 22, 1977; 50 FR 7517, Feb. 22, 1985; 50 FR 16668, Apr. 26, 1985; 52 FR 8847, Mar. 19, 1987; 54 FR 18280, Apr. 28, 1989; 57 FR 6475, Feb. 25, 1992; 62 FR 40599, July 29, 1997; 72 FR 69121, Dec. 6, 2007; 77 FR 25359, Apr. 30, 2012; 82 FR 61446, Dec. 28, 2017] § 511.3 Definitions. As used in this part: Contract research organization means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evalua tion of reports, and preparation of ma terials to be submitted to the Food and Drug Administration. Investigator means an individual who actually conducts a clinical investiga tion (i.e., under whose immediate di rection the drug is administered or dis pensed to a subject). In the event an in vestigation is conducted by a team of individuals, the investigator is the re sponsible leader of the team. ‘‘Sub investigator’’ includes any other indi vidual member of that team. Sponsor means a person who takes re sponsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic insti tution, private organization, or other organization. The sponsor does not ac tually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-in vestigator, and the employees are in vestigators. Sponsor-Investigator means an indi vidual who both initiates and conducts an investigation, and under whose im mediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those ap plicable to an investigator and a spon sor. [77 FR 25359, Apr. 30, 2012] PART 514—NEW ANIMAL DRUG APPLICATIONS Subpart A—General Provisions Sec. 514.1 Applications. 514.3 Definitions. 514.4 Substantial evidence. 514.5 Presubmission conferences. 514.6 Amended applications. 514.7 Withdrawal of applications without prejudice. 514.8 Supplements and other changes to an approved application. 514.11 Confidentiality of data and informa tion in a new animal drug application file. 514.12 Confidentiality of data and informa tion in an investigational new animal drug notice. 514.15 Untrue statements in applications. Subpart B—Administrative Actions on Applications 514.80 Records and reports concerning expe rience with approved new animal drugs. 514.87 Annual reports for antimicrobial ani mal drug sales and distribution. 514.100 Evaluation and comment on applica tions. 514.105 Approval of applications. 514.106 Approval of supplemental applica tions. 514.110 Reasons for refusing to file applica tions. 514.111 Refusal to approve an application. 514.115 Withdrawal of approval of applica tions. 514.116 Notice of withdrawal of approval of application. 514.117 Adequate and well-controlled stud ies. 514.120 Revocation of order refusing to ap prove an application or suspending or withdrawing approval of an application. 514.121 Service of notices and orders. Subpart C—Hearing Procedures 514.200 Notice of opportunity for hearing; notice of participation and requests for hearing; grant or denial of hearing. 514.201 Procedures for hearings. Subparts D–E [Reserved] Subpart F—Judicial Review 514.235 Judicial review. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00100 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 91 Food and Drug Administration, HHS § 514.1 AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 354, 356a, 360b, 360ccc, 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 sec tion 512(b) of the act shall be submitted in the form and contain the informa tion described in paragraph (b) of this section, as appropriate to support the particular submission. If any part of the application is in a foreign lan guage, 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 au thorized attorney, agent, or official. If the applicant or such authorized rep resentative does not reside or have a place of business within the United States, the application must also fur nish the name and post office address of, and must be countersigned by, an authorized attorney, agent, or official residing or maintaining a place of busi ness within the United States. Perti nent information may be incorporated in, and will be considered as part of, an application on the basis of specific ref erence to such information, including information submitted under the provi sions of § 511.1 of this chapter, in the files of the Food and Drug Administra tion; 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. (b) Applications for new animal drugs shall be submitted in triplicate and as sembled in the manner prescribed by paragraph (b)(15) of this section, and shall include the following informa tion, as appropriate to support the par ticular submission: (1) Identification. Whether the submis sion is an original or supplemental ap plication; the name and the address of the applicant; the date of the applica tion; the trade name(s) (if one has been proposed) and chemical name(s) of the new animal drug. Upon receipt, the ap plication will be assigned a number NADA , which shall be used for all correspondence with respect to the ap plication. (2) Table of contents and summary. The application shall be organized in a co hesive fashion, shall contain a table of contents which identifies the data and other material submitted, and shall contain a well-organized summary and evaluation of the data in the following form: (i) Chemistry: (a) Chemical structural formula or description for any new animal drug substance. (b) Relationship to other chemically or pharmacologically related drugs. (c) Description of dosage form and quantitative composition. (ii) Scientific rationale and purpose the new animal drug is to serve: (a) Clinical purpose. (b) Highlights of laboratory studies: The reasons why certain types of stud ies were done or omitted as related to the proposed conditions of use and to information already known about this class of compounds. Emphasize any un usual or particularly significant phar macological effects or toxicological findings. (c) Highlights of clinical studies: The rationale of the clinical study plan showing why types of studies were done, amended, or omitted as related to laboratory studies and prior clinical experience. (d) Conclusions: A short statement of conclusions combining the major points of effectiveness and safety as they relate to the use of the new ani mal drug. (3) Labeling. Three copies of each piece of all labeling to be used for the article (total of 9). (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. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00101 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 92 21 CFR Ch. I (4–1–23 Edition) § 514.1 (iii) Labeling for prescription veteri nary drugs should bear adequate infor mation for use under which veterinar ians can use the new animal drug safe ly and for the purposes for which it is intended, including those purposes for which it is to be advertised or rep resented, 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 conspicu ously displayed. (v) Labeling for new animal drugs in tended for use in the manufacture of medicated feeds shall include: (a) Specimens of labeling to be used for such new animal drug with ade quate directions for the manufacture and use of finished feeds for all condi tions for which the new animal drug is intended, recommended, or suggested in any of the labeling, including adver tising, sponsored by the applicant. In gredient labeling may utilize collective names as provided in § 501.110 of this chapter. (b) Representative labeling proposed to be used for Type B and Type C medi cated feeds containing the new animal drug. (vi) Draft labeling may be submitted for preliminary consideration of an ap plication. 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. A complete list of all articles used for production of the new animal drug in cluding a full list of the composition of each article: (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 prepara tion of the finished dosage form, re gardless 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 propri etary name is used, it should be fol lowed by a complete quantitative statement of composition. Reasonable alternatives for any listed component may be specified. (ii) A full statement of the composi tion of the new animal drug. The state ment shall set forth the name and amount of each ingredient, whether ac tive or not, contained in a stated quan tity of the new animal drug in the form in which it is to be distributed (for ex ample, amount per tablet or milliliter) and a batch formula representative of that to be employed for the manufac ture 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 pro duced by fermentation: (a) Source and type of microorganism used to produce the new animal drug. (b) Composition of media used to produce the new animal drug. (c) Type of precursor used, if any, to guide or enhance production of the an tibiotic during fermentation. (d) Name and composition of preserv ative, if any, used in the broth. (e) A complete description of the ex traction and purification processes in cluding the names and compositions of the solvents, precipitants, ion ex change resins, emulsifiers, and all other agents used. (f) If the new animal drug is produced by a catalytic hydrogenation process (such as tetracycline from chlortetra cycline), a complete description of each chemical reaction with graphic for mulas used to produce the new animal drug, including the names of the cata lyst used, how it is removed, and how the new animal drug is extracted and purified. (5) Manufacturing methods, facilities, and controls. A full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of the new ani mal drug. This description should in clude full information with respect to VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00102 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 93 Food and Drug Administration, HHS ยง 514.1 any new animal drug in sufficient de tail to permit evaluation of the ade quacy of the described methods of man ufacture, processing, and packing, and the described facilities and controls to determine and preserve the identity, strength, quality, and purity of the new animal drug, and the following: (i) If the applicant does not himself perform all the manufacturing, proc essing, 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 per son fully describing, directly or by ref erence, 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 ยง 514.8. (ii) A description of the qualifica tions, including educational back ground and experience, of the technical and professional personnel who are re sponsible for assuring that the new ani mal 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 fa cilities including building and equip ment used in manufacturing, proc essing, packaging, labeling, storage, and control operations. (iv) The methods used in the syn thesis, extraction, isolation, or purifi cation of any new animal drug. When the specifications and controls applied to such new animal drugs are inad equate in themselves to determine its identity, strength, quality, and purity, the methods should be described in suf ficient detail, including quantities used, times, temperature, pH, solvents, etc., to determine these characteris tics. Alternative methods or variations in methods within reasonable limits that do not affect such characteristics of the new animal drug may be speci fied. A flow sheet and indicated equa tions should be submitted when needed to explain the process. (v) Precautions to insure proper iden tity, strength, quality, and purity of the raw materials, whether active or not, including: (a) The specifications for acceptance and methods of testing for each lot of raw material. (b) A statement as to whether or not each lot of raw materials is given a se rial number to identify it, and the use made of such numbers in subsequent plant operations. (vi) The instructions used in the manufacturing, processing, packaging, and labeling of each dosage form of the new animal drug, including: (a) The method of preparation of the master formula records and individual batch records and the manner in which these records are used. (b) The number of individuals check ing weight or volume of each indi vidual ingredient entering into each batch of the new animal drug. (c) A statement as to whether or not the total weight or volume of each batch is determined at any stage of the manufacturing process subsequent to making up a batch according to the formula card and, if so, at what stage and by whom it is done. (d) The precautions used in checking the actual package yield produced from a batch of the new animal drug with the theoretical yield. This should in clude a description of the accounting for such items as discards, breakage, etc., and the criteria used in accepting or rejecting batches of drugs in the event of an unexplained discrepancy. (e) The precautions used to assure that each lot of the new animal drug is packaged with the proper label and la beling, including provisions for label ing storage and inventory control. (f) Any special precautions used in the operations. (vii) The analytical controls used during the various stages of the manu facturing, processing, packaging, and labeling of the new animal drug, in cluding a detailed description of the collection of samples and the analyt ical procedures to which they are sub jected. 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) A description of practicable meth ods of analysis of adequate sensitivity VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00103 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 94 21 CFR Ch. I (4–1–23 Edition) § 514.1 to determine the amount of the new animal drug in the final dosage form should be included. The dosage form may be a finished pharmaceutical prod uct, a Type A medicated article, a Type B or a Type C medicated feed, or a product for use in animal drinking water. Where two or more active ingre dients are included, methods should be quantitative and specific for each ac tive ingredient. (b) If the article is one that is rep resented to be sterile, the same infor mation with regard to the manufac turing, processing, packaging, and the collection of samples of the drug should be given for sterility controls. Include the standards used for accept ance of each lot of the finished drug. (viii) An explanation of the exact sig nificance of any batch control numbers used in the manufacturing, processing, packaging, and labeling of the new ani mal drug, including such control num bers 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 re spect to the characteristics of and the test methods employed for the con tainer, 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 sta bility of the new animal drug in the final dosage form, including informa tion showing the suitability of the ana lytical methods used. A description of any additional stability studies under way 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 dis pensing, for the solution prepared as directed. If the new animal drug is in tended for use in the manufacture of Type C medicated feed as defined in § 558.3 of this chapter, stability data de rived from studies in which representa tive 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 Ad ministration 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 medi cated feeds, the applicant shall justify its absence with data. (xi) Additional procedures employed which are designed to prevent contami nation and otherwise assure proper control of the product. An application may be refused unless it includes ade quate 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 pu rity in conformity with good manufac turing practice and identifies each es tablishment, showing the location of the plant conducting these operations. (6) Samples. Samples of the new ani mal drug and articles used as compo nents and information concerning them may be requested by the Center for Veterinary Medicine as follows: (i) Each sample shall consist of four identical, separately packaged subdivi sions, each containing at least three times the amount required to perform the laboratory test procedures de scribed in the application to determine compliance with its control specifica tions for identity and assays. Each of the samples submitted shall be appro priately packaged and labeled to pre serve its characteristics, to identify the material and the quantity in each subdivision of the sample, and to iden tify each subdivision with the name of the applicant and the new animal drug application to which it relates. In cluded are: (a) A sample or samples of any ref erence standard and blank used in the procedures described in the application for assaying each new animal drug and other assayed components of the fin ished new animal drug. (b) A representative sample or sam ples of each strength of the finished VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00104 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 95 Food and Drug Administration, HHS § 514.1 dosage form proposed in the applica tion and employed in the clinical in vestigations and a representative sam ple or samples of each new animal drug from the batch(es) employed in the production of such dosage form. (c) A representative sample or sam ples of finished market packages of each strength of the dosage form of the new animal drug prepared for initial marketing and, if any such sample is not from a representative commercial scale production batch, such a sample from a representative commercial scale production batch, and a rep resentative sample or samples of each new animal drug from the batch(es) employed in the production of such dosage form, provided that in the case of new animal drugs marketed in large packages the sample should contain only three times a sufficient quantity of the new animal drug to allow for performing the control tests for drug identity and assays. (ii) The following information shall be included for the samples when re quested: (a) For each sample submitted, full information regarding its identity and the origin of any new animal drug con tained therein (including a statement whether it was produced on a labora tory, pilot-plant, or full-production scale) and detailed results of all labora tory tests made to determine the iden tity, strength, quality, and purity of the batch represented by the sample, including assays. (b) For any reference standard sub mitted, a complete description of its preparation and the results of all lab oratory tests on it. If the test methods used differed from those described in the application, full details of the methods employed in obtaining the re porting results. (7) Analytical methods for residues. Ap plications shall include a description of practicable methods for determining the quantity, if any, of the new animal drug in or on food, and any substance formed in or on food because of its use, and the proposed tolerance or with drawal period or other use restrictions to ensure that the proposed use of this drug will be safe. When data or other adequate information establish that it is not reasonable to expect the new animal drug to become a component of food at concentrations considered un safe, a regulatory method is not re quired. (i) The kind of information required by this subdivision may include: Com plete experimental protocols for deter mining drug residue levels in the edible products, and the length of time re quired 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 estab lish a disappearance curve; if the drug is to be used in combination with other drugs, possible effects of interaction demonstrated by the appropriate dis appearance curve or depletion patterns after drug withdrawal under appro priate (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 perform ance data in the treated animal; if the drug is to be used in more than one species, drug residue studies or appro priate 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 de termined 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 deter mined in blood where feasible. Samples may be combined where necessary. Where residues are suspected or known to be present in litter from treated ani mals, it may be necessary to include data with respect to such residues be coming components of other agricul tural commodities because of use of lit ter from treated animals. (ii) A new animal drug that has the potential to contaminate human food VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00105 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 96 21 CFR Ch. I (4–1–23 Edition) § 514.1 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 ef fectiveness. (i) An application may be refused unless it contains full reports of adequate tests by all methods rea sonably applicable to show whether or not the new animal drug is safe and ef fective for use as suggested in the pro posed labeling. (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 ob tained are clearly set forth of acute, subacute, and chronic toxicity, and un less it contains appropriate clinical laboratory results related to safety and efficacy. Such information should in clude identification of the person who conducted each investigation, a state ment 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 effective ness 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 favor able 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. In clude any evaluation of the safety or effectiveness of the new animal drug that has been made by the applicant’s veterinary or medical department, ex pert committee, or consultants. (v) If the new animal drug is a com bination of active ingredients or ani mal drugs, an application may be re fused unless it includes substantial evi dence of the effectiveness of the com bination new animal drug as required in § 514.4. (vi) An application shall include a complete list of the names and post of fice addresses of all investigators who received the new animal drug. This may be incorporated in whole or in part by reference to information sub mitted under the provisions of § 511.1 of this chapter. (vii) Explain any omission of reports from any investigator to whom the in vestigational new animal drug has been made available. The unexplained omis sion of any reports of investigations made with the new animal drug by the applicant or submitted to him by an in vestigator or the unexplained omission of any pertinent reports of investiga tions 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 clin ical study to a contract research orga nization, the application is required to include a statement containing the name and address of the contract re search organization, identifying the clinical study, and listing the obliga tions transferred. If all obligations gov erning 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 au dited or reviewed. (9) Veterinary feed directive. Three copies of a veterinary feed directive (VFD) must be submitted in a form that accounts for the information de scribed under § 558.6(b)(3) and 558.6(b)(4) of this chapter. (10) Supplemental applications. If it is a supplemental application, full infor mation shall be submitted on each pro posed change concerning any state ment made in the approved applica tion. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00106 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 97 Food and Drug Administration, HHS § 514.1 (11) Applicant’s commitment. It is un derstood that the labeling and adver tising for the new animal drug will pre scribe, recommend, or suggest its use only under the conditions stated in the labeling which is part of this applica tion and if the article is a prescription new animal drug, it is understood that any labeling which furnishes or pur ports to furnish information for use or which prescribes, recommends, or sug gests a dosage for use of the new ani mal drug will also contain, in the same language and emphasis, information for its use including indications, ef fects, dosages, routes, methods, and frequency and duration of administra tion, any relevant hazards, contra indications, side effects, and pre cautions contained in the labeling which is part of this application. It is understood that all representations in this application apply to the drug pro duced until changes are made in con formity with § 514.8. (12) Additional commitments. (i) New animal drugs as defined in § 510.3 of this chapter, intended for use in the manu facture of animal feeds in any State will be shipped only to persons who may receive such drugs in accordance with § 510.7 of this chapter. (ii) The methods, facilities, and con trols described under item 5 of this ap plication 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 ap plication, either a statement that the study was conducted in compliance with the good laboratory practice regu lations set forth in part 58 of this chap ter, 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. The ap plicant is required to submit either a claim for categorical exclusion under § 25.30 or § 25.33 of this chapter or an en vironmental assessment under § 25.40 of this chapter. (15) Assembling and binding the appli cation. Assemble and bind an original and two copies of the application as follows: (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 applica tion 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 sequen tial in each volume or continuous and sequential throughout the application. (v) Include complete labeling in each of the copies. It is suggested that label ing 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 ap plication information applicable to the specific dosage form, such as labeling, composition, stability data, and meth od of manufacture. (vii) Submit in folders amendments, supplements, and other correspondence sent after submission of an original ap plication. The front cover of these sub missions 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 applica tion is submitted for a new animal drug which has a stimulant, depres sant, 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 ci tations affecting § 514.1, see the List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and at www.govinfo.gov. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00107 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 98 21 CFR Ch. I (4–1–23 Edition) § 514.3 § 514.3 Definitions. The definition and interpretation of terms contained in this section apply to those terms as used throughout sub chapter E. Adverse drug experience is any adverse event associated with the use of a new animal drug, whether or not considered to be drug related, and whether or not the new animal drug was used in ac cordance with the approved labeling (i.e., used according to label directions or used in an extralabel manner, in cluding but not limited to different route of administration, different spe cies, different indications, or other than labeled dosage). Adverse drug ex perience includes, but is not limited to: (1) An adverse event occurring in ani mals in the course of the use of an ani mal drug product by a veterinarian or by a livestock producer or other ani mal owner or caretaker. (2) Failure of a new animal drug to produce its expected pharmacological or clinical effect (lack of expected ef fectiveness). (3) An adverse event occurring in hu mans from exposure during manufac ture, testing, handling, or use of a new animal drug. ANADA is an abbreviated new animal drug application including all amend ments and supplements. Applicant is a person or entity who owns or holds on behalf of the owner the approval for an NADA or an ANADA, and is responsible for compli ance with applicable provisions of the act and regulations. Increased frequency of adverse drug ex perience is an increased rate of occur rence of a particular serious adverse drug event, expected or unexpected, after appropriate adjustment for drug exposure. NADA is a new animal drug applica tion including all amendments and sup plements. Nonapplicant is any person other than the applicant whose name appears on the label and who is engaged in manu facturing, packing, distribution, or la beling of the product. Potential applicant means any person: (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 supple mental 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 means one or more conferences between a potential applicant and FDA to reach a binding agreement establishing a submission or investigational requirement. Presubmission conference agreement means that section of the memo randum of conference headed ‘‘Pre submission Conference Agreement’’ that records any agreement on the sub mission or investigational requirement reached by a potential applicant and FDA during the presubmission con ference. Product defect/manufacturing defect is the deviation of a distributed product from the standards specified in the ap proved application, or any significant chemical, physical, or other change, or deterioration in the distributed drug product, including any microbial or chemical contamination. A manufac turing defect is a product defect caused or aggravated by a manufacturing or related process. A manufacturing de fect may occur from a single event or from deficiencies inherent to the man ufacturing process. These defects are generally associated with product con tamination, product deterioration, manufacturing error, defective pack aging, damage from disaster, or label ing error. For example, a labeling error may include any incident that causes a distributed product to be mistaken for, or its labeling applied to, another prod uct. Serious adverse drug experience is an adverse event that is fatal, or life threatening, or requires professional intervention, or causes an abortion, or stillbirth, or infertility, or congenital anomaly, or prolonged or permanent disability, or disfigurement. Unexpected adverse drug experience is an adverse event that is not listed in the current labeling for the new animal drug and includes any event that may be symptomatically and pathophysiologically related to an VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00108 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 99 Food and Drug Administration, HHS § 514.4 event listed on the labeling, but differs from the event because of greater se verity or specificity. For example, under this definition hepatic necrosis would be unexpected if the labeling re ferred only to elevated hepatic en zymes or hepatitis. [68 FR 15365, Mar. 31, 2003, as amended at 69 FR 51170, Aug. 18, 2004] § 514.4 Substantial evidence. (a) Definition of substantial evidence. Substantial evidence means evidence consisting of one or more adequate and well-controlled studies, such as a study in a target species, study in laboratory animals, field study, bioequivalence study, or an in vitro study, on the basis of which it could fairly and reasonably be concluded by experts qualified by scientific training and experience to evaluate the effectiveness of the new animal drug involved that the new ani mal drug will have the effect it pur ports or is represented to have under the conditions of use prescribed, rec ommended, or suggested in the labeling or proposed labeling thereof. Substan tial evidence shall include such ade quate and well-controlled studies that are, as a matter of sound scientific judgment, necessary to establish that a new animal drug will have its intended effect. (b) Characteristics of substantial evi dence—(1) Qualifications of experts. Any study that is intended to be part of substantial evidence of the effective ness of a new animal drug shall be con ducted by experts qualified by sci entific training and experience. (2) Intended uses and conditions of use. Substantial evidence of effectiveness of a new animal drug shall demonstrate that the new animal drug is effective for each intended use and associated conditions of use for and under which approval is sought. (i) Dose range labeling. Sponsors should, to the extent possible, provide for a dose range because it increases the utility of the new animal drug by providing the user flexibility in the se lection of a safe and effective dose. In general, substantial evidence to sup port dose range labeling for a new ani mal drug intended for use in the diag nosis, cure, mitigation, treatment, or prevention of disease must consist of at least one adequate and well-controlled study on the basis of which qualified experts could fairly and reasonably conclude that the new animal drug will be effective for the intended use at the lowest dose of the dose range suggested in the proposed labeling for that in tended use. Substantial evidence to support dose range labeling for a new animal drug intended to affect the structure or function of the body of an animal generally must consist of at least one adequate and well-controlled study on the basis of which qualified experts could fairly and reasonably conclude that the new animal drug will be effective for the intended use at all doses within the range suggested in the proposed labeling for the intended use. (ii) [Reserved] (3) Studies—(i) Number. Substantial evidence of the effectiveness of a new animal drug for each intended use and associated conditions of use shall con sist of a sufficient number of current adequate and well-controlled studies of sufficient quality and persuasiveness to permit qualified experts: (A) To determine that the param eters selected for measurement and the measured responses reliably reflect the effectiveness of the new animal drug; (B) To determine that the results ob tained 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, rec ommended, or suggested in the pro posed labeling. (ii) Types. Adequate and well-con trolled studies that are intended to provide substantial evidence of the ef fectiveness of a new animal drug may include, but are not limited to, pub lished studies, foreign studies, studies using models, and studies conducted by or on behalf of the sponsor. Studies using models shall be validated to es tablish an adequate relationship of pa rameters measured and effects ob served in the model with one or more significant effects of treatment. (c) Substantial evidence for combination new animal drugs—(1) Definitions. The following definitions of terms apply to this section: VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00109 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 100 21 CFR Ch. I (4–1–23 Edition) § 514.4 (i) Combination new animal drug means a new animal drug that contains more than one active ingredient or ani mal drug that is applied or adminis tered simultaneously in a single dosage form or simultaneously in or on animal feed or drinking water. (ii) Dosage form combination new ani mal drug means a combination new ani mal drug intended for use other than in animal feed or drinking water. (iii) Antibacterial with respect to a particular target animal species means an active ingredient or animal drug: That is approved in that species for the diagnosis, cure, mitigation, treatment, or prevention of bacterial disease; or that is approved for use in that species for any other use that is attributable to its antibacterial properties. But, antibacterial does not include ionophores or arsenicals intended for use in combination in animal feed or drinking water. (iv) Appropriate concurrent use exists when there is credible evidence that the conditions for which the combina tion new animal drug is intended can occur simultaneously. (2) Combination new animal drugs that contain only active ingredients or animal drugs that have previously been sepa rately approved. (i) For dosage form combination new animal drugs, except for those that contain a nontopical antibacterial, 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, a sponsor shall dem onstrate: (A) By substantial evidence, as de fined 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 com bination 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 appro priate 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 regi mens if FDA, based on scientific infor mation, has reason to believe the ac tive ingredients or animal drugs are physically incompatible or have dis parate dosing regimens. (ii) For combination new animal drugs intended for use in animal feed or drinking water that contain only ac tive ingredients or animal drugs that have previously been separately ap proved for the particular uses and con ditions of use for which they are in tended in combination, the sponsor shall demonstrate: (A) By substantial evidence, as de fined 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 com bination makes a contribution to the effectiveness of the combination new animal drug; (B) For such combination new animal drugs that contain more than one anti bacterial 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 ac tive ingredients or animal drugs used in the combination provides appro priate concurrent use for the intended target animal population; and (D) That the active ingredients or animal drugs intended for use in drink ing water are physically compatible if FDA, based on scientific information, has reason to believe the active ingre dients or animal drugs are physically incompatible. (3) Other combination new animal drugs. For all other combination new animal drugs, the sponsor shall dem onstrate by substantial evidence, as de fined in this section, that the combina tion new animal drug will have the ef fect it purports or is represented to have under the conditions of use pre scribed, recommended, or suggested in the proposed labeling and that each ac tive ingredient or animal drug contrib utes to the effectiveness of the com bination new animal drug. [64 FR 40756, July 28, 1999] VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00110 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 101 Food and Drug Administration, HHS § 514.5 § 514.5 Presubmission conferences. (a) General principle underlying the conduct of a presubmission conference. The general principle underlying the conduct of any presubmission con ference is that there should be candid, full, and open communication. (b) Requesting a presubmission con ference. A potential applicant is enti tled to one or more conferences prior to the submission of an NADA, supple mental NADA, or an ANADA to reach an agreement establishing part or all of a submission or investigational re quirement. A potential applicant’s re quest for a presubmission conference must be submitted to FDA in a signed letter. The letter must include a pro posed agenda that clearly outlines the scope, purpose, and objectives of the presubmission conference and must list the names and positions of the rep resentatives who are expected to at tend the presubmission conference on behalf of the applicant. (c) Timing. A potential applicant may request one or more presubmission con ferences at any time prior to the filing of a NADA, supplemental NADA, or an ANADA. A request for a presubmission conference must be received by FDA at least 30 calendar days in advance of the requested conference date. FDA will schedule the presubmission conference at a time agreeable to both FDA and the potential applicant. (d) Advance information. The potential applicant must provide to FDA, at least 30 calendar days before a sched uled presubmission conference, a de tailed agenda, a copy of any materials to be presented at the conference, a list of proposed indications and, if avail able, a copy of the proposed labeling for the product under consideration, and copies of materials evaluated or referenced relative to issues listed in the agenda for the conference. If the materials are not provided or are not sufficient to provide the basis for meaningful discussion, FDA may elect to postpone part or all of the meeting until sufficient materials are provided to FDA. (e) Conduct of a presubmission con ference. The potential applicant and FDA may each bring consultants to the presubmission conference. The pre submission conference(s) will be di rected primarily at establishing agree ment between FDA and the potential applicant regarding a submission or in vestigational requirement. The submis sion or investigational requirement may include, among other things, the number, types, and general design of studies that are necessary to dem onstrate the safety and effectiveness of a new animal drug for the intended uses and conditions of use prescribed, recommended, or suggested in the pro posed labeling for the new animal drug. (f) Documentation of a presubmission conference—(1) Memorandum of con ference—(i) Preparation. FDA will pre pare a memorandum for each pre submission conference that will in clude, among other things, any back ground pertinent to the request for meeting; a summary of the key points of discussion; agreements; and action items and assignments of responsi bility. That portion of the memo randum of conference that documents any agreements reached regarding all or part of a submission or investiga tional requirement will be included under the heading ‘‘Presubmission Con ference Agreement.’’ If the pre submission conference agreement sec tion of the memorandum is silent on an issue, including one that was discussed in the conference or addressed by mate rials provided for the conference, such silence does not constitute agreement between FDA and the potential appli cant on the issue. (ii) Sending a copy to the potential ap plicant. FDA will send a copy of the memorandum to the potential appli cant for review no later than 45 cal endar days after the date of the con ference (iii) Requests for changes or clarifica tion. If a potential applicant requests changes to, or clarification of, the sub stance of the memorandum, the re quest must be sent to FDA within 30 calendar days from the date a copy of the memorandum is sent to the appli cant. If the potential applicant re quests changes or clarification, FDA will send the potential applicant a re sponse to their request no later than 45 calendar days after the date of receipt of the request. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00111 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 102 21 CFR Ch. I (4–1–23 Edition) § 514.6 (iv) Administrative record. A copy of FDA’s original memorandum of con ference and, as appropriate, a copy of an amended memorandum to correct or clarify the content of the original memorandum will be made part of the administrative file. (2) Field studies. If FDA requires more than one field study to establish by substantial evidence that the new ani mal drug is effective for its intended uses under the conditions of use pre scribed, recommended, or suggested in the proposed labeling, FDA will provide written scientific justification for re quiring more than one field study. Such justification must be provided no later than 25 calendar days after the date of the conference at which the re quirement for more than one field study is established. If FDA does not believe more than one field study is re quired but the potential applicant vol untarily proposes to conduct more than one field study, FDA will not pro vide such written justification. If FDA requires one field study to be con ducted at multiple locations, FDA will provide justification for requiring mul tiple locations verbally during the pre submission conference and in writing as part of the memorandum of con ference. (g) Modification of presubmission con ference agreements. An agreement made under a presubmission conference re quested under section 512(b)(3) of the act and documented in a memorandum of conference is binding on the poten tial applicant and FDA and may only be modified if: (1) FDA and the potential applicant mutually agree to modify, in part or in whole, the agreement and such modi fication 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 require ment essential to the determination of safety or effectiveness of the new ani mal drug appeared after the con ference. (h) When the terms of a presubmission conference agreement are not valid. (1) A presubmission conference agreement will no longer be valid if: (i) The potential applicant makes to FDA, before, during, or after the pre submission conference, any untrue statement of material fact; or (ii) The potential applicant fails to follow any material term of the agree ment; and (2) A presubmission conference may no longer be valid if the potential ap plicant submits false or misleading data relating to a new animal drug to FDA. (i) Dispute resolution. FDA is com mitted to resolving differences between a potential applicant and FDA review ing divisions with respect to require ments for the investigation of new ani mal drugs and for NADAs, supple mental NADAs, and ANADAs as quick ly and amicably as possible through a cooperative exchange of information and views. When administrative or pro cedural disputes arise, a potential ap plicant should first attempt to resolve the matter within the appropriate re view division beginning with the indi vidual(s) most directly assigned to the review of the application or investiga tional exemption. If the dispute cannot be resolved after such attempts, the dispute shall be evaluated and adminis tered in accordance with applicable regulations (21 CFR 10.75). Dispute res olution procedures may be further ex plained by guidance available from the Center for Veterinary Medicine. [69 FR 51170, Aug. 18, 2004] § 514.6 Amended applications. The applicant may submit an amend ment to an application that is pending, including changes that may alter the conditions of use, the labeling, safety, effectiveness, identity, strength, qual ity, or purity of the drug or the ade quacy of the manufacturing methods, facilities, and controls to preserve them, in which case the unamended ap plication may be considered as with drawn and the amended application may be considered resubmitted on the date on which the amendment is re ceived by the Food and Drug Adminis tration. The applicant will be notified of such date. § 514.7 Withdrawal of applications without prejudice. The sponsor may withdraw his pend ing application from consideration as a VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00112 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 103 Food and Drug Administration, HHS § 514.8 new animal drug application upon writ ten 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 re tained by the Food and Drug Adminis tration although it is considered with drawn. The applicant shall be furnished a copy at cost on request. § 514.8 Supplements and other changes to an approved application. (a) Definitions. (1) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cos metic Act (the act) apply to those terms when used in this part. (2) The following definitions of terms apply to this part: (i) Assess the effects of the change means to evaluate the effects of a man ufacturing change on the identity, strength, quality, purity, and potency of a drug as these factors may relate to the safety or effectiveness of the drug. (ii) Drug substance means an active ingredient as defined under § 210.3(b)(7) of this chapter. (iii) Minor changes and stability report (MCSR) means an annual report that is submitted to the application once each year within 60 days before or after the anniversary date of the application’s original approval or on a mutually agreed upon date. The report must in clude minor manufacturing and control changes made according to § 514.8(b)(4) or state that no changes were made; and stability data generated on com mercial or production batches accord ing to an approved stability protocol or commitment. (iv) Specification means the quality standard (i.e., tests, analytical proce dures, and acceptance criteria) pro vided in an approved application to confirm the quality of drugs including, for example, drug substances, Type A medicated articles, drug products, intermediates, raw materials, reagents, components, in-process materials, con tainer closure systems, and other ma terials used in the production of a drug. For the purpose of this defini tion, the term ‘‘acceptance criteria’’ means numerical limits, ranges, or other criteria for the tests described. (b) Manufacturing changes to an ap proved application—(1) General provi sions. (i) The applicant must notify FDA about each change in each condi tion established in an approved appli cation beyond the variations already provided for in the application. The no tice is required to describe the change fully. Depending on the type of change, the applicant must notify FDA about it in a supplement under paragraph (b)(2) or (b)(3) of this section or by inclusion of the information in the annual report to the application under paragraph (b)(4) of this section. (ii) The holder of an approved appli cation 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 require ments of paragraphs (b)(2) and (b)(3) of this section, an applicant must make a change provided for in those para graphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a sup plement 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 amend ment to a supplement providing for a change under paragraph (b)(2) or (b)(3) of this section, the applicant must in clude a statement certifying that a field copy has been provided to the ap propriate FDA district office. No field copy is required for a supplement pro viding for a change made to a drug manufactured outside of the United States. (v) A supplement or annual report de scribed in paragraph (b)(4) of this sec tion 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 dis tribution of the drug made using the change (major changes). (i) A supple ment must be submitted for any change in the drug, production process, VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00113 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 104 21 CFR Ch. I (4–1–23 Edition) § 514.8 quality controls, equipment, or facili ties that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug. (ii) These changes include, but are not limited to: (A) Except those described in para graphs (b)(3) and (b)(4) of this section, changes in the qualitative or quan titative formulation of the drug, in cluding inactive ingredients, or in the specifications provided in the approved application; (B) Changes requiring completion of appropriate clinical studies to dem onstrate the equivalence of the drug to the drug as manufactured without the change; (C) Changes that may affect drug substance or drug product sterility as surance, such as changes in drug sub stance, 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 man ufacture 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 con tainer 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 prod uct; (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) Changes in the virus or adven titious agent removal or inactivation method(s), (2) Changes in the source material or cell line, and (3) Establishment of a new master cell bank or seed; (G) Changes to a drug under an appli cation that is subject to a validity as sessment because of significant ques tions regarding the integrity of the data supporting that application. (iii) The applicant must obtain ap proval 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 la beled ‘‘Prior Approval Supplement.’’ Except for submissions under para graph (b)(2)(v) of this section, the fol lowing information must be contained in the supplement: (A) A completed Form FDA 356V; (B) A detailed description of the pro posed 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 ef fects of the change; (F) The data derived from such stud ies; (G) Appropriate documentation (for example, updated master batch records, specification sheets) including previously approved documentation (with the changes highlighted) or ref erences to previously approved docu mentation; (H) For a natural product, a recom binant 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 re quirements 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 stand ard operating procedures must be pro vided 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 ex pedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hard ship on the applicant. Such a supple ment and its mailing cover must be plainly marked: ‘‘Prior Approval Sup plement-Expedited Review Requested.’’ (v) Comparability Protocols. An appli cant may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00114 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 105 Food and Drug Administration, HHS § 514.8 to demonstrate the lack of adverse ef fect for specified types of manufac turing changes on the identity, strength, quality, purity, and potency of the drug as these factors may relate to the safety or effectiveness of the drug. Any such protocols, if not in cluded in the approved application, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribu tion of the drug produced with the manufacturing change. The supple ment, if approved, may subsequently justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect. A comparability protocol sup plement must be labeled ‘‘Prior Ap proval Supplement—Comparability Protocol.’’ (3) Changes requiring submission of a supplement at least 30 days prior to dis tribution of the drug made using the change (moderate changes). (i) A supple ment must be submitted for any change in the drug, production process, quality controls, equipment, or facili ties that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug. (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 de scribed 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) An increase or decrease in produc tion scale during finishing steps that involves different equipment, and (2) Replacement of equipment with that of a different design that does not affect the process methodology or proc ess operating parameters. (C) Relaxation of an acceptance cri terion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and reg ulatory requirements. (iii) A supplement submitted under paragraph (b)(3)(i) or (b)(3)(vi) of this section is required to give a full expla nation 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 la beled ‘‘Supplement-Changes Being Ef fected in 30 Days.’’ (iv) Pending approval of the supple ment by FDA and except as provided in paragraph (b)(3)(vi) of this section, dis tribution 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 para graphs (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 ac cordance with paragraph (b)(2) of this section; or (B) Any of the information required under paragraph (b)(3)(iv) of this sec tion is missing. In this case, the appli cant must not distribute the drug made using the change until the supplement has been amended to provide the miss ing information. (vi) The agency may designate a cat egory of changes for the purpose of pro viding that, in the case of a change in such category, the holder of an ap proved application may commence dis tribution of the drug involved upon re ceipt 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 sup plement 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 rep resented 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, VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00115 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 106 21 CFR Ch. I (4–1–23 Edition) § 514.8 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 manufac turing change. (4) Changes and updated stability data to be described and submitted in an an nual report (minor changes). (i) Changes in the drug, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as these factors may relate to the safety or effectiveness of the drug must be documented by the applicant in an annual report to the application as described under paragraph (a)(2)(iii) of this section. The report must be la beled ‘‘Minor Changes and Stability Report.’’ (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 con sistent with FDA statutory and regu latory 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, with out a change from one container clo sure 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 appli cation or published in an official com pendium; (F) An extension of an expiration dating period based upon full shelf-life data on production batches obtained from a protocol approved in the appli cation; (G) The addition or revision of an al ternative analytical procedure that provides the same or increased assur ance of the identity, strength, quality, purity, or potency of the drug being tested as the analytical procedure de scribed in the approved application, or deletion of an alternative analytical procedure; and (H) The addition by embossing, de bossing, or engraving of a code imprint to a solid oral dosage form drug prod uct other than a modified release dos age form, or a minor change in an ex isting 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 imple mented; (F) Data from studies and tests per formed to assess the effects of the change; (G) For a natural product, recom binant DNA-derived protein/ polypeptide, complex or conjugate of a drug substance with a monoclonal anti body, 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.) in cluding previously approved docu mentation (with the changes high lighted) or references to previously ap proved documentation; (I) Updated stability data generated on commercial or production batches according to an approved stability pro tocol or commitment; and (J) Any other information as directed by FDA. (c) Labeling and other changes to an approved application—(1) General provi sions. The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00116 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 107 Food and Drug Administration, HHS § 514.8 for in the application. The notice is re quired to describe the change fully. (2) Labeling changes requiring the sub mission and approval of a supplement prior to distribution of the drug made using the change (major changes). (i) Ad dition of intended uses and changes to package labeling require a supplement. These changes include, but are not lim ited to: (A) Revision in labeling, such as up dating information pertaining to ef fects, dosages, adverse reactions, con traindications, which includes informa tion headed ‘‘adverse reactions,’’ ‘‘warnings,’’ ‘‘precautions,’’ and ‘‘con traindications,’’ 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) The parts of the labeling fur nishing directions, warnings, and infor mation for use of the drug are the same in language and emphasis as labeling approved or permitted; and (2) Any other parts of the labeling are consistent with and not contrary to such approved or permitted labeling. (3) Prescription drug labeling not re quiring an approved supplemental ap plication is submitted in accordance with § 514.80(b)(5)(ii). (D) Any other changes in labeling, except ones described in paragraph (c)(3) of this section. (ii) The applicant must obtain ap proval of the supplement from FDA prior to distribution of the drug. The supplement must contain the fol lowing: (A) A completed Form FDA 356V; (B) A detailed description of the pro posed change; (C) The drug(s) involved; (D) The data derived from studies in support of the change; and (E) Any other information as di rected by FDA. (3) Labeling changes to be placed into effect prior to receipt of a written notice of approval of a supplemental application. (i) Labeling changes of the following kinds that increase the assurance of drug safety proposed in supplemental applications must be placed into effect immediately: (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 label ing, promotional labeling, or drug ad vertising of false, misleading, or unsup ported intended uses or claims for ef fectiveness; 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 supple mental applications may be placed into effect prior to written notice of ap proval from FDA of a supplemental ap plication. (iii) A supplement submitted under paragraph (c)(3) of this section must in clude 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—Label ing Changes Being Effected’’; (B) Two sets of printed copies of any revised labeling to be placed in use, identified with the new animal drug ap plication number; and (C) A statement by the applicant that all promotional labeling and all drug advertising will promptly be re vised consistent with the changes made in the labeling on or within the new animal drug package no later than upon approval of the supplemental ap plication. (iv) If the supplemental application is not approved and the drug is being distributed with the proposed labeling, FDA may initiate an enforcement ac tion 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 ap plication. (4) Changes providing for additional distributors to be reported under Records and reports concerning experience with approved new animal drugs (§ 514.80). Supplemental applications as described VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00117 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 108 21 CFR Ch. I (4–1–23 Edition) § 514.11 under paragraph (c)(2) of this section will not be required for an additional distributor to distribute a drug that is the subject of an approved new animal drug application or abbreviated new animal drug application if the condi tions described under § 514.80(b)(5)(iii) are met. (d) Patent information. The applicant must comply with the patent informa tion requirements under section 512(c)(3) of the act. (e) Claimed exclusivity. If an applicant claims exclusivity under section 512(c)(2)(F) of the act upon approval of a supplemental application for a change in its previously approved drug, the applicant must include such a statement. (f) Good laboratory practice for nonclin ical laboratory studies. A supplemental application that contains nonclinical laboratory studies must include, with respect to each nonclinical study, ei ther a statement that the study was conducted in compliance with the re quirements set forth in part 58 of this chapter, or, if the study was not con ducted in compliance with such regula tions, a brief statement of the reason for the noncompliance. [71 FR 74782, Dec. 13, 2006] § 514.11 Confidentiality of data and in formation in a new animal drug ap plication file. (a) For purposes of this section the NADA file includes all data and infor mation submitted with or incorporated by reference in the NADA, INAD’s in corporated into the NADA, supple mental NADA’s, reports under §§ 514.80 and 510.301 of this chapter, master files, and other related submissions. The availability for public disclosure of any record in the NADA file shall be han dled in accordance with the provisions of this section. (b) The existence of an NADA file will not be disclosed by the Food and Drug Administration before the appli cation has been approved, unless it has been previously disclosed or acknowl edged. (c) If the existence of an NADA file has not been publicly disclosed or ac knowledged, 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 acknowl edged before the application has been approved, no data or information con tained 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 advi sory committee or pursuant to an ex change of important regulatory infor mation with a foreign government. (e) After an application has been ap proved, the following data and informa tion 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 infor mation 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 sum maries shall consist of the following: (i) For an NADA approved prior to July 1, 1975, internal agency records that describe such data and informa tion, e.g., a summary of basis for ap proval or internal reviews of the data and information, after deletion of: (a) Names and any information that would identify the investigators. (b) Any inappropriate gratuitous comments unnecessary to an objective analysis of the data and information. (ii) For an NADA approved after July 1, 1975, a summary of such data and in formation prepared in one of the fol lowing two alternative ways shall be publicly released when the application is approved. (a) The Center for Veterinary Medi cine may at an appropriate time prior to approval of the NADA require the applicant to prepare a summary of such data and information, which will be reviewed and, where appropriate, re vised by the Center. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00118 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 109 Food and Drug Administration, HHS § 514.15 (b) The Center for Veterinary Medi cine may prepare its own summary of such data and information. (3) A protocol for a test or study, un less it is shown to fall within the ex emption established for trade secrets and confidential commercial informa tion in § 20.61 of this chapter. (4) Adverse reaction reports, product experience reports, consumer com plaints, and other similar data and in formation, 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 analyt ical method, unless it serves no regu latory or compliance purpose and is shown to fall within the exemption es tablished 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 dis closed to the public are available for public disclosure at the time any one of the following events occurs unless ex traordinary circumstances are known: (1) The NADA has been abandoned and no further work is being under taken 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 with drawn, 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 in formation. (g) The following data and informa tion 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 con fidential commercial or financial infor mation as defined in § 20.61 of this chap ter: (1) Manufacturing methods or proc esses, including quality control proce dures. (2) Production, sales, distribution, and similar data and information, ex cept that any compilation of such data and information aggregated and pre pared in a way that does not reveal data or information which is not avail able for public disclosure under this provision is available for public disclo sure. (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 in formation 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 pre viously been publicly disclosed or ac knowledged. (b) The availability for public disclo sure of all data and information in an INAD file shall be handled in accord ance with provisions established in § 514.11. § 514.15 Untrue statements in applica tions. Among the reasons why an applica tion for a new animal drug or animal feed bearing or containing a new ani mal drug may contain an untrue state ment of a material fact are: (a) Differences in: (1) Conditions of use prescribed, rec ommended, or suggested by the appli cant for the product from the condi tions of such use stated in the applica tion; VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00119 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 110 21 CFR Ch. I (4–1–23 Edition) § 514.80 (2) Articles used as components of the product from those listed in the ap plication; (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 con trols described in the application; (5) Labeling from the specimens con tained 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 informa tion obtained from: (1) Investigations as to the safety, ef fectiveness, identity, strength, quality, or purity of the drug, made by the ap plicant 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, effec tiveness, 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 non compliance. [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? Who is required to establish, maintain, and report required information re lating to experiences with a new animal drug? Is information from foreign sources required? 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 manufac turing practices? 514.80(a)(5). 514.80(b) Reporting requirements. What are the requirements for reporting product/manufacturing defects? 514.80(b)(1) Three-day NADA/ANADA field alert re port. 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 unex pected 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. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00120 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 111 Food and Drug Administration, HHS § 514.80 Purpose 21 CFR Paragraph and Title What are the general requirements for submission of periodic drug experi ence reports, e.g., method of submission, submission date and fre quency, when is it to be submitted, how many copies? How do I petition to change the date of submission or frequency of sub missions? 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? How should the distribution data be submitted? 514.80(b)(4)(i) Distribution data. What labeling materials should be submitted? How do I report changes to the labeling materials since the last report? 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 stud ies? 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 re ported? 514.80(b)(4)(iii)(C). 514.80(b)(4)(iv) Adverse drug experiences. How do I report product/manufacturing defects and adverse drug experi ences 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 seri ous, expected, and unexpected adverse drug experiences? 514.80(b)(4)(v) Summary report of increased fre quency 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 pro motional labeling to FDA? 514.80(b)(5)(ii) Advertisements and promotional la beling. 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 la beling? 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) through (b)(5)(iii)(B)(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 ap plication?) 514.80(c) Multiple applications. What information has to be submitted to the common application and re lated application? 514.80(c)(1) through (c)(4). What reports must be submitted to FDA electronically? How can I apply for a waiver from the electronic reporting requirements? How do I obtain Form FDA 1932 and Form FDA 2301? 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. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00121 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 112 21 CFR Ch. I (4–1–23 Edition) § 514.80 Purpose 21 CFR Paragraph and Title What are the requirements for allowing access to these records and re ports, 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 electroni cally? 514.80(g) Mailing addresses. What happens if the applicant fails to establish, maintain, or make the re quired reports? What happens if the applicant refuses to allow FDA access to, and/or copying and/or verify records and 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. (1) Each applicant must establish and maintain indexed and complete files containing full records of all information pertinent to safety or effectiveness of a new animal drug that has not been previously sub mitted as part of the NADA or ANADA. Such records must include information from domestic as well as foreign sources. Each nonapplicant must estab lish and maintain indexed and com plete files containing full records of all information pertinent to safety or ef fectiveness of a new animal drug that is received or otherwise obtained by the nonapplicant. Such records must include information from domestic as well as foreign sources. (2) Each applicant must submit re ports of data, studies, and other infor mation concerning experience with new animal drugs to the Food and Drug Administration (FDA) for each ap proved NADA and ANADA, as required in this section. A nonapplicant must submit data, studies, and other infor mation 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, stud ies, and other information described in this section from domestic, as well as foreign sources. (3) FDA reviews the records and re ports required in this section to facili tate 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 sus pending 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 re quirements 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. (b) Reporting requirements—(1) Three day NADA/ANADA field alert report. This report provides information per taining to product and manufacturing defects that may result in serious ad verse drug events. The applicant (or nonapplicant through the applicant) must submit the report to the appro priate FDA District Office or local FDA resident post within 3 working days of first becoming aware that a de fect may exist. The information ini tially may be provided by telephone or other telecommunication means, with prompt written followup using Form FDA 1932 ‘‘Veterinary Adverse Drug Reaction, Lack of Effectiveness, Prod uct Defect Report.’’ The mailing cover for these reports must be plainly marked ‘‘3-Day NADA/ANADA Field Alert Report.’’ If the applicant elects to also report directly to the FDA’s Center for Veterinary Medicine (CVM), the applicant must submit the report to CVM in electronic format as de scribed in paragraph (d)(1) of this sec tion, unless the applicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00122 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 113 Food and Drug Administration, HHS § 514.80 (2) Fifteen-day NADA/ANADA alert re port—(i) Initial report. This report pro vides information on each serious, un expected adverse drug event, regardless of the source of the information. The applicant (or nonapplicant through the applicant) must submit the report to FDA within 15 working days of first re ceiving the information. The report must be submitted to FDA in elec tronic format as described in paragraph (d)(1) of this section, unless the appli cant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format. (ii) Followup report. The applicant must promptly investigate all adverse drug events that are the subject of 15 day NADA/ANADA alert reports. If this investigation reveals significant new information, a followup report must be submitted within 15 working days of receiving such information. A followup report must be submitted to FDA in electronic format as described in para graph (d)(1) of this section, unless the applicant obtains a waiver under para graph (d)(2) of this section or FDA re quests the report in an alternate for mat. The followup report must state the date of the initial report and pro vide the additional information. If ad ditional information is sought but not obtained within 3 months of the initial report, a followup report is required de scribing the steps taken and why addi tional information was not obtained. (3) Nonapplicant report. Nonapplicants must forward reports of adverse drug experiences to the applicant within 3 working days of first receiving the in formation. The applicant must then submit the report(s) to FDA as re quired in this section. The non applicant must maintain records of all nonapplicant reports, including the date the nonapplicant received the in formation concerning adverse drug ex periences, the name and address of the applicant, and a copy of the adverse drug experience report including the date such report was submitted to the applicant. If the nonapplicant elects to also report directly to FDA, the non applicant must submit the report to FDA in electronic format as described in paragraph (d)(1) of this section, un less the nonapplicant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alter nate format. (4) Periodic drug experience report. This report must be accompanied by a completed Form FDA 2301 ‘‘Trans mittal of Periodic Reports and Pro motional Materials for New Animal Drugs.’’ It must be submitted every 6 months for the first 2 years following approval of an NADA or ANADA and yearly thereafter. Reports required by this section must contain data and in formation for the full reporting period. The 6-month periodic drug experience reports must be submitted within 30 days following the end of the 6-month reporting period. The yearly periodic drug experience reports must be sub mitted within 90 days of the anniver sary date of the approval of the NADA or ANADA. Any previously submitted information contained in the report must be identified as such. For yearly (annual) periodic drug experience re ports, the applicant may petition FDA to change the date of submission or fre quency of reporting, and after approval of such petition, file such reports on the new filing date or at the new re porting frequency. Also, FDA may re quire a report at different times or more frequently. The periodic drug ex perience report must contain the fol lowing: (i) Distribution data. (A) Information about the distribution of each new ani mal drug product, including informa tion on any distributor-labeled prod uct. This information must include the total number of distributed units of each size, strength, or potency (e.g., 100,000 bottles of 100 5-milligram tab lets; 50,000 10-milliliter vials of 5-per cent solution). This information must be presented in two categories: Quan tities distributed domestically and quantities exported. (B) Applicants submitting annual sales and distribution reports for anti microbial new animal drug products under § 514.87 have the option not to re port distribution data under paragraph (b)(4)(i)(A) of this section for the ap proved applications that include these same products, but only provided each of the following conditions are met: VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00123 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 114 21 CFR Ch. I (4–1–23 Edition) § 514.80 (1) Applicants must have submitted complete periodic drug experience re ports under this section for such appli cations for at least 2 full years after the date of their initial approval. (2) Applicants must ensure that the beginning of the reporting period for the annual periodic drug experience re ports for such applications is January 1. For applications that currently have a reporting period that begins on a date other than January 1, applicants must request a change in reporting submission date such that the report ing period begins on January 1 and ends on December 31, as described in paragraph (b)(4) of this section. (3) Applicants that change their re porting submission date must also sub mit a special drug experience report, as described in paragraph (b)(5)(i) of this section, that addresses any gaps in dis tribution data caused by the change in date of submission. (4) Applicants who choose not to re port under paragraph (b)(4)(i)(A) of this section must ensure that full sales and distribution data for each product ap proved under such applications are al ternatively reported under § 514.87, in cluding products that are labeled for use only in nonfood-producing animals. (ii) Labeling. Applicant and dis tributor current package labeling, in cluding package inserts (if any). For large-size package labeling or large shipping cartons, a representative copy must be submitted (e.g., a photocopy of pertinent areas of large feed bags). A summary of any changes in labeling made since the last report (listed by date of implementation) must be in cluded with the labeling or if there have been no changes, a statement of such fact must be included with the la beling. (iii) Nonclinical laboratory studies and clinical data not previously re ported. (A) Copies of in vitro studies (e.g., mutagenicity) and other nonclinical laboratory studies conducted by or oth erwise obtained by the applicant. (B) Copies of published clinical trials of the new animal drug (or abstracts of them) including clinical trials on safe ty and effectiveness, clinical trials on new uses, and reports of clinical experi ence 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 clip pings, 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. Sup porting information is not to be re ported. (iv) Adverse drug experiences. (A) Product/manufacturing defects and ad verse drug experiences not previously reported under paragraphs (b)(1) and (2) of this section must be reported indi vidually 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. (B) Reports of adverse drug experi ences 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 pro vide a full text copy of these publica tions. (C) Reports of previously not re ported adverse drug experiences that occur in postapproval studies must be reported individually to FDA in elec tronic format as described in paragraph (d)(1) of this section, unless the appli cant obtains a waiver under paragraph (d)(2) of this section or FDA requests the report in an alternate format. (v) Summary report of increased fre quency of adverse drug experience. The applicant must periodically review the incidence of reports of adverse drug ex periences to determine if there has been an increased frequency of serious (expected and unexpected) adverse drug events. The applicant must evaluate the increased frequency of serious (ex pected or unexpected) adverse drug events at least as often as reporting of periodic drug experience reports. The applicant must report the increased frequency of serious (expected and un expected) adverse drug events in the periodic drug experience report. Sum maries of reports of increased fre quency of adverse drug events must be VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00124 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 115 Food and Drug Administration, HHS § 514.80 submitted in narrative form. The sum maries must state the time period on which the increased frequency is based, time period comparisons in deter mining increased frequency, references to any reports previously submitted under paragraphs (b)(1), (2), and (3) and (b)(4)(iv)(A) and (C) of this section, the method of analysis, and the interpreta tion of the results. The summaries must be submitted in a separate sec tion within the periodic drug experi ence report. (5) Other reporting—(i) Special drug ex perience report. Upon written request, FDA may require that the applicant submit a report required under § 514.80 at different times or more frequently than the timeframes stated in § 514.80. (ii) Advertisements and promotional la beling. The applicant must submit at the time of initial dissemination one set of specimens of mailing pieces and other labeling for prescription and over-the-counter new animal drugs. For prescription new animal drugs, the applicant must also submit one set of specimens of any advertisement at the time of initial publication or broad cast. Mailing pieces and labeling de signed to contain product samples must be complete except that product samples may be omitted. Each submis sion of promotional labeling or adver tisements must be accompanied by a completed Form FDA 2301. (iii) Distributor’s statement. At the time of initial distribution of a new animal drug product by a distributor, the applicant must submit a special drug experience report accompanied by a completed Form FDA 2301 containing the following: (A) The distributor’s current product labeling. (1) The distributor’s labeling must be identical to that in the approved NADA/ANADA except for a different and suitable proprietary name (if used) and the name and address of the dis tributor. The name and address of the distributor must be preceded by an ap propriate qualifying phrase as per mitted by the regulations such as ‘‘manufactured for’’ or ‘‘distributed by.’’ (2) Other labeling changes must be the subject of a supplemental NADA or ANADA as described under § 514.8. (B) A signed statement by the dis tributor stating: (1) The category of the distributor’s operations (e.g., wholesale or retail), (2) That the distributor will dis tribute the new animal drug only under the approved labeling, (3) That the distributor will promote the product only for use under the con ditions stated in the approved labeling, (4) That the distributor will adhere to the records and reports require ments of this section, and (5) That the distributor is regularly and lawfully engaged in the distribu tion or dispensing of prescription prod ucts if the product is a prescription new animal drug. (c) Multiple applications. Whenever an applicant is required to submit a peri odic drug experience report under the provisions of § 514.80(b)(4) with respect to more than one approved NADA or ANADA for preparations containing the same new animal drug so that the same information is required to be re ported for more than one application, the applicant may elect to submit as a part of the report for one such applica tion (the primary application) all the information common to such applica tions in lieu of reporting separately and repetitively on each. If the appli cant elects to do this, the applicant must do the following: (1) State when a report applies to multiple applications and identify all related applications for which the re port is submitted by NADA or ANADA number. (2) Ensure that the primary applica tion contains a list of the NADA or ANADA numbers of all related applica tions. (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 in cluded in the report for that particular NADA/ANADA. (d) Format for submissions—(1) Elec tronic submissions. Except as provided in paragraph (d)(2) of this section, reports submitted to FDA under paragraphs VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00125 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 116 21 CFR Ch. I (4–1–23 Edition) § 514.80 (b)(2)(i) and (ii), (b)(3), and (b)(4)(iv)(A) and (C) of this section and reports sub mitted to CVM under paragraph (b)(1) of this section must be submitted in an electronic format that FDA can proc ess, review, and archive. Data provided in electronic submissions must be in conformance with the data elements in Form FDA 1932 and FDA technical doc uments describing transmission. As necessary, FDA will issue updated technical documents on how to provide the electronic submission (e.g., method of transmission and processing, media, file formats, preparation, and organiza tion of files). Unless requested by FDA, paper copies of reports submitted elec tronically should not be submitted to FDA. (2) Waivers. An applicant or non applicant may request, in writing, a temporary waiver of the electronic sub mission requirements in paragraph (d)(1) of this section. The initial re quest may be by telephone or email to CVM’s Division of Veterinary Product Safety, with prompt written followup submitted as a letter to the applica tion(s). FDA will grant waivers on a limited basis for good cause shown. If FDA grants a waiver, the applicant or nonapplicant must comply with the conditions for reporting specified by FDA upon granting the waiver. (3) Paper forms. If approved by FDA before use, a computer-generated equivalent of Form FDA 1932 may be used for reports submitted to the ap propriate FDA District Office or local FDA resident post under paragraph (b)(1) of this section and to FDA under paragraph (d)(2) of this section, and a computer-generated equivalent of Form FDA 2301 may be used for reports submitted to FDA under paragraph (b)(4) of this section. Form FDA 1932 may be obtained on the FDA website, by telephoning CVM’s Division of Vet erinary Product Safety, or by submit ting a written request to the following address: Food and Drug Administra tion, Center for Veterinary Medicine, Division of Veterinary Product Safety (HFV–240), 7500 Standish Pl., Rockville, MD 20855–2764. Form FDA 2301 may be obtained on the FDA website, by tele phoning CVM’s Division of Surveil lance (HFV–210), or by submitting a written request to the following ad dress: Food and Drug Administration, Center for Veterinary Medicine, Divi sion of Surveillance (HFV–210), 7500 Standish Pl., Rockville, MD 20855–2764. (e) Records to be maintained. The ap plicants and nonapplicants must main tain records and reports of all informa tion required by this section for a pe riod of 5 years after the date of submis sion. (f) Access to records and reports. The applicant and nonapplicant must, upon request from any authorized FDA offi cer or employee, at all reasonable times, permit such officer or employee to have access to copy and to verify all such required records and reports. (g) Mailing addresses. Three-day alert reports must be submitted to the ap propriate FDA District Office or local FDA resident post. Addresses for Dis trict Offices and resident posts may be obtained on the FDA website. Other re ports not required to be submitted to FDA in electronic format must be sub mitted to the following address: Food and Drug Administration, Center for Veterinary Medicine, Document Con trol Unit (HFV–199), 7500 Standish Pl., Rockville, MD 20855–2764. (h) Withdrawal of approval. If FDA finds that the applicant has failed to establish the required records, or has failed to maintain those records, or failed to make the required reports, or has refused access to an authorized FDA officer or employee to copy or to verify such records or reports, FDA may withdraw approval of the applica tion to which such records or reports relate. If FDA determines that with drawal of the approval is necessary, the agency shall give the applicant notice and opportunity for hearing, as pro vided in § 514.200, on the question of whether to withdraw approval of the application. (i) Disclaimer. Any report or informa tion submitted under this section and any release of that report or informa tion by FDA will be without prejudice and does not necessarily reflect a con clusion that the report or information constitutes an admission that the drug caused or contributed to an adverse event. A person need not admit, and may deny, that the report or informa tion constitutes an admission that a VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00126 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 117 Food and Drug Administration, HHS § 514.100 drug caused or contributed to an ad verse event. [68 FR 15365, Mar. 31, 2003, as amended at 81 FR 29141, May 11, 2016; 85 FR 45512, July 29, 2020] § 514.87 Annual reports for anti microbial animal drug sales and distribution. (a) The applicant for each new ani mal drug product approved under sec tion 512 of the Federal Food, Drug, and Cosmetic Act, or conditionally ap proved under section 571 of the Federal Food, Drug, and Cosmetic Act, and containing an antimicrobial active in gredient, 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-pro ducing animal species, including infor mation on any distributor-labeled product. (b) This report must identify the ap proved or conditionally approved appli cation 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 ac tive ingredient contained in the prod uct; (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 speci fied on the approved label; (4) For each such product, the num ber of units sold or distributed in the United States (i.e., domestic sales) for each month of the reporting year; and (5) For each such product, the num ber of units sold or distributed outside the United States (i.e., quantities ex ported) for each month of the reporting year. (c) Each report must also provide a species-specific estimate of the per centage 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 spe cies-specific percentages reported for each product must account for 100 per cent of its sales and distribution; therefore, a fifth category of ‘‘other species/unknown’’ must also be re ported. (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 Dis tribution Report.’’ (e) Sales and distribution data and information reported under this sec tion will be considered to fall within the exemption for confidential com mercial information established in § 20.61 of this chapter and will not be publicly disclosed, except that sum mary reports of such information ag gregated in such a way that does not reveal information that is not avail able for public disclosure under this provision will be prepared by FDA and made available to the public as pro vided in paragraph (f) of this section. (f) FDA will publish an annual sum mary report of the data and informa tion it receives under this section for each calendar year by December 31 of the following year. Such annual re ports 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 commer cial information, each individual datum appearing in the summary re port 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 con sistent 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 VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00127 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 118 21 CFR Ch. I (4–1–23 Edition) § 514.100 furnished written comment on any ap parent deficiencies in the application. (b) When the description of the meth ods used in, and the facilities and con trols used for, the manufacture, proc essing, 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 consider ation 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 an alytical 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 re quest until all of the requested samples are received. If the samples are not re ceived within 90 days after the request, the application will be considered with drawn without prejudice. (d) The information contained in an application may be insufficient to de termine whether a new animal drug is safe or effective in use if it fails to in clude (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 ade quate 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 administra tion and any relevant hazards, contra indications, side effects, and pre cautions under which practitioners li censed by law to administer such drug can use the drug for the purposes for which it is intended, including all pur poses for which it is to be advertised, or represented, in accordance with § 201.105 of this chapter, and informa tion concerning hazards, contraindica tions, side effects, and precautions rel evant 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 infor mation for use including indications, effects, dosages, routes, methods, and frequency and duration of administra tion and any relevant warnings, haz ards, contraindications, side effects, and precautions, which is contained in the labeling that is part of the applica tion in accordance with § 201.105 of this chapter. (e) The information contained in an application will be considered insuffi cient to determine whether a new ani mal drug is safe and effective for use when there is a refusal or failure upon written notice to furnish inspectors au thorized by the Food and Drug Admin istration an adequate opportunity to inspect the facilities, controls, and records pertinent to the application. (f) On the basis of preliminary con sideration of an application or supple mental application containing type written 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 con sidered withdrawn without prejudice to future filing on the date of issuance of the letter citing the inadequacies con tained in the application, unless within 30 days the sponsor chooses to avail himself of the opportunity for hearing as prescribed by § 514.111. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00128 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 119 Food and Drug Administration, HHS § 514.106 § 514.105 Approval of applications. (a) The Commissioner shall forward for publication in the FEDERAL REG ISTER a regulation prescribing the con ditions under which the new animal drug may be used, including the name and address of the applicant; the condi tions and indications for use covered by the application; any tolerance, withdrawal period, or other use restric tions; any tolerance required for the new animal drug substance or its me tabolites in edible products of food-pro ducing animals; and, if such new ani mal drug is intended for use in animal feed, appropriate purposes and condi tions of use (including special labeling requirements) applicable to any animal feed; and such other information the Commissioner deems necessary to as sure safe and effective use. (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 ap plications. (a) Within 180 days after a supple ment to an approved application is filed pursuant to § 514.8, the Commis sioner shall approve the supplemental application in accordance with proce dures set forth in § 514.105(a)(1) and (2) if he/she determines that the applica tion satisfies the requirements of ap plicable statutory provisions and regu lations. (b) The Commissioner will assign a supplemental application to its proper category to ensure processing of the application. (1) Category I. Supplements that ordi narily do not require a reevaluation of any of the safety or effectiveness data in the parent application. Category I supplements include the following: (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 construc tion 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, dele tion, or revision of certain statements, e.g., trade name, storage, expiration dates, etc). (vi) A change in promotional mate rial for a prescription new animal drug not exempted by § 514.8(c)(2)(i)(C)(1) through (c)(2)(i)(C)(3). (vii) Changes in manufacturing proc esses that do not alter the method of manufacture or change the final dosage form. (viii) A change in bulk drug ship ments. (ix) A change in an analytical meth od or control procedures that do not alter the approved standards. (x) A change in an expiration date. (xi) Addition of an alternate manu facturer, 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. Supplements that may require a reevaluation of certain safety or effectiveness data in the parent ap plication. Category II supplements in clude the following: (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 regi men (schedule of dosing). (v) Addition of a new therapeutic claim to the approved uses of the prod uct. (vi) Addition of a new or revised ani mal production claim. (vii) Addition of a new species. (viii) A change in the prescription or over-the-counter status of a drug prod uct. (ix) A change in statements regard ing side effects, warnings, precautions, and contraindications, except the addi tion of approved statements to con tainer, package, and promotional label ing, and prescription drug advertising. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00129 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 120 21 CFR Ch. I (4–1–23 Edition) § 514.110 (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 sub stance. (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 manufac ture of a new animal drug, or a change from one commercial batch size to an other without any change in manufac turing procedure), or changes in the methods, facilities, or controls used for the manufacture, processing, pack aging, or holding of the new animal drug (other than use of an establish ment not covered by the approval that is in effect) that give increased assur ance that the drug will have the char acteristics of identity, strength, qual ity, 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 applica tion 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 rea sons: (1) It does not contain complete and accurate English translations of any pertinent part in a foreign language. (2) Fewer than three copies are sub mitted. (3) It is incomplete on its face in that it is not properly organized and in dexed. (4) On its face the information con cerning required matter is so inad equate that the application is clearly not approvable. (5) The new animal drug is to be man ufactured, prepared, propagated, com pounded, or processed in whole or in part in any State in an establishment that has not been registered or exempt ed from registration under the provi sions 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 ap plicant and to receive communications on all matters pertaining to the appli cation. (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. ). Such applications will be referred to the U.S. Department of Agriculture for action. (8) It fails to include, with respect to each nonclinical laboratory study con tained in the application, either a statement that the study was con ducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compli ance with such regulations, a brief statement of the reasons for the non compliance. (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 estab lish that the requested action is sub ject 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 ap plicant shall be notified within 30 days of receipt of the application and shall be given the reasons therefore. (d) If the applicant disputes the find ings that his application is not accept able 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] VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00130 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 121 Food and Drug Administration, HHS § 514.111 § 514.111 Refusal to approve an appli cation. (a) The Commissioner shall, within 180 days after the filing of the applica tion, inform the applicant in writing of his intention to issue a notice of oppor tunity 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 re quired to be submitted pursuant to sec tion 512(b) of the act do not include adequate tests by all methods reason ably applicable to show whether or not such drug is safe for use under the con ditions 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 fa cilities and controls used for the manu facture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and pu rity; or (4) Upon the basis of the information submitted to the Food and Drug Ad ministration as part of the application, or upon the basis of any other informa tion 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 ac count any chemically or pharmacologi cally related substances; (iii) Safety factors which, in the opinion of experts qualified by sci entific training and experience to evaluate the safety of such drugs, are appropriate for the use of animal ex perimentation 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 informa tion submitted as part of the applica tion 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 edi ble 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 in gested by man or animal or, after ap propriate tests for evaluation of the safety of such drug, induces cancer in man or animal, except that this sub paragraph shall not apply with respect to such drug if the Commissioner finds that, under the conditions of use speci fied in proposed labeling and reason ably certain to be followed in practice: (i) Such drug will not adversely af fect the animal for which it is in tended; and (ii) No residue of such drug will be found (by methods of examination pre scribed or approved by the Commis sioner 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 estab lish that the requested action is sub ject to categorical exclusion under § 25.30 or § 25.33 of this chapter. (10) The drug fails to satisfy the re quirements 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 pre scribed, recommended, or suggested in its proposed labeling, was not con ducted in compliance with the good VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00131 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 122 21 CFR Ch. I (4–1–23 Edition) § 514.115 laboratory practice regulations as set forth in part 58 of this chapter and no reason for the noncompliance is pro vided or, if it is, the differences be tween 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 expedi tiously notify the applicant of an op portunity for a hearing on the question of whether such application is approv able, unless by the 30th day following the date of issuance of the letter in forming 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 hear ing; 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 ap proval of an application approved pur suant to section 512(c) of the act and give the applicant prompt notice of his action and afford the applicant the op portunity for an expedited hearing on a finding that there is an imminent haz ard to the health of man or of the ani mals for which such new animal drug or animal feed is intended. (b) The Commissioner shall notify in writing the person holding an applica tion approved pursuant to section 512(c) of the act and afford an oppor tunity 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 in formation respecting all such changes and unless there is in effect an ap proval 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 sec tion 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 reason ably 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 appli cation 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 sub stantial evidence that such drug will have the effect it purports or is rep resented 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 applica tion and that is essential to show that the drug is safe for use under the condi tions prescribed, recommended, or sug gested 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 VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00132 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 123 Food and Drug Administration, HHS ยง 514.117 reason for the noncompliance is pro vided or, if it is, the differences be tween 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 applica tion approved pursuant to section 512(c) of the act and afford an oppor tunity 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 re quired records, or has repeatedly or de liberately 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 informa tion 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 pre serve 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 informa tion 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 mis leading in any particular and was not corrected within a reasonable time after receipt of written notice from the Secretary specifying the matter com plained of. (d) Approval of an application pursu ant 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 ani mal drug application on the grounds that the drug subject to such applica tion is no longer being marketed and information is included in support of this finding, provided none of the con ditions cited in paragraphs (a), (b), and (c) of this section pertain to the sub ject 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 sec tion. Withdrawal of approval of an ap plication 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 sec tion 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 ap plication shall be revoked. [40 FR 13825, Mar. 27, 1975, as amended at 50 FR 7517, Feb. 22, 1985; 64 FR 63204, Nov. 19, 1999] ยง 514.116 Notice of withdrawal of ap proval of application. When an approval of an application submitted pursuant to section 512 of the act is withdrawn by the Commis sioner, he will give appropriate public notice of such action by publication in the FEDERAL REGISTER. ยง 514.117 Adequate and well-controlled studies. (a) Purpose. The primary purpose of conducting adequate and well-con trolled studies of a new animal drug is to distinguish the effect of the new ani mal drug from other influences, such as spontaneous change in the course of the disease, normal animal production performance, or biased observation. One or more adequate and well-con trolled studies are required to estab lish, by substantial evidence, that a new animal drug is effective. The char acteristics described in paragraph (b) of this section have been developed over a period of years and are generally recognized as the essentials of an ade quate and well-controlled study. Well controlled, as used in the phrase ade quate and well controlled, emphasizes an important aspect of adequacy. The Food and Drug Administration (FDA) considers these characteristics in de termining whether a study is adequate and well controlled for purposes of sec tion 512 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b). Adequate and well-controlled studies, VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00133 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 124 21 CFR Ch. I (4–1–23 Edition) § 514.117 in addition to providing a basis for de termining whether a new animal drug is effective, may also be relied upon to support target animal safety. The re port of an adequate and well-controlled study should provide sufficient details of study design, conduct, and analysis to allow critical evaluation and a de termination of whether the character istics of an adequate and well-con trolled study are present. (b) Characteristics. An adequate and well-controlled study has the following characteristics: (1) The protocol for the study (pro tocol) and the report of the study re sults (study report) must include a clear statement of the study objec tive(s). (2) The study is conducted in accord ance with an appropriate standard of conduct that addresses, among other issues, study conduct, study personnel, study facilities, and study documenta tion. The protocol contains a state ment acknowledging the applicability of, and intention to follow, a standard of conduct acceptable to FDA. The study report contains a statement de scribing adherence to the standard. (3) The study is conducted with a new animal drug that is produced in accord ance with appropriate manufacturing practices, which include, but are not necessarily limited to, the manufac ture, 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 spe cific formulation and production proc ess used to manufacture the new ani mal drug used in the study. (4) The study uses a design that per mits 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 deter mination of the effectiveness of a new animal drug, certain of the controls listed below would be appropriate and preferred depending on the study con ducted: (i) Placebo concurrent control. The new animal drug is compared with an inac tive preparation designed to resemble the new animal drug as far as possible. (ii) Untreated concurrent control. The new animal drug is compared with the absence of any treatment. The use of this control may be appropriate when objective measurements of effective ness, not subject to observer bias, are available. (iii) Active treatment concurrent con trol. The new animal drug is compared with known effective therapy. The use of this control is appropriate when the use of a placebo control or of an un treated concurrent control would un reasonably compromise the welfare of the animals. Similarity of the new ani mal drug and the active control drug can mean either that both drugs were effective or that neither was effective. The study report should assess the ability of the study to have detected a difference between treatments. The evaluation of the study should explain why the new animal drugs should be considered effective in the study, for example, by reference to results in pre vious placebo-controlled studies of the active control. (iv) Historical control. The results of treatment with the new animal drug are quantitatively compared with expe rience historically derived from the adequately documented natural history of the disease or condition, or with a regimen (therapeutic, diagnostic, pro phylactic) whose effectiveness is estab lished, in comparable animals. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concur rent control populations, historical control designs are usually reserved for special circumstances. Examples in clude studies in which the effect of the VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00134 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 125 Food and Drug Administration, HHS § 514.117 new animal drug is self-evident or stud ies of diseases with high and predict able mortality, or signs and symptoms of predictable duration or severity, or, in the case of prophylaxis, predictable morbidity. (5) The study uses a method of select ing animals that provides adequate as surances that the animals are suitable for the purposes of the study. For ex ample, 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 as surance that the animals have the dis ease or condition being studied, or, in the case of prophylactic agents, evi dence of susceptibility and exposure to the condition against which prophy laxis 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 exper imental 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, du ration 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 as signment of animals to an experi mental unit to account for pertinent variables and method of assignment of a treatment or a control to the experi mental units. When the effect of such variables is accounted for by an appro priate 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 mini mize bias on the part of observers and analysts of the data that are adequate to prevent undue influences on the re sults and interpretation of the study data. The protocol and study report ex plain the methods of observation and recording of the animal response vari ables 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 re port describe the methods for con ducting the study, including any appro priate analytical and statistical meth ods, used to collect and analyze the data resulting from the conduct of the study, describe the criteria used to as sess response, and, when appropriate, justify the selection of the methods to assess animal response. (9) There is an analysis and evalua tion of the results of the study in ac cord with the protocol adequate to as sess the effects of the new animal drug. The study report evaluates the meth ods 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 per formed. (c) Field studies. (1) Field conditions as used in this section refers to condi tions which closely approximate the conditions under which the new animal drug, if approved, is intended to be ap plied or administered. (2) Studies of a new animal drug con ducted under field conditions shall, consistent with generally recognized scientific principles and procedures, use an appropriate control that per mits comparison, employ procedures to minimize bias, and have the character istics 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 condi tions need not or should not be the same as the level of control in labora tory 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 evalua tion of the study. Adequate and well controlled field studies shall balance the need to control study conditions VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00135 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 126 21 CFR Ch. I (4–1–23 Edition) § 514.120 with the need to observe the true effect of the new animal drug under closely approximated actual use conditions. (d) Waiver. The Director of the Center for Veterinary Medicine (the Director) may, on the Director’s own initiative or on the petition of an interested per son, waive in whole or in part any of the criteria in paragraph (b) of this sec tion with respect to a specific study. A petition for a waiver is required to set forth clearly and concisely the specific criteria from which waiver is sought, why the criteria are not reasonably ap plicable to the particular study, what alternative procedures, if any, are to be, or have been employed, and what results have been obtained. The peti tion is also required to state why the studies so conducted will yield, or have yielded, substantial evidence of effec tiveness, notwithstanding nonconform ance with the criteria for which waiver is requested. (e) Uncontrolled studies. Uncontrolled studies or partially controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness or target animal safety. Such studies, carefully conducted and documented, may provide corroborative support of adequate and well-controlled studies regarding effectiveness and may yield valuable data regarding safety of the new animal drug. Such studies will be considered on their merits in light of the characteristics listed here. Isolated case reports, random experience, and reports lacking the details which per mit scientific evaluation will not be considered. [63 FR 10770, Mar. 5, 1998] § 514.120 Revocation of order refusing to approve an application or sus pending or withdrawing approval of an application. The Commissioner, upon his own ini tiative 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 appli cation that previously has had its ap proval refused, suspended, or with drawn. § 514.121 Service of notices and orders. All notices and orders under this sub chapter E and section 512 of the act pertaining to new animal drug applica tions shall be served: (a) In person by any officer or em ployee of the Department designated by the Commissioner; or (b) By mailing the order by certified mail addressed to the applicant or re spondent at his last known address in the records of the Food and Drug Ad ministration. Subpart C—Hearing Procedures § 514.200 Notice of opportunity for hearing; notice of participation and requests for hearing; grant or de nial of hearing. (a) The notice to the applicant of op portunity for a hearing on a proposal by the Commissioner to refuse to ap prove an application or to withdraw the approval of an application will be published in the FEDERAL REGISTER to gether with an explanation of the grounds for the proposed action. The notice will describe how to request a hearing. An applicant has 30 days after publication of the notice to request a hearing. (b) If the applicant fails to request a hearing within the 30-day timeframe, the Commissioner, without further no tice, will publish a final order denying or withdrawing approval of the applica tion. (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 Divi sion of Dockets Management 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, to gether with a detailed description and analysis of the factual information (in cluding 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. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00136 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B 127 Food and Drug Administration, HHS Pt. 515 (2) If the Commissioner determines upon review of the data and informa tion 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 ap plication (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 informa tion submitted in the objections and request for a hearing that a hearing is justified, the Commissioner will pub lish a notice setting forth the fol lowing: (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 res olution at the hearing; (v) The presiding officer, or a state ment 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 ap plicant 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 protec tion 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] § 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 re quest(s) for hearing together with the data and information submitted and the Commissioner’s findings and con clusions shall be included in the record certified by the Commissioner. (b) Judicial review of an order with drawing approval of a new drug appli cation, whether or not a hearing has been held, may be sought by a manu facturer or distributor of an identical, related, or similar drug product, as de fined in § 310.6 of this chapter, in a United States court of appeals pursu ant to section 505(h) of the act. [42 FR 4717, Jan. 25, 1977] PART 515—MEDICATED FEED MILL LICENSE Subpart A—Applications Sec. 515.10 Medicated feed mill license applica tions. 515.11 Supplemental medicated feed mill li cense applications. Subpart B—Administrative Actions on Licenses 515.20 Approval of medicated feed mill li cense applications. 515.21 Refusal to approve a medicated feed mill license application. 515.22 Suspension and/or revocation of ap proval of a medicated feed mill license. 515.23 Voluntary revocation of medicated feed mill license. 515.24 Notice of revocation of a medicated feed mill license. VerDate Sep<11>2014 16:35 May 05, 2023 Jkt 259076 PO 00000 Frm 00137 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT PC31aw or le y on L A P 50 LW 1R 2 w ith $ $ JO B